2.preformulation for the scientist

7/27/2019 2.preformulation for the scientist

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DEFINITION:

Characterization of physical, chemical and mechanicalproperties of new drug molecule in order to develop safe,effective,and stable dosage form.

GOAL OF PREFORMULATION:

To formulate an elegant, safe, efficacious dosage formwith good bioavailability.

To formulate new dosage form of already existing drug.

Determination of all the properties of drug and the bestsuitable dosage form for the drug molecule.


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Pharmaceutical factor mainly include those parameters of drugwhich affect the final dosage form manufacturing process like..

Flow propertyDensity

CompressibilityHygroscopicityElectrostatic chargeOsmolarityRheologyWettabilitySyringabilty


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1)FLOW PROPERTY(A) Introduction

Flow property is an important factor that determines the fate ofdrug molecule.

Sufficient flow is required for uniformity of dosage form. So itis necessary to judge the flow of material in preformulationstage of the dosage form.

However extreme increase in flow may improve weightuniformity but may reduce content uniformity throughincreased segregation.

(B) Method of determination

By Angle of repose

By hopper flow rate By bulk density

By angle of spatula

By vibrational capillary method


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LATEST TECHNOLOGY TO DETERMINE FLOW

PROPERTY

REPOSOGRAPH: It is a stable instrument which at best can only indicate

comparative flow properties.

The formation of sharp cone would mean poor flowproperty while a good spread would indicate a superiorflow property.

FT (FREEMAN TECHNOLOGY) RHEOMETER: An instrument for measuring flow property.

It can discriminate between the samples that differby 1% Moisture.

Important for optimizing granulation because

moisture variation have significant impact on final

product quality.


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NEW MEASUREMENT SYSTEM TO EVALUATE

POWDER FLOWABILITY BASED ON

VIBRATIONAL CAPILLARY METHOD: Evaluates flowability of micrometer sizes particles

under actual flow condition.

The amplitude and frequency of vibration iscontrolled by computer and mass of powder

discharged from vibrating capillary tube is

measured by digital balance.

The mass flow rate is measured by digitalprocessing.

[Chemical Abstract ,Jan. 2007, 146:9806]


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Angle of Repose

Indirect method of quantifying powder flowability,becauseof their relationship with interparticle cohesion.

It is a maximum angle between the surface of a pile of

powder & horizontal plane.

Angle of repose is measured by the equation:

tan=h /r

here, h=height of conical heap &

r=radius of horizontal plane of powder


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DETERMINATION OF

ANGLE OF REPOSE

Static angle of repose Fixed height cone,

Fixed base cone,

Tilting table

Dynamic angle of repose Rotating cylinder

Rotating Drum

Drained angle of repose Ledge type,Crater type


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RELATION BETWEEN ANGLE OF REPOSE

& TYPE OF FLOW & TYPE OF POWDER

Angle of

repose

Type of flow Type of

powder

40 Very poor Very Cohesive


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HAUSNERS RATIO

This is a simplex index that can be determined on

small quantities of powder.

Hausner-ratio= Tapped density max)

poured density(P min)

Hausner ratio Type of Flow

1.5

Good flow

Moderate

Poor flow


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(C)FACTOR AFFECTING FLOW

PROPERTY

Particle size and Particle size distribution

Particle shape and Surface roughness

Density and Porosity

Hygroscopicity

Electrostatic charge


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(D) IMPROVEMENT OF

FLOWABILITY

By addition of glidant By addition of fine or by size reduction

By wet granulation

By removing static charge

By densification with the help of slugging

Using auger feed equipment

By addition of flow activator. Eg. MgO By use silicon treated powder for Hygroscopic &

moist powder. e.g. silicon coated talc or Na-

bicarbonate By altering process condition like vibration assistedhopper or forced feeder

By use of spray drying : Advantose 100 maltosepowder has improved flow property than MCC byusing this process.


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2. DENSITY

(A) INTRODUCTION :

The ratio of mass to volume is known asdensity.

