ionic conductivity in non-ionic compounds

Western Kentucky UniversityTopSCHOLAR®

Masters Theses & Specialist Projects Graduate School

8-1-2013

Ionic Conductivity in Non-Ionic CompoundsUsha Kranthi AvalaWestern Kentucky University, [email protected]

Follow this and additional works at: http://digitalcommons.wku.edu/thesesPart of the Chemicals and Drugs Commons, Inorganic Chemistry Commons, and the Medicinal-

Pharmaceutical Chemistry Commons

This Thesis is brought to you for free and open access by TopSCHOLAR®. It has been accepted for inclusion in Masters Theses & Specialist Projects byan authorized administrator of TopSCHOLAR®. For more information, please contact [email protected].

Recommended CitationAvala, Usha Kranthi, "Ionic Conductivity in Non-Ionic Compounds" (2013). Masters Theses & Specialist Projects. Paper 1279.http://digitalcommons.wku.edu/theses/1279

http://digitalcommons.wku.edu?utm_source=digitalcommons.wku.edu%2Ftheses%2F1279&utm_medium=PDF&utm_campaign=PDFCoverPages

http://digitalcommons.wku.edu/theses?utm_source=digitalcommons.wku.edu%2Ftheses%2F1279&utm_medium=PDF&utm_campaign=PDFCoverPages

http://digitalcommons.wku.edu/Graduate?utm_source=digitalcommons.wku.edu%2Ftheses%2F1279&utm_medium=PDF&utm_campaign=PDFCoverPages

http://digitalcommons.wku.edu/theses?utm_source=digitalcommons.wku.edu%2Ftheses%2F1279&utm_medium=PDF&utm_campaign=PDFCoverPages

http://network.bepress.com/hgg/discipline/902?utm_source=digitalcommons.wku.edu%2Ftheses%2F1279&utm_medium=PDF&utm_campaign=PDFCoverPages




IONIC CONDUCTIVITY IN NON-IONIC COMPOUNDS

A Thesis

Presented to

The Faculty of the Department of Chemistry

Western Kentucky University

Bowling Green, Kentucky

In Partial Fulfillment

Of the Requirements for the Degree

Master of Science

By

Usha Kranthi Avala

August 2013

I want to dedicate my thesis to my parents, Avala Srinivasa Rao and Avala Sharmila, my

fiancé, Laxmman Reddy Sainapuram, and to my sister Mulagundla Ujwala, who have

been my inspiration and without whom I would not be standing in this position where I

am now. Also, I would like to dedicate my thesis to my research advisor Dr. Quentin

Lineberry, who guided me throughout my research and who taught me new things.

iv

ACKNOWLEDGMENTS

I would like to convey my deepest gratitude and respect for my thesis and

research advisor, Dr. Quentin Lineberry, for his overwhelming support and

encouragement. This research would not have been possible without him. I would like to

thank him for his patience and for trusting me with this research. Dr. Lineberry’s valuable

comments helped me to develop a broader perspective of my thesis topic. He always

guided and corrected me with patience every time I was wrong. I also thank Dr. Alan

Riga for his support to start this research and also for providing me with the chemicals

required.

I gratefully acknowledge Dr. Yan Cao and Dr. Stuart Burris for their supervision

and valuable time invested in reading and providing corrections to this thesis. I am very

thankful that in the middle of their busy schedules they accepted my invitation to be a

part of my committee.

I would like to specially thank Dr. Cathleen Webb and Dr. Rajalingam

Dakshinamurthy for having faith in me and supporting me financially through a teaching

assistantship and helping me out every time I sought their advice.

I would like to thank and mention the people who have been my pillars of support

and who have always found time to help me. I thank Soujanya Siddavaram, Vasudha

Kodali, Gokul Abhishek and Sindhu Murthy for staying by my side during the good

times and bad. Last but not least, I would like to thank my family.

v

CONTENTS

I. Introduction ..................................................................................................................... 1

A. Thermal Analysis ........................................................................................................ 1

B. Pharmaceuticals ........................................................................................................... 2

C. Instrumentation............................................................................................................ 3

1. Dielectric Thermal Analysis .................................................................................... 3

a. Parameters measured by DEA ............................................................................. 7

2. Differential Scanning Calorimetry .......................................................................... 8

a. Instrument ............................................................................................................ 9

i.Heat flux ............................................................................................................. 9

ii. Power Compensation ..................................................................................... 10

b. Calibration.......................................................................................................... 11

c. Sample preparation............................................................................................. 12

d. Component characterization .............................................................................. 13

e. Melting Point ...................................................................................................... 14

3. Thermogravimetric Analysis ................................................................................. 16

a. Principle ............................................................................................................. 16

b. Calibration.......................................................................................................... 16

vi

i. Calibration of temperature .............................................................................. 16

ii. Weight calibration .......................................................................................... 17

iii. Baseline calibration ....................................................................................... 17

D. Amorphous and crystalline nature of drugs ................................................................ 19

II. Materials and Methods ................................................................................................. 23

A. Dielectric Thermal Analysis ................................................................................... 25

B. Differential Scanning Calorimetry .......................................................................... 27

C. Thermogravimetric Analysis ................................................................................... 30

III. Results and Discussion ............................................................................................... 32

A. TGA.. ..................................................................................................................... 32

B. DSC… .................................................................................................................... 38

C. DEA.. ...................................................................................................................... 44

IV. Conclusion .................................................................................................................. 62

Bibilography ............................................................................................................... 63

vii

LIST OF FIGURES

Figure 1. Theory of Dielectric Analysis ............................................................................. 6

Figure 2. Cole-Cole plot ..................................................................................................... 7

Figure 3. cross section of DSC heat flux cell.................................................................... 10

Figure 4. Schematic representation of DSC power compensation cell ............................. 11

Figure 5. An idealized DSC curve .................................................................................... 14

Figure 6. DSC curve of indium ......................................................................................... 15

Figure 7. TGA curve of calcium oxalate .......................................................................... 18

Figure 8. Chemical structure of Lidocaine ....................................................................... 23

Figure 9. Chemical structure of Procainamide ................................................................. 23

Figure 10. Chemical structure of Ketoconazole ............................................................... 24

Figure 11. Chemical structure of Nifedipine. ................................................................... 24

Figure 12. Interdigitated single plate sensor ..................................................................... 26

Figure 13. Gold plated parallel plate sensor ..................................................................... 27

Figure 14. Overlay of 5 DSC runs of indium.................................................................... 29

Figure 15. Overlay of TGA curves of Calcium oxalate. ................................................... 31

Figure 16. TGA curve of Lidocaine .................................................................................. 34

Figure 17. TGA curve of Nifedipine................................................................................. 35

Figure 18. TGA curve of Ketoconazole ............................................................................ 36

Figure 19. TGA curve of Procainamide ............................................................................ 37

usha_Thesis.doc#_Toc361643042






viii

Figure 20. DSC curve of Nifedipine ................................................................................. 40

Figure 21. DSC curve of Ketoconazole ............................................................................ 41

Figure 22. DSC curve of Procainamide ............................................................................ 42

Figure 23. DSC curve of Lidocaine .................................................................................. 43

Figure 24. DEA curve of Ketoconazole with single surface sensor ................................. 47

Figure 25. DEA curve of Ketoconazole with Parallel plate sensor ................................. 48

Figure 26. DEA curve of Procainamide with single plate sensor ..................................... 49

Figure 27. DEA curve of Procainamide with parallel plate sensor ................................... 50

Figure 28. DEA curve of Lidocain with single surface sensor ......................................... 51

Figure 29. DEA curve of Lidocaine with parallel plate sensor ......................................... 52

Figure 30. DEA curve of Nifedipine with single plate sensor .......................................... 53

Figure 31. DEA curve of Nifedipine with parallel plate sensor ....................................... 54

Figure 32. Overlay of DSC and DEA curves of Ketoconazole ........................................ 58

Figure 33. Overlay of DSC and DEA curves of Lidocaine .............................................. 59

Figure 34. Overlay of DSC and DEA curves of Nifedipine ............................................. 60

Figure 35. Overlay of DSC and DEA curves of Procainamide ........................................ 61













ix

LIST OF TABLES

Table 1. Transitions observed by DSC curve15

................................................................. 13

Table 2. List of drugs studied. .......................................................................................... 25

Table 3. Analysis of DSC data of Indium ......................................................................... 28

Table 4. TGA weight loss and DTG peak analysis ........................................................... 30

