Lecture 4

Purity test definition of transparency color and reaction medium solutions of drugs

Purity test impurities their types and methods of determination Reference

solutions Test limit the amount of inorganic impurities in medicines

PhD Logoyda Liliya

Preformulationbull Preformulation is branch of Pharmaceutical science that

utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance

bull Prior to the development of any dosage form new drug it is essential that certain fundamental physical amp chemical properties of drug powder are determined

bull This information may dictate many of subsequent event amp approaches in formulation development

bull This first learning phase is called as preformulation

2

Preformulationbull Preformulation is branch of Pharmaceutical science that

utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance

bull Prior to the development of any dosage form new drug it is essential that certain fundamental physical amp chemical properties of drug powder are determined

bull This information may dictate many of subsequent event amp approaches in formulation development

bull This first learning phase is called as preformulation

2

INTRODUCTION

DEFINITION-Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage formrdquo

Preformulation commences when a newly synthesized drug shows a sufficient pharmacologic promise in animal model to warrant evaluation in man

3

e) Potential hazards

f) Initial bulk lots

- Lot number

- Crystallization solvent(s)

- Particle size range

- Melting point

- volatiles

g) Analytical methods

- HPLC assay

- TLC assay

- UV Visible spectroscopyContdhellip

4

Preliminary Evaluation

ORGANOLEPTIC PROPERTIES

COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM-YELLOW SULFUROUS BITTER

SHINY FRUITY SWEET

AROMATIC TASTELESS

ODOURLESS TASTELESS

5

bull The substance may exhibit an inherent odor characteristic of major functional groups present

bull Odor greatly affects the flavor of a preparation or food stuff

Taste-bull If taste is considered as unpalatable consideration is

to be given to the use of a less soluble chemical form of the drug

bull The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product

6

Odour

PURITY

bull Designed to estimate the levels of all known amp significant impurities amp contaminates in the drug substance under evaluation

bull Study performed in an analytical research amp development group

bull It is another parameter which allows for comparison with subsequent batches

bull Occasionally an impurity can affect stabilityeg - Metal contamination

- Appearance

7

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

e) Potential hazards

f) Initial bulk lots

- Lot number

- Crystallization solvent(s)

- Particle size range

- Melting point

- volatiles

g) Analytical methods

- HPLC assay

- TLC assay

- UV Visible spectroscopyContdhellip

4

Preliminary Evaluation

ORGANOLEPTIC PROPERTIES

COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM-YELLOW SULFUROUS BITTER

SHINY FRUITY SWEET

AROMATIC TASTELESS

ODOURLESS TASTELESS

5

bull The substance may exhibit an inherent odor characteristic of major functional groups present

bull Odor greatly affects the flavor of a preparation or food stuff

Taste-bull If taste is considered as unpalatable consideration is

to be given to the use of a less soluble chemical form of the drug

bull The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product

6

Odour

PURITY

bull Designed to estimate the levels of all known amp significant impurities amp contaminates in the drug substance under evaluation

bull Study performed in an analytical research amp development group

bull It is another parameter which allows for comparison with subsequent batches

bull Occasionally an impurity can affect stabilityeg - Metal contamination

- Appearance

7

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

ORGANOLEPTIC PROPERTIES

COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM-YELLOW SULFUROUS BITTER

SHINY FRUITY SWEET

AROMATIC TASTELESS

ODOURLESS TASTELESS

5

bull The substance may exhibit an inherent odor characteristic of major functional groups present

bull Odor greatly affects the flavor of a preparation or food stuff

Taste-bull If taste is considered as unpalatable consideration is

to be given to the use of a less soluble chemical form of the drug

bull The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product

6

Odour

PURITY

bull Designed to estimate the levels of all known amp significant impurities amp contaminates in the drug substance under evaluation

bull Study performed in an analytical research amp development group

bull It is another parameter which allows for comparison with subsequent batches

bull Occasionally an impurity can affect stabilityeg - Metal contamination

- Appearance

7

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull The substance may exhibit an inherent odor characteristic of major functional groups present