Density = Mass (gms.)/ Volume (ml.)

TYPES OF DENSITY :

(a) Bulk density

(b)Tapped density(c)True density

(d)Granule density :- may affectcompressibility, tablet porosity,disintegration, dissolution


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(B) Method of Determination

Parameter Method

1. Bulk density Measuring cylinder

2. Tapped Density Mechanical Device

Mercury Displacement

3. True Density Helium densitometer

(Helium Pycnometer)Mercury Instrution

Porosimetry


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Bulk density measurement:

It is determined by pouring

presieved (40-mesh) bulk drug into agraduate cylinder via-a large funneland measuring the volume andweight.

Tapped density measurement:

It is determined by placing agraduated cylinder containing anknown mass of drug or formulation

on a mechanical tapper apparatus,which is operated for a fixednumbers of taps(about-1000)untillthe powder bed volume has reacheda minimum.

M t f T D it


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Measurement of True Density:

True density can be determined usingthree methods:

displacement of a liquid, displacement of a gas (pycnometry), or

floatation in a liquid.

The liquid displacement is tedious and

tends to underestimate the true density. Displacement of a gas is more

accurate, but needs relativelyexpensive instrumentation. Gaspycnometers rely on the measurementof pressure changes, as a referencevolume of gas, typically helium, addedto, or deleted from, the test cell.

As an alternative, the floatation methodis simple to use and inexpensive.


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An improved method for fast online

measuring of density of sol id

substances:A densitometer for measuring of bulk density of solid

& liquid consists of one vibrator means, to support

pre-weighed samples to be tested in container with

predefined shapes on this vibrator & atleast oneultrasonic sensor operatively connected to control

unit such that sensor is adapted to transmit and

receive reflected ultrasonic pulses to ascertain

density of samples utilizing the said values of the filllevels of samples in containers.

(chemical abstract ,October 2007)


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(C)CORRELATION WITH FLOWABILITY

Carrs index = Tapped density- Bulk density/ Tapped density

Hausner ratio = Tapped density / Bulk density

(D)IMPORTANCE

In case of combination therapy or physical mixture ,if bothdrug or drug & excipients have different density then creates

problem of segregation (demixing).

Important in decide size & type of processing equipment.

E.g. decide size of capsule formulation, Suppositories. Devereux et.al. compared GI transit time of multiple unit

formulation of densities 2.8g/cm3 & 1.5g/cm3 & found

significantly delayed gastric emptying of heavier pdt.

(Review article, IJPS, sept-oct,2008)


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3. COMPRESSIBILITY(A) INTRODUCTION

Compressibility is the ability of powder to decrease involume under pressure.

Neumann and Carr developed a simple test to evaluateflowability of a powder by comparing the poured (fluff) density(Pmin)and tapped density (Pmax) of a powder and the rate at

which it packed down.

Useful empirical guide is given by the Carr's compressibilityindex. here compressibility is misnomer since compression is notinvolved.

%compressibility = Tapped density bulk density * 100

Tapped density


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Relationship between powder flowability and

% compressibilitySR. NO % COMPRESSIBILTY RANGE FLOW DESCRIPTIONS

1 5-15 Excellent (free flowing granules)

2 12-16 Good ( free flowing powder

granules)

3 18-21 Fair to passable ( powder

granules

4 23-28 Poor ( very fluid powder)

5 28-35 Poor ( fluid cohesive powder)

6 35-38 Very poor ( fluid cohesive

powder)

7 >40 Extremely poor ( cohesivepowder)


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(B) The characteristics Of material may be :-

1. PLASTICITY

Plastic material are capable of permanentdeformation, also exhibit a degree of brittleness(fragmentability)

But plastic material will get bonding after

Viscoelastic deformation.

2. FRAGMENTABILITY

If material is fragmentable, neither lubricantmixing time nor dwell time affecting the tabletstrength.


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3. ELASTICITY

E.g. paracetamol, acetyl salicylic acid

If material is elastic, it rebound whencompression force is released.