Table 5. Standard deviation of TGA curves of Calcium oxalate monohydrate. ............... 33

Table 6. Summary of TGA data ........................................................................................ 33

Table 7. Standard deviation values for DSC peak of Indium. .......................................... 39

Table 8. Summary of DSC data. ....................................................................................... 39

Table 9. Summary of DEA data with single surface sensor ............................................. 45

Table 10. Summary of DEA data with parallel plate sensor............................................. 46

x

IONIC CONDUCTIVITY IN NON-IONIC COMPOUNDS

Usha Kranthi Avala August 2013 67 Pages

Directed By: Dr. Quentin Lineberry, Dr. Yan Cao, and Dr. Stuart Burris

Department of Chemistry Western Kentucky University

The main objective of this work is to investigate the ionic conductivity of the drugs

under certain conditions and also to compare the ionic conductivities of drugs determined

by single surface sensors and parallel plate sensors. The ionic conductivity of various

materials at their pre-melt and melt states are studied in order to further study a recently

discovered phenomenon. Polar solids like Lidocaine, Ketoconazole, Procainamide and

Nifedipine were examined in this study. Experimental studies show an increase in ionic

conductivity in both pre-melt (20 -30 °C below melting temperature) and melt transition

regions. Results of ionic conductivity of both parallel plate and single surface sensor at

different frequencies are compared. At 1000 Hz, all the samples show an increase in ionic

conductivity with both parallel plate and single surface sensor, but at 0.1 Hz frequency,

no increase in ionic conductivity is observed with parallel plate sensor except for

Nifedipine.

1

I. INTRODUCTION

A. Thermal Analysis

Thermal analysis is a collection of techniques that measure the properties of a

material as a function of temperature. It is useful in measuring different physical

properties, thermal transitions, and chemical reactions of sample materials as a function

of temperature, heating rate, and time1. The most commonly used thermal analytical

techniques in the characterization of pharmaceuticals are thermogravimetric analysis

(TGA) for weight loss or gain, differential scanning calorimetry (DSC) for heat flow, and

dielectric analysis (DEA) for ionic conductivity and dielectric properties2. DEA and DSC

are material characterization techniques that can analyze a wide variety of solids, liquids,

and polymers. These techniques are fast, reliable and employ small amounts of samples

for analysis. Materials like acetanilide, anthracene, polyethylene, and nylon 6 were

evaluated using DSC and DEA which revealed unique ionic conductivity behavior of

materials2, 3

. DEA uniquely measures dielectric properties of the materials which reveal

physico-chemical properties of the drug under testing3.

DEA employs parallel plate or an interdigitated array of electrodes for

measurement of two fundamental properties of the material, as a function of frequency,

time, and temperature4. The capacitance property is defined as the ability of the material

to store the charge; conductance is the ability to transfer the charge. When the material is

heated above its melting point, conductive properties become important, but at low

temperatures, the capacitive property dominates. At higher temperatures, the dipoles can

align themselves in the direction of the electric field which allows measuring the current,

due to which conductive property dominates at higher temperatures5. The electrical

2

properties evaluated by DEA use a wide range of frequencies ranging from 0.1Hz to

100,000Hz and wide temperature range depending on the model of instrument5.

DEA measures three important quantities: Tan delta, loss factor, and permittivity.

Permittivity, denoted by е', is a measure of the alignment of the dipoles to the electric

field and is proportional to capacitance. Loss factor, denoted by е'', is energy required to

align dipoles in the direction of electric field and also to move ions. Loss factor is

proportional to conductance6. Tan delta is the ratio of the loss factor to permittivity. After

heating, when the material starts to melt, the ability for movement of dipoles increases

which then increases the ionic conductivity of the material. DSC allows measuring the

heat flow through the sample and certain other physical properties of the material like

melting and crystallization temperatures6. TGA studies reveal degradation of the drug and

its stability. Thus, TGA, DSC, and DEA were used to characterize the samples which

have different roles in pharmaceutical industry.

B. Pharmaceuticals

Pharmaceutical drugs may be polar or non-polar in nature. In polar drugs the

electron density is not symmetrically distributed within the drug which leads to existence

of positive and negative dipoles7. Water is a good example of a polar compound. In non-

polar drugs there is symmetrical distribution of electron density which makes them

insoluble in water. One of the ways to increase the solubility of non-polar drugs is

converting them into ionized forms8. The

polar nature of the drug affects its

bioavailability. A drug must be relatively non-polar to cross some membranes in the

body. If a drug is too non-polar, it affects its bioavailability by binding too tightly to

3

proteins or food components. Pharmaceutical drugs can be modified into an ionisable

form known as a pharmaceutical salt9. These forms are generally used when the parent

drug is chemically unstable, difficult for administration, or due to its pharmacokinetic

profile like improper absorption. More than one salt form of a drug can be produced in

the market, but they are considered therapeutically equivalent. The ionized form of the

drug is more polar and more soluble than the parent drug10

. The drug, which is known as

the active pharmaceutical ingredient (API) is mixed with excipients in the formulations.

These excipients not only fill up the amount in formulations but also play a role in drug

properties like dissolution and bioavailability. The dielectric properties of the medium

also play an important role in the solubility of the drug. At higher dielectric constant, the

drug is converted into more ionized form which increases its solubility. All these

properties are considered before formulation of any drug11

.

C. Instrumentation

Thermal analytical instruments like DEA, TGA and DSC require a small amount

of sample for analysis. Due to this reason, these techniques play a major role in chemical

industries. DEA provides information about the dielectric properties along with the ionic

conductivity of the sample with respect to time, temperature and frequency. DSC

measures properties like melting temperature and crystallization temperature of the

sample with respect to time and temperature1. TGA measures the weight loss or gain with

respect to time and temperature.

1. Dielectric Thermal Analysis

DEA is used to analyze various materials like gels, thin films, solids, powders,

and liquids. Because of this, it is used in various chemical industries. Dielectric analysis

4

is a technique used to measure ionic response of a material with respect to temperature,

frequency and time1. The dielectric analyzer is frequency-dependent electrical response

where the sample is exposed to alternating electric field (sinusoidal voltage) by placing it

on a single surface gold ceramic interdigitated sensor or on a gold plated parallel plate

sensor. This electric field produces polarization within the sample which causes the

dipoles to oscillate with same frequency as that of the electric field but with small shift in

phase angle (δ), see Figure 1. The comparison between the applied voltage and measured

current gives the shift in phase angle16

. DEA measures the structural relaxation and

molecular motions present in a sample. As long as dipole moments are present in a

sample, it allows the measurement of secondary relaxations using DEA5. Secondary

relaxations are those movements which are active in the bulk of the sample. The

measurement of dielectric properties of the drug is due to mobility of dipoles within the

drug sample. Ionic conductivity is generally seen in polar drugs rather than non-polar

drugs. Sometimes, ionic conductivity is also seen in non-polar drugs. Ionic conductivity

in non-polar drugs is usually due to the presence of polar impurities which exhibit ionic

conductivity6. Polarization is faster when the sample is in a liquid state, as the liquid state

has higher mobility for the ions when compared to the solid state. Therefore, the samples

of higher amorphous content have higher polarization, which increases ionic

conductivity.

DEA measures the two fundamental electrical characteristics of a material as a

function of time, temperature, and frequency. These properties are contradictory to each

other where capacitance is the ability of a sample to store electrical charge and

conductance is the ability to conduct or transfer electrical charge in the sample6. In

5

viscous samples, the ions have ease of mobility under the applied electric field. This

increases ionic conductivity within the sample. The properties of the sample like

molecular mobility, response time to an electric field, and polarization time of the sample

are given by tan delta values. The time taken for the dipoles to align in the direction of

the field is known as polarization time or relaxation time12

. The current measured is

divided into capacitance and conductance. Information about chemical and rheological

properties like molecular movement and polarization in the drug and polymers is given

by molecular mobility of the sample which in turn relates to capacitance and

conductance12

. The sample is placed between the electrodes, and an alternating electric

field is applied which creates polarization in the sample which leads to oscillation in

dipoles in the same frequency but with shift in phase angle δ as seen in Figure 113

.

Capacitance, which is related to induced dipoles and alignment of dipoles, is given by

measurement of permittivity. In the same way, conductance is given by the measurement

of loss factor which is related to dipole loss factor and ionic conductance. Both imaginary

and real parts are present in complex dielectric constant2.