bull Odor greatly affects the flavor of a preparation or food stuff

Taste-bull If taste is considered as unpalatable consideration is

to be given to the use of a less soluble chemical form of the drug

bull The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product

6

Odour

PURITY

bull Designed to estimate the levels of all known amp significant impurities amp contaminates in the drug substance under evaluation

bull Study performed in an analytical research amp development group

bull It is another parameter which allows for comparison with subsequent batches

bull Occasionally an impurity can affect stabilityeg - Metal contamination

- Appearance

7

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

PURITY

bull Designed to estimate the levels of all known amp significant impurities amp contaminates in the drug substance under evaluation

bull Study performed in an analytical research amp development group

bull It is another parameter which allows for comparison with subsequent batches

bull Occasionally an impurity can affect stabilityeg - Metal contamination

- Appearance

7

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study

bull Thin layer chromatography is a wide ranging applicability amp is an excellent tool for characterizing the purity

bull HPLC paper chromatography amp gas chromatography are also useful

bull More quantitative information can be obtained by using quantitative differential scanning colorimetry

8

PURITY

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle

Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles

Solubilization of any material in any solvent depends on proper selection of solubilising agents

9

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution

10

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

If solubility is lt1mgml indicates need for salt formation to improve solubility

If solubility is lt1mgml in pH= 1 to 7 preformulation study should be initiated

Solubility should ideally be measured at two temperatures 4degC and 37degC

4degC to ensure Physical stability

37degC to support Biopharmaceutical evaluation11

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Description Parts of solvent required for one part of solute

Very soluble lt 1 Freely soluble 1 - 10

Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000

Very slightly soluble

1000 - 10000

Insoluble gt 10000 12

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate

For eg A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH

13

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Analytic method that are particularly useful for solubility measurement include HPLC UV spectroscopy Fluorescence spectroscopy and Gas chromatography

Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug

14

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Methods of Preparations

bull Melting Method

bull Solvent Method

bull Melting - Solvent Method

bull Hot Melt Extrusion Technique

15

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

1 Melting Method or Fusion Method

bull The physical mixture of a drug and water soluble carrier is heated until it melts

bull The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring

bull The final solid mass is crushed pulverized and sieved

bull To facilitate faster solidification the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate

16

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Advantages bull Simplicity of methodbull Supersaturation of a solute or a drug in a system can

often be obtained by quenching the melt rapidly from high temperature

bull Disadvantage bull Some drugs or carriers may decompose or evaporate

during fusion process at high temperatures

eg succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point

17

1 Melting Method or Fusion Method

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

2 Solvent Method

bull They are prepared by dissolving a physical mixture of two solid components in a common solvent followed by evaporation of the solvent

bull The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone sulphathiazole - pvp

18

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Advantage - Thermal decomposition of drugs or carriers can be

prevented because of low temperature required for the evaporation of organic solvents

bull Disadvantages

- High cost of preparation

- Difficulty in completely removing the solvent

- Difficulty in producing crystal forms

19

2 Solvent Method

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

3 Melting Solvent Method bull It is prepared by first dissolving the drug in a

suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent

bull Advantages

Same as above two methods

bull Disadvantage

From practical stand point it is only limited to drugs with a low therapeutic dose eg below 50mg

20

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Advantages - There are no concerns with solvent handling or

recovery after processing- It is simple and continuous process for preparation of tablets and granulations- The process is faster and there were fewer steps

than the wet granulation method - Can be used for formulating sustained release granules

eg Diltiazem granules21

4 Hot Melt Extrusion Method

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Methods of Determination of Solid Dispersion Systems

bull Thermal analysis

a) Cooling curve method

b) Thaw-melt method

c) Thermoscopic method

d) Differential thermal analysis (DTA)

e) Zone Melting Method

22

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull X-Ray diffraction Method

bull Microscopic method

bull Spectroscopic method

bull Thin layer chromatography

bull Solubility determinations

23

Methods of Determination of Solid Dispersion Systems

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

e) Zone Melting Method

- It is primarily used for ultra purification of metal and inorganic and

organic metal

24

A Thermal Analysis

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

B X-Ray Diffraction Method

bull In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles

bull Counter and film methods detect diffraction intensity bull Counter method provides better resolution of