Elastic material may lead to capping &lamination

They require wet massing to induce plasticityor plastic tableting material.

4. PUNCH FILMING [STICKING]: This may lead to chipping of tablet.


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(C) METHOD OF IMPROVEMENT

If plastic material add fragmentable excipient

e.g.. Lactose .

If Elastic material By plastic tableting material

Wet granulation ,Pre compression.

If sticky material By change in salt form,

By using high excipient ratio,By wet massing,

By addition of Mg-stearate.


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NPTAB Technology:

Innovative technology combining pellet coatingwith direct compression.

Active drug is sprayed on carrier containing sugarsphere & these layered spheres are directlycompressed.

Multifunctional co-processesed excepients with

improved compression properties are used forimproved tabletting performance.

(CHEMICAL ABSTRACT, July 20,2009,151,No.3: 63288g)


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4. HYGROSCOPICITY(A) INTRODUCTION

Hygroscopicity: - It is the tendency ofmaterial to absorb moisture fromatmosphere & be dynamic equilibrium withwater in the atmosphere.

Deliquescent: - It is the hygroscopicsubstance which absorb moisture from airand they can be liquefied by partially orwholly forming solution.

Efflorescent: - a substance which loseswater to form a lower hydrate or becomeanhydrous is term as efflorescent.


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List of examples:

Hygroscopic & Deliquescent Efflorescent

Ephedrine atropine

Hyoscymine cocaine

Phenobarbital codeine

Pilocarpine scopolamine

Physostigmine caffeine

Glycerinated gelatin & PEG base of suppositoryare hygroscopic in nature.


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(B)METHOD OF DETERMINATION

To carry out study, sample of compound are accuratelyweighed into container and placed at various humid

condition for period of upto 2 weeks.

If Weight gain Deliquescent or Hygroscopic

If Weight loss Efflorescent

Also determined by TGA, GC, & KF titration

Versaperm has deviced a WVTR meter that can measurethe permeability of package to moisture in as little as

30 min.so that humidity can be accurately controlled.


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(C) IMPORTANCE:

It affects the flow property.

It affects compression characteristic ,

granulation & hardness of final tablet.

It also affects compaction. Important in aerosol.

Affects chemical stability of hydrolysable

drug.


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(E) METHODS OF IMPROVEMENT

For granulation of hygroscopic material use non-aqueous solvent.

For efflorescent material , use anhydrous salt.

Add finely powdered adsorbents like MgO or Mgcarbonate.

Perform the entire tableting operation undercontrolled humidity condition.

Store in desiccant, foil, blister, glass bottle.

Use of Ion-exchange resins.

Eg. Complexation of Ranitidine with Indion234.

( Journal of Pharmaceutical Research, vol.8.No.2,Apr 2009:112-115)

E amples:


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Examples:

Starch is hygroscopic ,but on pregelatinization it exhibitslower propensity for moisture, thus providing excellent

stabilization for moisture sensitive active drugs. A new multifunctional excipient, Galen IQ.

Problem associated with Hygroscopic material:

Stick- slip mechanism of powder flow:

It is pulsatile flow of granular material. It causes

problem in die filling for tableting.

The length of stick slip event increases withmoisture content, increasing load, etc .

(Chemical Abstract vol.146:9803)


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5. ELECTROSTATIC CHARGE

A) INTRODUCTION:

Electrostatic charges are the consequence ofclassic attraction & repulsion effect between thecharges.

Electrostatic charge is produced: By separation of positive & negative charge

By mechanical impact By friction between two surface

By rupturing of particle

By separation of solid & liquid surface

Pharmaceutical processing procedure such asmixing,micronizing, milling, sieving, rubbing,compressing, spray drying & congealing, pancoating & packaging can induce static charge.


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(B) METHOD OF DETERMINATION:

INOSTAT, measures negative charge on the

surface in volts/cm, when material is flowing fromhopper.