е* = е' - i е'' or е * = [( е')

2 + (е'')

2]

½

Where, е' is permittivity, е'' is loss factor, i= imaginary unit, and е* is dielectric constant.

6

Hendrick, K.B. Planar interdigitated dielectric sensor. Soc.Adv.Mater.Pro.Eng. J. 1983, 19, 1-3.

Figure 1. Theory of Dielectric Analysis

Both loss factor and permittivity are frequency and temperature dependent

responses. Tan delta is the ratio of loss factor and permittivity. Response time is related

to an electric field, tan delta values are related to molecular mobility, and these are

related to polarization and relaxation of excited molecules14

. A curve is plotted against е''

and е' known as Cole-Cole plot (Figure 2) which is a semicircular plot in which the

highest point or peak of the plot is considered the critical frequency at which dispersion

occurs. Figure 2 shows an example of a Cole-Cole plot of microporous and mesoporous

materials. When alternating electric field is applied, a very finite time is required for

alignment of dipoles in the field of alternating electric current. But at higher frequencies,

dipoles cannot follow the given electric field, and, due to this, dielectric constant falls and

dispersion is seen in the material. This leads to dipole loss which results to loss factor

peak14

. Dispersion is the state in which the particles are dispersed in a continuous phase

but in a different state. At low frequencies due to accumulation of charges at the electrode

7

interfaces, conduction and interfacial polarization occurs, which leads to a straight line in

a Cole-Cole plot2, 15

. At higher frequencies polymers with weak or induced dipoles show

dispersion. However, in a sample like liquid crystals dispersion occurs at significantly

higher frequencies. Higher permittivity is seen in liquid samples when compared to

polymers and chemicals15

. Sometimes the complex polymers and chemicals have

different relaxation times. Due to this, they show more than one semicircular arc in the

plot; therefore, these complexes are analyzed based on different semicircular arcs rather

than considering a single semicircular arc2.

Cheng, Q.; Pavlinel, V.; Lengalova, A.; Li, C.; Belza, T.; Saha, P. Electrorheological Proeprties of New mesoporous

Material with Conducting Polypyrrole in Mesoporous Silica. Microporous and Mesoporous Materials. 2006, 94, 193-199.

Figure 2. Cole-Cole plot

a. Parameters measured by DEA

The two fundamental characteristics of DEA are capacitance (е') and conductance

(е'') 5

. High frequency permittivity is the capacitance which can also be referred to as

dielectric constant. The capacitive component of DEA has the ability to store an electrical

charge, and at low temperatures this component is more prominent17

. At high

8

temperatures, the ability to transfer the electric charge increases as dispersion is seen at

that temperature, which makes the conductive nature of the material more prominent18

.

The three main signals that are reported by DEA are permittivity, loss factor, and tan

delta. Permittivity, denoted by е' is a measure of the alignment of the dipoles to the

electric field and is proportional to capacitance. Loss factor, denoted by е'' is energy

required to align dipoles in electric field and also to move dipoles. Loss factor is

proportional to conductance19, 20

. Tan delta is a measure of ratio of the loss factor to

permittivity. It provides information about molecular mobility and response time to

electric field19

.

Ionic conductivity is one of the properties measured using dielectric analysis.

Viscosity of the sample affects its ionic conductivity because fluidity is identified by the

ease with which ionic components can migrate through the sample under the applied

electric field. Under an applied electric field, the orientation of dipoles will be in the

direction of the field, and the time taken to align in that direction is considered

polarization or relaxation time21, 22

.

2. Differential Scanning Calorimetry

A wide range of materials can be analyzed using DSC, which includes plastics,

polymers, pharmaceuticals, and more. DSC is used to measure the heat flow through the

sample relative to reference material as a function of temperature or time1. The data gives

information about various properties of the sample, like glass transition temperature (Tg),

sample purity by melting point, heat capacity (Cp), crystallization temperature (Tc), and

stability of the drug.

9

a. Instrument

DSC measures the heat flow associated with structure (amorphous and crystalline)

and changes in structure (transitions) of materials as a function of time and temperature in

a controlled atmosphere. It also measures the properties like exothermic and endothermic

reactions which reveal information about the physical and chemical properties of the

material23

. The results of the DSC analysis also vary depending on the heating rate,

isothermal hold, starting temperature, ending temperature, type of purge gas, its flow rate,

and parameters considered for calibration. To obtain better results, it is advised to start

and end the experiment below and above the temperature of interest which gives a linear

baseline on each side of the transition17

. Heating rate varies based on the type of sample

analyzed. It may vary from 1 °C to 100

°C /minute. Frequently used heating rates for

analysis of pharmaceuticals are 10-20 °C /min. Lower heating rates are generally used to

study the purity of the sample, i.e. 1-2 °C /min

3,4, 28. There are two types of DSC – heat

flow and power compensation.

i. Heat flux

Figure 2 is a schematic representation of a heat flux DSC cell. This cell measures

change in temperature ∆T, between sample and reference. The heat flux, i.e. providing or

absorbing the heat from the sample, takes place from a large single furnace present in the

cell. This type of cell has advantages of better baseline, sample-atmosphere interaction,

and sensitivity24

. DSC cell consists of two stages, one for the sample pan and the other

for the reference pan. Both the reference and sample pans are placed in the DSC cell

usually in an inert atmosphere with temperature predetermined by the program12

.

10

The DSC cell is considered the heart of a DSC as it is connected to different

purging gases required depending on the chemistry of the sample, shown in Figure 3. It

consists of the sample pan and the reference pan. Both are made up of the same material.

The reference pan is empty and a sample is placed in the sample pan25

. The DSC cell is

usually an inert atmosphere which is created by purging the cell with nitrogen gas, but

gases like hydrogen, helium, or air can also be used based on the type of sample being

analyzed.

Laye, P.G. Differential Thermal Analysis and Differential Scanning Calorimetry. Principles of Thermal Analysis and Calorimetry.

Haines, P.J.2002, 55-92.

Figure 3. cross section of DSC heat flux cell

ii. Power Compensation

Different amounts of power are used by different furnaces in order to maintain the

temperature difference between reference and sample. This is more advantageous as it

has better resolution and also has faster heating and cooling rates. Figure 4 shows the

11

design of a power compensation DSC cell, which includes two platinum heaters that

independently heat the sample and reference23

. The temperature difference between both

of them is measured by a platinum resistance thermometer. The purge gas is allowed to

contact the sample and reference through the holes in the compartment lids.

Though there are differences between heat flux and power compensation DSC

cells, the transition heats are comparable and the fusion and crystallization temperatures

are the same12

.

Hatakeyama, T.; Liu, Z. Thermal Analysis. Handbook of Thermal Analysis. 1998, 3-80.

Figure 4. Schematic representation of DSC power compensation cell

b. Calibration

The results obtained from instruments are only reliable when the instrument is

calibrated properly. Calibration should be done at regular time intervals to verify the

instrument for its better performance and consistency. Standard methods for calibration

are provided by American Society for Testing and Materials (ASTM)1. Materials like

12

indium, tin, and lead are used as standards for calibration of the instrument. Calibration in

sub-ambient temperatures is done using refrigerated cooling system (RCS), and

sometimes liquid nitrogen is used, and mentioned metals are used for calibration above

room temperature. Both heating and cooling cycles are calibrated for better results.

Following calibration, the enthalpy changes associated with amorphous and crystalline

phases of the sample and their characteristic temperatures can be measured14

. In

calibration, a clean DSC cell and calibration materials of high purity play an important

role.

c. Sample preparation

Sample preparation plays a crucial role in any experiment3. DSC pans are made of

aluminum, platinum, copper, etc which may be a closed pan, open pan, pin hole pan or

sealed pan based on the type of sample chosen for analysis. Pin hole pans are generally

used when an experiment goes to higher temperature where there are chances of bursting

of the pan due to reaction at that high temperature and also to expose the sample to

reactive gases4. When the sample is volatile in nature, closed pans are preferred, while

sealed pans are preferred to avoid liberation of heat from the sample or its formed

product.

Sample size may vary depending on type of sample and its density. The smaller

the sample size, the smaller the thermal gradient which gives better results. For polymers

and pharmaceuticals the average size of the sample ranges between 5 mg to 10 mg. For

loosely packed powder to increase their thermal contact with the pan, they are pressed by

applying slight pressure. For better analysis of the sample it is evenly spread at the

bottom of pan such that it is in proper contact with the pan. If the particles of the sample

13

are of different sizes and shapes, grinding of the sample is preferred in order to get

reproducible results28

.

d. Component characterization

DSC is used to characterize different components that occur within the sample

during the heating process. Table 1 shows the different transitions that can take place

within the sample.