diffraction and relative intensity which can be easily compared

bull This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000

25

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

C Microscopic Method

bull It has been used to study polymorphism and morphology of solid dispersion

bull The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope

bull The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP

26

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

D Spectroscopic Method bull In the UV study the spectra of pure drug and

the dispersed drug are scanned

bull eg The spectrum of the dispersed beta ndashcarotene resembles that betandashcarotene is dissolved in organic solvents but do not indicate the molecular dispersion of drug in polymer

27

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

E Thin Layer Chromatography

bull TLC characteristics of pure and dispersed drugs are studied to test whether the drugs are decomposed by process

bull A single spot with same lsquoRf rsquovalue is expected for both the pure and processed samples in thin layer plate

28

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

F Solubility determinations bull Results from aqueous solubility studies of drug

in various concentrations of carrier would indicate interactions between drug and carrier

bull Such studies indicated weak or insignificant interactions between griseofulvin and PEG 6000

bull Increased rate of dissolution due to solubility of the drug by carrier can be predicted by this method

29

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Pharmaceutical Applications

bull To obtain a homogenous distribution of small amount of drugs at solid state

bull To stabilize unstable drugsbull To dispense liquid or gaseous compoundsbull To formulate a faster release priming dose in a

sustained release dosage formbull To formulate sustained release dosage or

prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers

30

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Chemistry of b-cyclodextrin

bull Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone

bull The interior cavity is hydrophobic and the outside of the molecule is hydrophilic

31

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Characteristics of β-cyclodextrin

bull Glucose unit ndash 07bull Molecular wt ndash 1135bull Solubility ndash 185g100ml

bull Cavity diameter ndash 64 Ao

bull Diameter of outer periphery ndash 154 Ao

bull Approx vol of cavity ndash 262 (Ao)3

32

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Method of preparation of -cyclodextrin complex

bull Physical mixture method

bull Kneading method

bull Co-evaporation method

bull Solid dispersion method

bull Spray drying method

bull Neutralization method

33

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Physical mixture method

bull Here the drug and b-cyclodextrin (12) are mixed physically with spatula amp then the pulverized powder is passed through 100

bull Eg Diclofinac sodium

34

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Kneading method

bull Here the b-cyclodextrin is dissolved in small vol of water-methanol solution(64)

bull To the above solution required drug is added in small amount

bull The slurry is then kneaded for 45 min amp dried at 45oc

bull The dried mass is pulverized and sieved through 100

bull Eg Nimesulide Omeprazole

35

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Co-evaporation method

bull In this method aq solution of b-cyclodextrin is added to an alcoholic solution of drug

bull The resulting mix is stirred for 1 hr amp evaporated at 45oc until it is dried

bull The dried mass is pulverized and sieved through 100

bull Eg Steroids amp Diclofenac sodium

36

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Solid dispersion method

bull Here the drug amp molar qty of b-cyclodextrin is dissolved in methanol

bull The solution is then evaporated in vacuum at 40oc with rotatory evaporator

bull The powder is stored under vacuum in dessicator for 3 days amp analysed

bull Eg Rifampicin

37

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Spray drying methodbull In this the drug amp double molar of β-cyclodextrin are

dissolved in methanol

bull The solution was then spray dried under foll conditions ndash

Feed rate ndash 10 mlmin Inlet temp - 95oc Outlet temp - 65oc Press ndash 5 bar Drying air ndash 35 m3

38

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull The powder is then collected amp stored under vacuum in dessicator for 3 days amp analysed

bull Eg Naproxene

39

Spray drying method

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Neutralization method

bull Here the drug amp b-cyclodextrin are dissolved in 01N HCl amp then 01N NaOH is added to precipitate the complex at pH-75

bull The ppt is washed with distilled water

bull Then it is pulverized amp sieved through 90 and stored in dessicator over fused CaCl2

bull Eg Ketoconazole

40

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Applications

bull To increase aq solubilitybull To increase dissolution rate of drugbull To improve bioavailability of drugbull To increase chemicalphysical stability bull To decrease drug irritation