ELPI(13-stage Electrical Low Pressure Impactor),

gives detailed charge profile of MDI aerosol

particles. This has practical application on lung

deposition of MDI aerosol.

Electrostatic testers which consists of electrostatic

voltage sensing probes.


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C) FACTORS AFFECTING STATIC CHARGE

Effect of particle shape. e.g.- PCM

Fine crystalline form >Crystalline form > Granuleswith EC > Granules with starch.

Effect of tablet excipient. e.g.- Acetaminophen withmannitol(+++) > SDL(++) > Mg stearate(+)

Effect of Particle size.

Effect of moisture.


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(D) IMPORTANCE

In preformulation of suspension . Affects flow property of powder.

Affects mixing process.

For thermal stability of emulsions. It may damage tablet machine.

It may affect compression coating.


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E) METHOD OF REMOVAL OF STATIC

CHARGE

Addition of diluents or lubricant. Surface coating of particle with

amphiphilic substance of o/w type. EgAerosol.

Use crystallization method using morepolar solvent. By granulation. Store under influence of air with

sufficient humidity.

Super critical fluid technology.Example: Poloxamer reduceelectrostatic charge on the surface ofpolystyrene.


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6. OSMOLARITY

A) INTRODUCTION It is a colligative property

DEFINITIONS: Osmoles : No. of osmotically active particles in

solution. Osmolarity : osmoles or milliosmoles per liter of

solution.

Osmolality :osmoles or milliosmoles per kg ofsolvent.

Isoosmotic: when two different solutions areseparated by semipermiable membrane have sameosmotic pressure so called as isoosmotic.

Isotonic: when two different solutions are separatedby biological membrane have same osmotic pressure

so called as isotonic.


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(B) Method of Determination

Osmolality should be measured carefully

with a vapour pressure or freezing pointosmometer or cryoscopic osmometer.

Vapour pressure osmometer: Measuresconcentration of osmotically active particles

that reduce V.P of solution. Membrane osmometer: Thisinvention is

directed to a membrane osmometer fordirect measurement of osmotic pressures.

( United States Patent 4455864 )

Clifton nanolitre osmometer


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(C) IMPORTANCE

Normal serum osmolality to be 285mosmol/kg.

Maintain osmolarity by 1%variation.

It should be proper maintained in Oral nutrition fluid

Peripheral infusion

Parenteral product

Ophthalmic preparation Administration of Paratonic solution can

lead to crenulation or lysis of RBC.


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7. RHEOLOGY

(A) DEFINITION

It describes flow of liquid and/or

deformation of solid under stress.

(B) TYPE OF FLOW:

Newtonian flow

Non Newtonian flow

NEWTONIAN FLOW


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NEWTONIAN FLOW

It is a flow in which a direct proportionality exists

between shear stress and shear rate. E.g. water, simple

organic liquid & dilute suspension , Glycerin.


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NON NEWTONIAN FLOWWhere there no direct relation between shear stress and shear rate.

There are three type

(1) PLASTIC FLOWIt is the Newtonian system at shear stress above yield

value. Eg. Flocculated suspension.

(2) PSEUDOPLASTIC FLOW

Here yield value not associated .As applies shear stressincreasing, viscosity decreases and disarrangedmolecules begin to align their long axes inline ofmolecules.

Eg. Aq. Dispersion of tragacanth, Na-CMC, PVP.

(3) DILATANT FLOW

Opposite to pseudoplastic flow

Increase in the shear rate, increasing in resistance toflow as viscosity increases.

E.g. deflocculated suspension of Mg magma


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RHEOGRAM


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(C)DETERMINATION OF VISCOSITY

Capillary viscometer

Falling sphere viscometer Cup and bob viscometer

Cone and plate viscometer

Brook field viscometer Ultrasonic Shear Rheometer :- For analysing

protein solution rheology.

Instron Capillary Rheometer :- Measures

viscosity as a function of rate of shear &temp at a high rate of shear.