Table 1. Transitions observed by DSC curve15

Exothermic Endothermic

Degradation Degradation

Condensation Vaporization

Oxidation Reduction

Decomposition Decomposition

Solidification Sublimation

Solvation Desolvation

Crystallization Fusion

Adsorption Deposition

- Glass transition

14

Both exothermic and endothermic transitions can be observed by DSC curve as

seen in Table 1. These exothermic and endothermic peaks are plotted against temperature

or time with differential heating rates. An imaginary DSC curve is shown in Figure 5 that

illustrates the most common transitions. It contains glass transition (Tg) at the beginning,

exothermic peak of crystallization (Tc), endothermic peak of melting (Tm), enthalpy of

crystallization (∆Hc), and enthalpy of fusion (∆Hf).

Figure 5. An idealized DSC curve

e. Melting Point

Melting point is an endothermic transition in which the solid state of the sample is

transformed to the liquid state. Heat of fusion (∆Hf), which is accurately attained by DSC

curve, is the amount of heat absorbed by the sample for its melting from solid to liquid

state. This melting endothermic peak reveals a number of characteristics of the sample

15

being analyzed18, 26

. This peak gives information about the purity of the compound, as

well as crystalline and amorphous content of the sample. Shape, width and height of the

peak are used to determine the purity of the sample19

. A sharp melting peak is observed

in pure crystalline materials. Pure amorphous samples do not have any melting peak; they

have glass transition due to small transition changes due to heat supplied20

. The onset of

melting point (To) is considered when the transition begins to deviate from the baseline,

as seen in Figure 6.

Figure 6. DSC curve of indium

16

3. Thermogravimetric Analysis

Thermogravimetric analysis measures weight change as a function of temperature,

time, and atmosphere.

a. Principle

TGA is used to measure the amount of weight change with its rate with respect to

time or temperature in a controlled atmosphere. The major parts of the TGA furnace, a

thermocouple, and a microgram balance. The TGA furnace can go up to temperature of

1500 °C. TGA uses platinum pans, ceramic pans, aluminum pans, and gold pans for

analysis. Samples are loaded onto microbalance1. The thermocouple will be placed close

to the sample pan, but care should be taken to see that the thermocouple does not touch

the sample or pan5.

b. Calibration

Calibration is a must for every instrument before use for analysis of samples. A

blank test is performed with an empty pan with the same experimental conditions as is

used for the sample i.e. purged with gas at 40 mL/min to balance and 60 mL/min to

furnace, heated from room temperature to 1000 °C at a heating rate of 20

°C/min. The

general conditions of the apparatus are given by this blank test. The noisy TGA curve is

indicative of error, one of the errors is that thermocouple is in contact with the sample

pan. It may be also due to vibration and shock in the instrument12

.

i. Calibration of temperature

The instrument is first calibrated using curie point temperature and then verified

using calcium oxalate. Curie metals are used for calibration of TGA having different

17

curie temperatures. Calibration is done with the use of permanent magnets and by

measuring the apparent weight change of the materials14

.

ii. Weight calibration

The instrument is calibrated for weight before starting the experiment. It uses

standard reference weights from TGA accessory kit to check the accuracy of TGA

balance. The instrument must be purged with the same gas that will be used for the

experiment. An empty tare pan that will be used for the experiment is loaded onto the

balance. Then, the reference weights are added and removed from the sample pan until

the weight is in limits and checked to acceptability of weight by the balance. When the

weight is acceptable, the balance is calibrated.

iii. Baseline calibration

The baseline may change due to a presence of volatile matter or might be due to

residual substance. Baseline calibration is required to ensure if the instrument is clean and

works properly. It is done by running an empty tarred pan in the same conditions used for

the experiment to 30 minutes and then heating from room temperature to 1000 °C

14.

Thermal stability and composition of materials can be predicted by TGA data

obtained. This is done depending on the weight change that occurred when the sample is

exposed to higher temperatures which causes evaporation, dehydration, decomposition,

and oxidation. Calcium oxalate monohydrate can be used for verification of the

instrument15

. A typical TGA curve of calcium oxalate monohydrate is shown in Figure 7.

The weight loss of calcium oxalate monohydrate at different stages can be predicted by

stoichiometry. The molecular weight of the calcium oxalate monohydrate is 146.064,

18

water is 18.004, carbon monoxide is 28, and carbon dioxide is 43.99. The first weight

loss is due to water from calcium oxalate monohydrate which gives calcium oxalate,

shown in Equation 1. The theoretical percentage of water mass loss is 12.3 % (18.004/

146.064). The second weight loss (Equation 2) is due to loss of carbon monoxide from

calcium oxalate which gives calcium carbonate. The theoretical percentage of carbon

monoxide is 19.2% (28/146.064). From calcium carbonate there is a loss of carbon

dioxide leaving calcium oxide. The loss of carbon dioxide gives the third weight loss

whose theoretical percentage is 30.2% (43.99/146.064), shown in Equation 3.

12.2%(1.19mg)

18.6%(1.82mg)

30.1%(2.95mg)

165.57°C

486.38°C

736.58°C

-0.2

0.0

0.2

0.4

0.6

De

riv.

We

igh

t (%

/°C

)

20

40

60

80

100

120

We

igh

t (%

)

0 200 400 600 800 1000

Temperature (°C)

Sample: ca ox-veri1Size: 9.8000 mg TGA

File: E:\TA\Data\TGA\usha\ca ox-veri1.001Operator: ushaRun Date: 26-Mar-13 10:18Instrument: 2950 TGA HR V6.0E

Universal V3.9A TA Instruments

Figure 7. TGA curve of calcium oxalate

19

1st Step

CaC2O4.H2O (s) CaC2O4 (s) + H2O (g).................... (1)

Calcium oxalate monohydrate Calcium oxalate

2nd

step

CaC2O4 (s) CaCO3 (s) + CO (g)……………….. (2)

Calcium oxalate Calcium carbonate

3rd

Step

CaCO3 (s) CaO (s) + CO2 (g)……………….. (3)

Calcium carbonate Calcium oxide

D. Amorphous and crystalline nature of drugs

Drugs can be crystalline or amorphous or a combination of crystalline and

amorphous. Crystalline solids have a long range molecular order; whereas, amorphous

solids have short range molecular order. The amorphous form of the drug is more useful,

as this form has more bioavailability. Based on this availability, new developments can

be made for poorly soluble drugs27, 29

. The amorphous and crystalline forms can be

distinguished by molecular order arrangement12, 19

.

Amorphous forms are also known as glassy solids, frustrated systems, and

disordered systems. As the molecular confirmation is random in these solids, they are

named disordered systems. The name frustrated system is derived due to symmetry and

geometric frustration at the molecular level30

. The amorphous content of the solid also

20

depends on certain physical properties like compatibility, flow property of the API (API

is the parent drug) or sometimes the excipients specific to the drug used in its preparation.

This may increase the dissolution property of the solid31

. During preparation of the solids,

defects may be created in the crystal structure which increases or decreases the molecular

mobility of the substance. Due to increase in development of a number of insoluble

crystalline solids in the pharmaceutical industry, the use of amorphous forms has

increased. Due to the flexibility of the molecules, amorphous forms are more

advantageous than crystalline forms. The amorphous forms have high energy which

increases their solubility and compressibility properties32

.

The advantage of the amorphous forms itself can be disadvantageous. The

disadvantages of amorphous forms restrict their wide use in pharmaceutical industry. The

amorphous nature of the solid can be surface or bulk phenomenon, i.e. the surface of the

material may be crystalline and the bulk of the sample might be amorphous and vise-

versa, which can be identified by its dielectric properties17, 33

.One of the properties of

amorphous forms is thermal instability. This property is advantageous because, thermal

instability increases its solubility. However, the thermal instability property of the

amorphous forms is also a disadvantage. Amorphous forms are converted to crystalline

forms by adding hydrophilic additives, but, thermal instability of amorphous solids

makes them unsuitable for adding any additives as they have the irreversible property of

converting to metastable crystalline forms, where the metastable form is a less stable

form of the crystalline form34

.