41

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Crystallinity

bull Crystal habit amp internal structure of drug can affect bulk amp physicochemical property of molecule

bull Crystal habit is description of outer appearance of crystal

bull Internal structure is molecular arrangement within the solid

42

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Change with internal structure usually alters crystal habit

Eg Conversion of sodium salt to its free acid form produce both change in internal structure amp crystal habit

43

Crystallinity

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Different shapes of crystalsbull Cubic or isometric - not

always cube shaped Also find as octahedrons (eight faces) and dodecahedrons (10 faces)

bull Tetragonal- similar to cubic crystals but longer along one axis than the other forming double pyramids and prisms

bull Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end) forming rhombic prisms or dipyramids (two pyramids stuck together)

bull Hexagonal - six-sided prisms When you look at the crystal on-end the cross section is a hexagon

bull Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division

bull Triclinic - usually not symmetrical from one side to the other which can lead to some fairly strange shapes

bull Monoclinic - like skewed tetragonal crystals often forming prisms and double pyramids

44

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

45

Different shapes of crystals

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Depending on internal structure compounds is classified as

1 Crystalline 2 Amorphous bull Crystalline compounds are characterized by

repetitious spacing of constituent atom or molecule in three dimensional array

bull In amorphous form atom or molecule are randomly placed

46

Different shapes of crystals

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Solubility amp dissolution rate are greater for amorphous form then crystalline as amorphous form has higher thermodynamic energy

Eg Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption

47

Different shapes of crystals

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Polymorphism

bull It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice

bull Different crystalline forms are called polymorphs

bull Polymorphs are of 2 types 1 Enatiotropic 2 Monotropic

48

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph

Eg Sulfur

bull One polymorph which is unstable at all temp amp pressure is called as Monotropic polymorph

Eg Glyceryl stearate

49

Polymorphism

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull Polymorph differ from each other with respect to their physical property such as

Solubility

Melting point

Density

Hardness

Compression characteristic

50

Polymorphism

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

bull During preformulation it is important to identify the polymorph that is stable at room temp

Eg 1)Chloromphenicol exist in AB amp C forms of these B form is more stable amp most preferable 2)Riboflavin has III amp III forms the III form shows 20 times more water solubility than form I

51

Polymorphism

Stability testinghellip

52

Stability testinghellip

52

Why Stabilitybull Provide a evidence on how the quality of a drug

substance or drug product varies with time under the influence of a variety of environmental factors such ashellip temperature Humidity and light

bull Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions

bull Because physical chemical or microbiological changes might impact the efficiency and security of the final product

53

Where and WhyStability Studies are preformed on bull Drug Substances (DS) The unformulated drug

substance that may subsequently be formulated with excipients to produce the dosage form

bull Drug Products (DP) The dosage form in the final immediate packaging intended for marketinghelliphellip

bull controlled and documented determination of acceptable changes of the drug substance or drug product

54

What are changes

bull Physical changes bull Appearance bull Melting point bull Clarity and color of solution bull moisture bull Crystal modification (Polymorphism) bull Particle sizebull Chemical changes bull Increase in Degradation bull Decrease of Assaybull Microbial changes 55

Chemical degradation studiesbull Hydrolysis

bull Oxidation

bull Reduction

bull Decarboxylation

bull Photolysis56

Stability studies at different stages

bull Stress- and accelerated Testing with drug substances

bull Stability on pre-formulation batches

bull Stress testing on scale-up Batches

bull Accelerated and long term testing for registration

bull On-going Stability testing

bull Follow-up Stabilities57

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Where and WhyStability Studies are preformed on bull Drug Substances (DS) The unformulated drug

substance that may subsequently be formulated with excipients to produce the dosage form

bull Drug Products (DP) The dosage form in the final immediate packaging intended for marketinghelliphellip

bull controlled and documented determination of acceptable changes of the drug substance or drug product