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D)IMPORTANCE

[1] FLUID For mixing

For particle size reduction of disperse system

Passing though orifice, pouring, packaging in bottle,

passing though hypodermic needle. Flow though pipe

Physical stability of disperse system

[2] QUASISOLIDS Spreading and adherence to skin

Removal from jar

Capacity of solids to mix with liquid

Release of drug from base


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[3] SOLID

Flow of powder from hopper and into a die cavity in

tableting or in encapsulation

Packagability of powder or granules solids.

[4] PROCESSING

Production capacity of the equipment

Processing efficiency

THIXOTROPHY:

In thixotropy apply shear stress convert gel sol &

remove shear stress convert sol gel, means gel to

sol to gel. Application :- for stability of suspension

e.g. conc. Parental suspension containing 40-70% w/v

of procaine penicillin G


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8. WETTABILITY

(A) INTRODUCTION

Wettability of a solid is an importantproperty with regards to formulation ofsolid dosage form.

Adsorption at solid surface is involvedin wetting & detergency.

It may influence granulation of solid,

penetration of dissolution fluid intotablet and granules & adhesion ofcoating material to tablet.


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(B) METHOD OF DETERMINATION : By contact angle:

The contact angle is the angle between a liquiddroplet and the surface over which it spreads.

Contact angle 00complete wetting.

Contact angle1800 No wetting .

By Draves test:

(C) IMPORTANCE: Crystal structure can influence the contact angle.

Problems associated with Wettability of powder arepoor dissolution rate & low adhesion of film coating.


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(C) IMPROVEMENT

Mixing with hydrophilic excipient like NaCMC (water soluble) and bentonite, Al Mgsilicate & colloidal silica (water insoluble).

Use of wetting agent (HLB value 6-9) whichacts by lowering contact angle. It displacesair & replace it with liquid phase.

Wetting of powder by non aqueous solventcan be enhanced by certain lanolinderivative.


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9. SYRINGABILTY

It is more mechanical property rather thanpharmaceutical property.

This phenomenon happens when a liquiddosage form passes through a syringe.

The flow of material is dependant on size &

shape of crystals of material. Plates can easily move one over another .so,no friction observed & can easily pass throughthe syringe.

While in case of needles or cubes or prisms ,they cant pass through the syringe easily.

So, we can arrange the degree of syringabiltyin following way:

Plates > Needles > Cubes > Prisms

REFERENCES


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REFERENCES

Alfred Martin, physical Pharmacy, 4thedition, 1999, B.I. Waverly, New Delhi.

Leon Lachman ,H.A. Lieberman , J.L.Kanig , the theory and practice ofindustrial pharmacy ,2nd edition

Leon Lachman, H, A. Lieberman, Pharmaceutical dosage formtablet volume1

Leon Lachman, H, A. Lieberman, Pharmaceutical dosage form-parentalDosage form volume 1

Michael E. Aulton, Pharmaceutics: The science of dosage form design ELBSpublication

Remington, the science and practice of pharmacy, 21st Edition

Encyclopedia of pharmaceutical technology vol. 14 Marcel Decker E.D.Summer et al. Journal of Pharmaceutical Science, 55:1441(1966)

G.Gold et al, Journal of Pharmaceutical Science, 57:667(1968)

F.Q. Danish et al, Journal of Pharmaceutical Science, 60:548(1971)

S.Dawoodbhai C.T. Rhodes Drug and Industrial Pharmacy, 15: 1577(1989)

Journal of pharmacuetical science( April 1999, vol. 88 no.4)

G.Dold, B.T. Palermo Journal of Pharmaceutical Science, 54:311. Manufaccturing chemist( Jan 2005, Jan 2004 , Dec-Jan 2003)

Chaquan Sun, Journal of Pharmaceutical Science, 93:646(2004).

Journal of pharmacuetical science( Dec 2005 vol.94 ,no. 12)

Indian Journal of pharmacuetical science (Sept-Oct 2008)

Chemical Abstracts.

Journal of Pharmaceutical Research,vol.8,No.2(Apr. 2009).


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