APIs in amorphous forms have more useful properties compared to crystalline

forms, like high dissolution rate which allows for high solubility of the drug. High

21

dissolution rate of the amorphous forms is due to the absence of lattice energy18

. The

amorphous forms have high energy levels which makes them less stable when compared

to crystalline forms20

. Due to their lower stability, during their preparation, additives like

crystallization inhibitors are added which are hydrophilic in nature which increase their

stability by increasing their wetting property35

. The amorphous form is also advantageous

in its mechanical properties like elastic modulus. Elastic modulus is the ability of the

substance to deform when force is applied. As crystalline solids are stiffer than

amorphous forms, they have higher elastic modulus36

.

The crystalline forms can be converted into amorphous forms using milling

technology, hot-melt technology, and also using solvent evaporation method37

. The

easiest method is the solvent method where a solvent is added as an additive which

dissolves the crystalline form of the solid without leaving any residue. If any form of

crystal is left then it again causes crystallization of the drug by the process of

nucleation38

. The crystalline forms have characteristic melting points which can be

determined by DSC, but the amorphous are characterized by their glass transition

temperatures as they do not have any melting peak8.

The amorphous forms are brittle below the glass transition temperature, and they

are in a rubbery state above the glass transition temperature15

. At the glass transition

temperature, the amorphous solid loses its thermal energy39

. A calibration curve is

prepared from which the crystalline content can be calculated using the equation13, 14, 18

.

Riga’s group and other groups like Bansal’s group used the equation below to determine

the percentage of crystallinity in the sample34, 11

.

22

Where, Xc is percent of crystallinity, ∆H is the heat of fusion of the sample and ∆Ho is

that of the 100% crystalline standard.

23

II. MATERIALS AND METHODS

The drugs analyzed were Lidocaine, Procainamide, Ketoconazole and Nifedipine.

These drugs were obtained from Dr. Alan Riga of Case Western Reserve University.

These drugs were of ≥98% pure and were used as-received.

Figure 8. Chemical structure of Lidocaine

Figure 9. Chemical structure of Procainamide

24

Figure 10. Chemical structure of Ketoconazole

Figure 11. Chemical structure of Nifedipine.

25

Table 2. List of drugs studied.

Drug Phase

Melting

Point (◦C)

Source Functional Category

Lidocaine Solid 68-70

Sigma

Aldrich

Local anesthetic and

antiarrhythmic

Nifedipine Solid 172-174

MP

Biomedicals,

LLC

Antianginal and

antihypertensive

Procainamide Solid 165-168

Sigma

Aldrich

Antiarrhythmic

Ketoconazole Solid 146-150 Spectrum Antifungal

A. Dielectric Thermal Analysis

The dielectric analyzer used for analysis of samples was DEA 2970 by TA

Instruments. Gold plated ceramic parallel plate sensors and ceramic interdigitated single

surface gold plated sensors were used for the study. Figures 12 and 13 show the

interdigitated single surface sensor and gold plated parallel plate sensor used for analysis.

The instrument was first calibrated. Two types of calibration were done. They are

electronics calibration and sensor calibration. Electronic calibration was done using

seven-position internal calibration fixture and two-position internal calibration fixture

provided by TA Instruments. Sensor calibration was performed each time a new sensor

was installed to make sure that the sensor to be used was clean. Once the sensor

26

calibration was completed, benzoic acid was used to verify the instruments performance

and repeatability at least once every 2 weeks, and then the samples were analyzed by

placing the sample on the electrode. Sample size of 15-20 mg was used and the analysis

was started according to the required specifications. The samples were studied by

scanning dielectric analyzer where the samples are heated to 30 °C above the melting

point as determined by DSC. Throughout the entire study, the instrument was purged

with nitrogen gas which helps to maintain the inertness in the chamber with a heating rate

of 10 °C /min. Ionic conductivity at frequencies of 0.1 Hz, 0.5 Hz, 10 Hz, 100 Hz, 1000

Hz, and 10000Hz was determined.

Figure 12. Interdigitated single plate sensor

27

Figure 13. Gold plated parallel plate sensor

B. Differential Scanning Calorimetry

DSC 2920 by TA Instruments was used for analysis of samples in this study.

Heat-cool-heat method was used for analyzing the samples. The instrument was purged

with nitrogen gas at a flow rate of 50 mL/min. Aluminum pans were used. Sample size of

5-10 mg was used. The samples were first equilibrated to -60 °C using refrigerated

cooling system. Then, the sample is heated to TGA temperature i.e. onset of 1st

decomposition temperature, at a heating rate of 10 °C. Then, it is cooled to 0 °C at a

heating rate of 2 °C. It is again heated to the same temperature as in 1st step at a heating

rate of 10 °C. DSC measures the difference in heat flow rate (mW = mJ/sec) between a

sample and inert reference as a function of time and temperature1, 5

.

The instrument was first calibrated and verified using indium. To test the

repeatability of the instrument, verification was done five times using indium, and Figure

14 shows the overlay of 5 runs of Indium. Table 3 summarizes the DSC data of indium

which is tested for instruments repeatability. For analysis of the samples, aluminum pans

were used, and a sample size of ~10 mg was used. Samples were heated to 20 °C above

the melting point with a heating rate of 10 °C/min. The cell was purged with nitrogen gas

in order to maintain the inertness of the cell.

28

Table 3. Analysis of DSC data of Indium

Sample ID Onset of melting

temperature (°C)

Heat of Fusion (J/g)

Indium run 1 156.5 23.6

Indium run 2 156.6 23.6

Indium run 3 156.5 23.6

Indium run 4 156.9 23.6

Indium run 5 156.5 23.6

29

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Heat Flow (W/g)

20

40

60

80

10

01

20

14

01

60

18

0

Te

mpe

ratu

re (

°C

)

in

diu

m-5

.00

1–

––

––

––

in

diu

m-2

.00

1–

– –

– in

diu

m-3

.00

1–

––

––

· in

diu

m-4

.00

1–

––

– –

in

diu

m-1

.00

1–

––

––

–

Exo U

pU

niv

ers

al V

4.1

D T

A I

nstr

um

ents

Fig

ure

14. O

ver

lay o

f 5 D

SC

ru

ns

of

ind

ium

30

C. Thermogravimetric Analysis

TGA 2950 by TA instruments was used for analysis of the samples. The

instrument was first verified using calcium oxalate monohydrate. Calcium oxalate

monohydrate was run for five times to test the repeatability of the instrument. Figure 15

shows the overlay of calcium oxalate runs. Platinum pans were used to analyze the

samples. The samples were kept isothermally at room temperature for 30 minutes and

then heated from room temperature to 1000 °C using a heating rate of 10 °C/min. All the

experiments were carried out in an inert nitrogen atmosphere with a flow rate of 40

mL/min to balance and 60 mL/min to furnace. Table 4 summarizes the TGA weight loss

and DTG peak analysis of Calcium oxalate which is tested to instrument repeatability.

Table 4. TGA weight loss and DTG peak analysis

Sample ID

(Calcium

Oxalate)

Weight Loss (%) DTG peak (°C) at weight loss

1st 2

nd 3

rd 1

st 2

nd 3

rd

Run 1 12.1 18.6 30.1 165.6 489.4 733.5

Run 2 12.2 18.7 30.0 164.2 490.8 734.8

Run 3 12.4 18.6 30.0 164.5 489.4 733.5

Run 4 12.4 18.7 30.0 164.2 490.8 734.8

Run 5 12.4 18.6 30.0 164.4 489.5 733.5

31

-0.2

0.0

0.2

0.4

0.6

Deriv. Weight (%/°C)

20

40

60

80

10

0

12

0

Weight (%)

02

00

40

06

00

80

01

00

0

Te

mpe

ratu

re (

°C

)

––

––

––

– c

a o

x-v

eri5

.00

1–

––

––

––

c

a o

x-v

eri1

.00

1–

––

––

· ca

ox-v

eri2

.00

1–

––

– –

ca

ox-v

eri3

.00

1–

––

––

– c

a o

x-v

eri4

.00

1

Univ

ers

al V

3.9

A T

A I

nstr

um

ents

Fig

ure

15. O

ver

lay o

f T

GA

cu

rves

of

Calc

ium

oxala

te.