54

What are changes

bull Physical changes bull Appearance bull Melting point bull Clarity and color of solution bull moisture bull Crystal modification (Polymorphism) bull Particle sizebull Chemical changes bull Increase in Degradation bull Decrease of Assaybull Microbial changes 55

Chemical degradation studiesbull Hydrolysis

bull Oxidation

bull Reduction

bull Decarboxylation

bull Photolysis56

Stability studies at different stages

bull Stress- and accelerated Testing with drug substances

bull Stability on pre-formulation batches

bull Stress testing on scale-up Batches

bull Accelerated and long term testing for registration

bull On-going Stability testing

bull Follow-up Stabilities57

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

What are changes

bull Physical changes bull Appearance bull Melting point bull Clarity and color of solution bull moisture bull Crystal modification (Polymorphism) bull Particle sizebull Chemical changes bull Increase in Degradation bull Decrease of Assaybull Microbial changes 55

Chemical degradation studiesbull Hydrolysis

bull Oxidation

bull Reduction

bull Decarboxylation

bull Photolysis56

Stability studies at different stages

bull Stress- and accelerated Testing with drug substances

bull Stability on pre-formulation batches

bull Stress testing on scale-up Batches

bull Accelerated and long term testing for registration

bull On-going Stability testing

bull Follow-up Stabilities57

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Chemical degradation studiesbull Hydrolysis

bull Oxidation

bull Reduction

bull Decarboxylation

bull Photolysis56

Stability studies at different stages

bull Stress- and accelerated Testing with drug substances

bull Stability on pre-formulation batches

bull Stress testing on scale-up Batches

bull Accelerated and long term testing for registration

bull On-going Stability testing

bull Follow-up Stabilities57

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Stability studies at different stages

bull Stress- and accelerated Testing with drug substances

bull Stability on pre-formulation batches

bull Stress testing on scale-up Batches

bull Accelerated and long term testing for registration

bull On-going Stability testing

bull Follow-up Stabilities57

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Scope bull Solubility Profile bull Hygroscopicity bull Thermal stability (Melting point Polymorphism) bull Chemical stability1048708 1 Batch1048708 Up to 3 month

Scope bull Determination of expire date bull Determination of preliminary specifications bull Release of clinical batches bull Monitoring of samples during the clinical phases bull Definition of storage conditions bull Definition of Tests for registration stability 1048708 Up to 36 month

1048708 Selection of samples bull API excipient batches1048708 Scope bull Appearance bull Appropriate physical-chemical parameter bull Assay Degradation products1048708 Up to 3 month

58

Stability studies at different stages

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Testing scope for Solid dosage

bull Physical-chemical properties ndash Appearance ndash Elasticity ndash Mean mass ndash Moisture ndash Hardness ndash Disintegration ndash Dissolutionbull Chemical properties ndash Assay ndash Degradation bull Microbial properties bull Container closure system properties ndash Functionality tests (eg extraction from blister)

Tablet amp Capsule

59

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Testing scope for Oral liquid

formbull Physical-chemical properties ndash pH ndash Color amp clarity of solution ndash Viscosity ndash Particle size distribution (for oral suspensions only)bull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

60

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Testing scope for LIQUID FORMS for inj and

PARENTRALbull Physical-chemical properties ndash pH ndash Loss on weight ndash Color amp clarity of solutionbull Chemical properties ndash Assay ndash Degradation products ndash Degradation preservatives ndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

61

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Testing scope for SEMI LIQUID FORMS

bull Physical-chemical properties ndash Appearance odor homogenesity consistency ndash Loss on weight Viscosity ndash Content uniformity (within the container)bull Chemical properties ndash Assay ndash Degradation products amp preservatives ndash Content preservatives ndash Degradationndash Content antioxidantsbull Microbial properties bull Container closure system properties ndash Functionality tests

62

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Climatic Zones Storage conditions