32

III. RESULTS AND DISCUSSION

A. TGA

TGA instrument was tested for repeatability of the instrument by running calcium

oxalate monohydrate five times and calculating the standard deviation. The standard

deviation was found to be around 0.14 for weight loss and 0.7 for decomposition

temperatures. The values of standard deviation for DTG peaks and weight loss are listed

in Table 5. TGA curves show the weight change of the drug throughout the temperature

range. All the samples are decomposed in the nitrogen atmosphere leaving almost no

residue. From the TGA data, the weight loss of the drugs can be determined. Lidocaine

and Nifedipine show only one weight loss leaving approximately no residue. From Figure

16, it is clear that Lidocaine has only one weight loss leaving no residue at the end of the

experiment. Lidocaine loses 100% of its weight at DTG temperature of 212 °C which is

peak centered. Figure 17 shows the weight loss of Nifedipine. It has two weight losses at

283 °C, where it loses around 97% and at 2

nd weight loss it loses around 3% of remaining

weight, leaving no residue. Figure 18 shows the TGA curve of Ketoconazole which has

two weight losses, 1st weight loss was around 355

°C and 2

nd weight loss around 570

°C

where all temperatures are peak centered. Ketoconazole loses 53% of its initial weight,

and then it loses 48% of its weight, leaving no residue at the end of the experiment.

Figure 19 shows the weight loss of Procainamide which has three weight losses of 50%,

27% and 24% at temperatures 295 °C, 376

°C, and 578

°C. All the TGA temperatures are

peak centered. The TGA temperature of 1st weight loss was used to determine the

conditions to run DSC experiments. Table 6 summarizes TGA data of all the drugs

analyzed.

33

Table 5. Standard deviation of TGA curves of Calcium oxalate monohydrate.

Sample ID

(Calcium

Oxalate)

Weight Loss (%) DTG peak (°C) at weight loss

1st 2

nd 3

rd 1

st 2

nd 3

rd

Run 1 12.1 18.6 30.1 165.6 489.4 733.5

Run 2 12.2 18.7 30.0 164.2 490.8 734.8

Run 3 12.4 18.6 30.0 164.5 489.4 733.5

Run 4 12.4 18.7 30.0 164.2 490.8 734.8

Run 5 12.4 18.6 30.0 164.4 489.5 733.5

Standard

Deviation

0.14

0.05

0.04

0.58

0.74

0.71

Table 6. Summary of TGA data

Sample

ID

1st Weight

Loss (%)

Temperature

(°C)

2nd

Weight

Loss (%)

Temperature

(°C)

Residue

(mg)

Lidocaine 100 212 - - 0

Nifidipine 97 283 3.0 - 0

Ketoconazole 53 355 48 571 0

Procainamide 50 295 27 376 0

34

21

2.9

8°C

99

.6%

(10

.3m

g)

Re

sid

ue

0%

-10123


-200

20

40

60

80

10

0

12

0

Weight (%)

02

00

40

06

00

80

01

00

0

Tem

pera

ture

(°C

)

Sa

mp

le:

lid

oca

ine

Siz

e:

1

0.3

48

0 m

gT

GA

File

: E

:...

\TG

A\u

sh

a\lid

oca

ine

20

12

10

05

.00

1O

pe

rato

r: u

sh

aR

un

Da

te:

5-O

ct-

12

16

:42

Instr

um

en

t: 2

95

0 T

GA

HR

V6

.0E

Univ

ers

al V

3.9

A T

A I

nstr

um

ents

Fig

ure

16.

TG

A c

urv

e o

f L

idoca

ine

35

28

2.5

°C

97

.6%

(9.2

1m

g)

2.6

9%

(0.2

54

mg

) Re

sid

ue

0%

-101234


-200

20

40

60

80

10

0

12

0Weight (%)

02

00

40

06

00

80

01

00

0

Tem

pera

ture

(°C

)

Sa

mp

le:

Nife

dip

ine

Siz

e:

9

.43

50

mg

TG

AF

ile

: E

:...

\TG

A\u

sh

a\N

ife

dip

ine

20

12

10

07

.00

1O

pe

rato

r: u

sh

aR

un

Da

te:

7-O

ct-

12

18

:21

Instr

um

en

t: 2

95

0 T

GA

HR

V6

.0E

Univ

ers

al V

3.9

A T

A I

nstr

um

ents

Fig

ure

17. T

GA

cu

rve

of

Nif

edip

ine

36

52

.8%

(5

.0m

g)

47

.6%

(4

.5m

g)

35

5.°

C

57

1.°

C

Re

sid

ue

0%

-0

.5

0.0

0.5

1.0

1.5

Deriv. Weight Change (%/°C)

-2

0

0

20

40

60

80

10

0

12

0

Weight (%)

0

20

0

40

0

60

0

80

0

10

00

Te

mpe

ra

ture

(°C

)

Sa

mp

le:

ke

toco

na

zo

le

Siz

e:

9.4

45

0 m

g

TG

A

File

: E

:...

\TG

A\k

eto

co

na

zo

le r

-1

20

12

10

22

.00

1

Op

era

tor:

ush

a

Ru

n D

ate

: 2

2-O

ct-

20

12

15

:39

Instr

um

en

t: 2

95

0 T

GA

HR

V6

.0E

Univ

ersal V

4.3

A T

A I

nstr

um

ents

Fig

ure

18. T

GA

cu

rve

of

Ket

oco

nazo

le

37

50

.2%

(3.2

mg

)

26

.7%

(1.7

mg

)

23

.5%

(1.5

mg

)

29

5.°

C

37

6.°

C

57

8.°

C

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

Deriv. Weight Change (%/°C)

-20

0

20

40

60

80

10

0

12

0

Weight (%)

0

20

0

40

0

60

0

80

0

10

00

Tem

pe

ratu

re (

°C

)

Sa

mp

le:

pro

ca

ina

mid

e

Siz

e:

6.4

53

0 m

g

TG

A

File

: E

:...

\TG

A\p

roca

ina

mid

e 2

01

21

00

5.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 0

5-O

ct-

20

12

22

:37

Instr

um

en

t: 2

95

0 T

GA

HR

V6

.0E

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

19.

TG

A c

urv

e o

f P

roca

inam

ide

38

B. DSC

The instrument was first tested for its repeatability by running indium five times

and then standard deviation for peak temperature and enthalpy was calculated. The

standard deviation was found to be 0.01 for onset of melting temperature and 0.005 for

heat of fusion, which indicates that the instrument is more accurate. The values of

standard deviation are listed in Table 7. DSC is used to determine the heat flow which

allows measurement of glass transition temperature, melting point (endotherm), and

crystallization temperature (exotherm). DSC heat-cool-heat method was used for

analysis. Figure 20 shows the DSC curve of Nifedipine, in which glass transition is seen

at 56 °C. The glass transition is seen during second heating of the sample. The glass

transition is the significant transition as it causes significant changes in physical and

reactive changes in the material due to significant changes in molecular mobility. The

endothermic peak gives the melting temperature of Nifedipine at 173 °C. Figure 21

shows the DSC curve of Ketoconazole for which glass transition temperature is seen at

46 °C with melting temperature at 152 °C. For Ketoconazole also glass transition is seen

during second heating. Figure 22 shows DSC curve of Procainamide with glass transition

and melting peak at 44 °C and 172 °C respectively. Figure 23 shows DSC curve for

Lidocaine. This is the only drug in which recrystallization of the sample is seen

prominently. Lidocaine does not have any glass transition during second heating also.

Nifedipine and Lidocaine have considerable melting peak during second heating also

which is not seen in other samples. Table 8 summarizes the DSC data.

39

Table 7. Standard deviation values for DSC peak of Indium.

Sample ID Onset of melting temperature

(°C)

Heat of Fusion (J/g)

Indium run 1

156.47

23.6

Indium run 1

156.45

23.6

Indium run 1

156.47

23.59

Indium run 1

156.48

23.59

Indium run 1

156.47

23.6

Standard deviation 0.01

0.005

Table 8. Summary of DSC data.