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone I

Temperate

Japan United Kingdom Northern Europe

Canada Russia United States

20 20 42 21 45

Climatic Zone II

Mediterranean Subtropical

Japan United States Southern Europe

264 22 52 25 60

63

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Climatic Zone

Countries

Calculated data

Temp MKT humidity degC degC rh

Derived data

Temp humidity degC rh

Climatic Zone III

Hot dry

Iran Iraq Sudan

264 279 35 30 35

Climatic Zone IV

Hot humid

Brazil Ghana Indonesia Nicaragua

Philippines

267 274 76 30 70

64

Climatic Zones Storage conditions

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

ICH Guidelines

bull Quality Guidelines ldquoQrdquo (chemical and pharmaceutical QA) ndash details see next slidebull Safety Guidelines ldquoSrdquo (in vitro and in vivo pre-clinical studies) ndash covering Carcinogenicity Testing Genotoxicity Testing Toxicokinetics and Pharmacokinetics hellip etcbull Efficacy Guidelines ldquoErdquo (clinical studies in human subject) ndash Covering clinical safety Dose Response Studies Good Clinical Practices Clinical evaluation hellip etcbull Multidisciplinary Guidelines ldquoMrdquo ndash Covering Medical Terminology Electronic Standards for Transmission of Regulatory Information helliphellip etc ndash Important for Stability raquo Guideline M4 The Common Technical Document (CTD)

65

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

ICH Q-Guidelines (Quality)bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV (Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

66

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Q1A(R2) Stability testing of New Drug Substances amp Products

bull Stability Testing in Climatic Zone I and II (Q1A)bull Photostability Testing (Q1B)bull Stability Testing for New Dosage Forms (Q1C)bull Bracketing and Matrixing Designs (Q1D)bull Evaluation of Stability Data (Q1E)bull Stability Testing in Climatic Zones III and IV

(Q1F)bull Validation of Analytical Procedures (Q2)bull Impurities (Q3)bull Biotechnological Products (Q5)bull Specifications (Q6)

67

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Study

Storage condition

Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

Drug substances - General case

Drug substances - intended for storage in a RefrigeratorStudy Storage condition Minimum time period

covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

68

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Drug substancesProduct- intended for storage in Freezer

Study Storage condition Minimum time period covered by data at submission

Long term -20degC plusmn 5degC 12 months

Drug products - General caseStudy Storage condition Minimum time period

covered by data at submission

Long term 25degC plusmn 2degC 60 plusmn 5 rh or

30degC plusmn 2degC 65 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 40degC plusmn 2degC 75 plusmn 5 rh 6 months

69

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Drug products - packaged in Semi-permeable containers

Study Storage condition Minimum time period covered by data at submission

Long term 25degC plusmn 2degC 40 plusmn 5 rh or

30degC plusmn 2degC 35 plusmn 5 rh

12 months

Intermediate 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Accelerated 30degC plusmn 2degC 65 plusmn 5 rh 6 months

Drug products - intended for storage in a Refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5degC plusmn 3degC 12 months

Accelerated 25degC plusmn 2degC 60 plusmn 5 rh 6 months

70

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71

Thank You

71

• Slide 1
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Slide 7
• Slide 8
• Slide 9
• Slide 10
• Slide 11
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• Slide 16
• Slide 17
• Slide 18
• Slide 19
• Slide 20
• Slide 21
• Slide 22
• Slide 23
• Slide 24
• Slide 25
• Slide 26
• Slide 27
• Slide 28
• Slide 29
• Slide 30
• Slide 31
• Slide 32
• Slide 33
• Slide 34
• Slide 35
• Slide 36
• Slide 37
• Slide 38
• Slide 39
• Slide 40
• Slide 41
• Slide 42
• Slide 43
• Slide 44
• Slide 45
• Slide 46
• Slide 47
• Slide 48
• Slide 49
• Slide 50
• Slide 51
• Slide 52
• Slide 53
• Slide 54
• Slide 55
• Slide 56
• Slide 57
• Slide 58
• Slide 59
• Slide 60
• Slide 61
• Slide 62
• Slide 63
• Slide 64
• Slide 65
• Slide 66
• Slide 67
• Slide 68
• Slide 69
• Slide 70
• Slide 71