Sample Glass transition

temp (°C)

Onset of

melting

temperature

(°C)

Enthalpy (J/g) Melting Peak

temp (°C)

Ketoconazole 46 148 107 152

procainamide 44.0 169 102 172

Nifidepine 56 155 773 173

Lidocaine - 67 1565 70

40

17

3.°

C

15

5.°

C

77

3.J

/g

56

.°C

(H)

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Heat Flow (W/g)

-10

0

-50

0

50

10

0

15

0

20

0

Tem

pera

ture

(°C

)

Sa

mp

le:

nife

dip

ine

Siz

e:

8.5

50

0 m

g

DS

C

File

: E

:\re

se

arc

h\D

SC

\nife

dip

ine

r-1

.00

1

Op

era

tor:

ush

a

Ru

n D

ate

: 1

1-A

pr-

20

13

09

:52

Instr

um

en

t: 2

92

0 M

DS

C V

2.4

F

Exo U

p

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

20. D

SC

cu

rve

of

Nif

edip

ine

41

15

2.°

C

14

8.°

C

10

7.J

/g

46

.°C

(H)

-4

-3

-2

-1

0

1

Heat Flow (W/g)

-10

0

-50

0

50

10

0

15

0

20

0

25

0

30

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

ke

toco

na

zo

le

Siz

e:

8.8

50

0 m

g

DS

C

File

: E

:...

\DS

C\k

eto

co

na

zo

le 2

01

21

02

7.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 2

7-O

ct-

20

12

17

:12

Instr

um

en

t: 2

92

0 M

DS

C V

2.4

F

Exo U

p

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

21. D

SC

cu

rve

of

Ket

oco

nazo

le

42

17

2.°

C

16

9.°

C

10

2.J

/g

44

.°C

(H)

-4

-3

-2

-1

0

1

Heat Flow (W/g)

-10

0

-50

0

50

10

0

15

0

20

0

25

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

pro

ca

ina

mid

e

Siz

e:

9.2

20

0 m

g

DS

C

File

: E

:...

\DS

C\p

roca

ina

mid

e 2

01

21

02

2.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 2

2-O

ct-

20

12

15

:55

Instr

um

en

t: 2

92

0 M

DS

C V

2.4

F

Exo U

p

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

22.

DS

C c

urv

e o

f P

roca

inam

ide

43

67

.°C

15

65

.J/g

70

.°C

-4

-2

0

2

4

6

8

10

Heat Flow (W/g)

-80

-60

-40

-20

0

20

40

60

80

10

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

lid

oca

ine

r-1

Siz

e:

8.5

50

0 m

g

DS

C

File

: E

:\re

se

arc

h\D

SC

\lid

oca

ine

r-1

.00

1

Op

era

tor:

ush

a

Ru

n D

ate

: 1

0-A

pr-

20

13

12

:58

Instr

um

en

t: 2

92

0 M

DS

C V

2.4

F

Exo U

p

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

23.

DS

C c

urv

e o

f L

idoca

ine

44

C. DEA

DEA is used to determine the ionic conductivity in the sample. Both surface

analysis and bulk analysis were done on the sample using frequency range of 0.1, 0.5,

1.5, 10, 100, 500, 1000Hz. Single surface sensor is used for surface analysis of the drugs

while parallel plate sensor is used for bulk analysis of sample14

. Figures 24, 26, 28 and 30

show single surface sensor DEA curves of Ketoconazole, Procainamide, Lidocaine and

Nifedipine respectively, in which an increase in ionic conductivity at premelt region (10-

30 ◦C is below its melting point) is observed at 0.1 Hz and 1000 Hz frequencies. Figures

25, 27, 29 and 31 represent DEA curves analyzed with parallel plate sensor of

Ketoconazole, Procainamide, Lidocaine and Nifedipine, respectively. In parallel plate

sensor increase in ionic conductivity is seen only at 1000 Hz frequency except for

Nifedipine which shows an increase in ionic conductivity at both 0.1 and 1000 Hz

frequency. Table 9 summarizes DEA data with single surface sensor and Table 10

summarizes DEA data with parallel plate sensor. The differences in temperatures noted

on the figures and in the tables are not representative of an actual shift in temperature of

the ionic conductivity increases at those frequencies, but are a result of the linear heating

rate that was used to heat the sample. The instrument scans through the frequencies while

the sample is being heated, which results in an apparent shift in temperature of the

responses as a function of frequency. The shift occurs at the earliest observed

temperature, regardless of frequency.

45

Table 9. Summary of DEA data with single surface sensor

Sample name Frequency of 0.1 Hz Frequency of 1000 Hz

Temperature(°C)

at the onset of

increase in log

ionic

conductivity

Log ionic

conductivity

(pmho/cm)

that

temperature

Temperature(°C)

at the onset of

increase in log

ionic

conductivity

Log ionic

conductivity

(pmho/cm)

that

temperature

Ketoconazole 143 18.4 138 59.0

Procainamide 149 50.0 143 159.3

Lidocaine 64 13.6 59 25.3

Nifedipine 156 23.5 151 73.7

46

Table 10. Summary of DEA data with parallel plate sensor

Sample name

Frequency of 0.1 Hz Frequency of 1000 Hz

Temperature(°C)

at the onset of

increase in log

ionic

conductivity

Log ionic

conductivity

(pmho/cm)

that

temperature

Temperature(°C)

at the onset of

increase in log

ionic

conductivity

Log ionic

conductivity

(pmho/cm)

that

temperature

Ketoconazole 149 0.27 132 16.01

Procainamide 169 1.3 173 22.6

Lidocaine 63 0.13 67 16.3

Nifedipine 176 0.12 169 7.1

47

18

.40

pm

ho

/cm

13

8.4

0°C

0.1

Hz

14

2.6

6°C

10

00

Hz

58

.69

pm

ho

/cm

0.1

1

10

10

0

10

00

10

00

0

1.0

E5

1.0

E6

Ionic Conductivity (pmho/cm)

20

40

60

80

10

0

12

0

14

0

16

0

18

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

ke

toco

na

zo

le-6

0

Siz

e:

2.5

00

0 m

m

DE

A

File

: E

:...

\DE

A\k

eto

co

na

zo

le-6

0 s

ing

le.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

8-M

ar-

20

13

12

:52

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

24. D

EA

cu

rve

of

Ket

oco

nazo

le w

ith

sin

gle

su

rface

sen

sor

(Blu

e-0.1

Hz,

Red

-1000 H

z)

48

14

8.6

2°C

0.2

46

5p

mh

o/c

m

0.1

Hz

16

.01

pm

ho

/cm

13

2.3

7°C

10

00

Hz

0.0

01

0.0

1

0.1

1

10

10

0

10

00

10

00

0

1.0

E5


0

20

40

60

80

10

0

12

0

14

0

16

0

18

0

Te

mpe

ra

ture

(°C

)

Sa

mp

le:

ke

too

na

zo

le-6

0 p

ara

lle

l

Siz

e:

0.5

00

0 m

m

DE

A

File

: E

:...

\DE

A\k

eto

co

na

zo

le-6

0 p

ara

lle

l.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

2-J

un

-20

13

15

:36

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ersal V

4.3

A T

A I

nstr

um

ents

Fig

ure

25. D

EA

cu

rve

of

Ket

oco

nazo

le w

ith

Para

llel

pla

te s

enso

r

(Blu

e-0.1

Hz,

Red

-1000 H

z)

49

10

00

Hz

14

3.4

1°C

15

9.3

pm

ho

/cm

0.1

Hz

14

8.4

1°C

50

.02

pm

ho

/cm

0.0

1

0.1

1

10

10

0

10

00

10

00

0

1.0

E5

1.0

E6

1.0

E7

1.0

E8


20

40

60

80

10

0

12

0

14

0

16

0

18

0

20

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

Pro

ca

ina

mid

e-6

0

Siz

e:

2.5

00

0 m

m

DE

A

File

: E

:...

\DE

A\P

roca

ina

mid

e-6

0 s

ing

le.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

5-M

ar-

20

13

08

:23

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ersal V

4.3

A T

A I

nstr

um

ents

Fig

ure

26. D

EA

cu

rve

of

Pro

cain

am

ide

wit

h s

ingle

pla

te s

enso

r

(Blu

e-0.1

Hz,

Red

-1000 H

z)

50

16

9.6

7°C

1.3

23

pm

ho

/cm

0.1

Hz

10

00

Hz

22

.62

pm

ho

/cm

17

2.7

9°C

0.1

1

10

10

0

10

00

10

00

0

1.0

E5

1.0

E6

1.0

E7

1.0

E8


20

40

60

80

10

0

12

0

14

0

16

0

18

0

20

0

Tem

pera

ture

(°C

)

Sa

mp

le:

Pro

ca

ina

mid

e-6

0 p

ara

lle

l

Siz

e:

0.5

00

0 m

m

DE

A

File

: E

:...

\DE

A\P

roca

ina

mid

e-6

0 p

ara

lle

l.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

3-J

un

-20

13

13

:17

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

27. D

EA

cu

rve

of

Pro

cain

am

ide

wit

h p

ara

llel

pla

te s

enso

r

(Blu

e-0.1

Hz,

Red

-1000 H

z)

51

0.1

Hz

13

.57

pm

ho

/cm

63

.46

°C

10

00

Hz

25

.27

pm

ho

/cm

59

.10

°C

0.0

1

0.1

1

10

10

0

10

00

10

00

0

1.0

E5

1.0

E6


20

40

60

80

10

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

Lid

oca

ine

Siz

e:

2.5

00

9 m

m

DE

A

File

: E

:\re

se

arc

h\D

EA

\Lid

oca

ine

-60

sin

gle

.00

1

Op

era

tor:

ush

a

Ru

n D

ate

: 0

6-M

ar-

20

13

14

:12

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

28. D

EA

cu

rve

of

Lid

oca

in w

ith

sin

gle

su

rface

sen

sor

(Blu

e-

0.1

Hz,

Red

-1000 H

z)

52

76

.22

°C

1.6

60

pm

ho

/cm

66

.75

°C

17

.04

pm

ho

/cm

10

00

Hz

0.1

Hz

0.0

00

1

0.0

01

0.0

1

0.1

1

10

10

0

10

00

10

00

0

1.0

E5


30

40

50

60

70

80

90

10

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

Lid

oca

ine

-60

pa

ralle

l

Siz

e:

0.6

12

4 m

m

DE

A

File

: E

:...

\DE

A\L

ido

ca

ine

-60

pa

ralle

l.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

2-J

un

-20

13

16

:32

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

29. D

EA

cu

rve

of

Lid

oca

ine

wit

h p

ara

llel

pla

te s

enso

r (

Blu

e-

0.1

Hz,

Red

-1000 H

z)

53

15

5.5

0°C

15

0.9

1°C

0.1

Hz

23

.51

pm

ho

/cm

10

00

Hz

73

.66

pm

ho

/cm

0.1

1

10

10

0

10

00

10

00

0

1.0

E5

1.0

E6


20

40

60

80

10

0

12

0

14

0

16

0

18

0

20

0

Te

mpe

ratu

re (

°C

)

Sa

mp

le:

Nife

dip

in-6

0

Siz

e:

2.5

00

0 m

m

DE

A

File

: E

:\re

se

arc

h\D

EA

\Nife

dip

in-6

0 s

ing

le.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 0

7-M

ar-

20

13

12

:36

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

30. D

EA

cu

rve

of

Nif

edip

ine

wit

h s

ingle

pla

te s

enso

r (

Blu

e-

0.1

Hz,

Red

-1000 H

z)

54

17

5.5

0°C

16

9.8

7°C

0.1

Hz

0.1

13

7p

mh

o/c

m

10

00

Hz

7.1

23

pm

ho

/cm

0.0

00

1

0.0

01

0.0

1

0.1

1

10

10

0

10

00

10

00

0


20

40

60

80

10

0

12

0

14

0

16

0

18

0

20

0

Tem

pera

ture

(°C

)

Sa

mp

le:

Nife

dip

ine

-60

pa

ralle

l

Siz

e:

0.5

00

0 m

m

DE

A

File

: E

:...

\DE

A\N

ife

dip

ine

-60

pa

ralle

l.0

01

Op

era

tor:

ush

a

Ru

n D

ate

: 1

3-J

un

-20

13

15

:29

Instr

um

en

t: 2

97

0 D

EA

V2

.1A

Univ

ers

al V

4.3

A T

A I

nstr

um

ents

Fig

ure

31. D

EA

cu

rve

of

Nif

edip

ine

wit

h p

ara

llel

pla

te s

enso

r

(Blu

e-0.1

Hz,

Red

-1000 H

z)

55

All of the drugs tested show an increase in ionic conductivity prior to melt and

also during melt. TGA is used to determine the weight change as a function of time and

temperature. The temperature of the first weight loss was used to determine DSC terminal

temperature. DSC heat-cool-heat method was used for analysis. This method helps to

know about the amorphous and crystalline content in the drug, as it relates to ionic

conductivity. The first heating converts the crystalline form of the drug to amorphous

form. Then, a slow cooling rate was used to maximize the ability of the sample to

recrystallize thermally. The amount of the sample that recrystallizes depends on specific

drug properties like the bonds that exist in the sample. The crystalline content and

amorphous content of the cooled sample is examined by heating it again, which can be

observed by glass transition and melting peak.

Glass transitions are only seen in amorphous samples. During the first heating, the

sample started to melt and endothermic melting peak was observed. When the samples

were allowed to cool at a slower rate, Lidocaine completely recrystallized, as it does not

show any glass transition during its second heating also. For Ketoconazole,

Procaianmide, and Nifedipine, glass transitions were observed during second heat of the

sample, with only small melting peak. This indicates that the drugs were not able to

recrystallize completely, or not at all, even with the slow heating rate.

Parallel plate sensor is used for bulk analysis of dielectric properties of drugs.

Here, the signal created in the sample has the ability to penetrate into bulk of the sample

which allows measurement of bulk dielectric properties. The lower sensor i.e. electrode

applies the voltage in the sample (excitation electrode) which polarizes the sample. The

polarization of sample creates current in it which is in turn measured by upper electrode

56

(response electrode). As both excitation and response electrode are present on lower and

upper electrode respectively, the signal should pass through bulk of sample for

measurement of current. Due to this parallel plate sensor is used for bulk analysis of

samples.

The single plate sensor is generally used for analysis of surface dielectric

properties as signal created in the sample can penetrate only the surface of the sample

being analyzed22

. The depth of electrical penetration depends on the width of the

electrodes21

. In the single surface sensor, one of the interdigitated comb acts as excitation

electrode and the current is measured through another interdigitated comb which acts as

response electrode. As both excitation and response electrodes are present on single

surface, the signal just passes over the surface of the sample without going into the bulk

of the sample. Due to this ceramic single surface sensor is used for surface analysis.

The analysis of samples using single surface sensor gave different results when

compared with results from parallel plate sensor. From the data of single surface sensor,

at 0.1 Hz frequency, there is increase in log ionic conductivity at 15-20 °C before the

melting point i.e. at their pre-melt region. However, in parallel plate sensor increase in

log ionic conductivity is seen at 0.1 Hz and 1000 Hz frequency.

The single surface sensor is generally used for surface analysis of samples.

Increase in log ionic conductivity is observed even at 0.1 Hz and also at 1000 Hz

frequency. Among the drugs chosen for analysis, Procainamide has higher ionic

conductivity. And, also increase in log ionic conductivity in pre-melt region is seen at 15

°C below its melting point. As Lidocaine has lower ionic conductivity when analyzed

57

using single surface sensor, it can be said that it is due to more crystallinity in nature

which has restricted movement of the ions and dipoles. For procainamide also, ionic

conductivity in pre-melt region is observed. The frequencies of the analysis in DEA

considered are for both surface analysis and bulk analysis.

The 100 Hz frequency is considered as break point between surface analysis and

bulk analysis21

. The frequencies less than break point frequency are considered for

surface analysis of sample and above that are considered for bulk analysis. The ionic

conductivity in pre-melt temperature regions might be due to presence of water content,

movement of ions, impurities, secondary relaxations present in molecules or that may

arise when small amounts of heat are given.

Figures 32, 33, 34, and 35 shows overlay of DSC and DEA curves of

Ketoconazole, Lidocaine, Nifedipine, and Procainamide from which it is clear that

increase in log ionic conductivity was observed both at pre melt temperature region (15-

20 °C) and also during its melting. The onset of melting was observed at 148 °C and the

increase in log ionic conductivity was observed 15- 20 °C before the onset of melting i.e.

at premelt region. The log ionic conductivity in pre-melt region increased to 102-10

5

pmho/cm. The polarization of the material allows the dipoles to align in direction of

applied field, which in turn allows measuring the conductivity of the sample. The same is

applicable for all other drugs in which increase in log ionic conductivity is seen at pre-

melt and melt regions.

58

152.21°C

147.74°C

107.8J/g

131.12°C

147.17°C

142.85°C

138.40°C

0.001

0.01

0.1

1

10

100

1000

10000

1.0E5

1.0E6

Ion

ic C

on

du

ctivity (

pm

ho

/cm

)

-4

-3

-2

-1

0

1

He

at

Flo

w (

W/g

)

-100

-50

0

50

100

150

200

250

300

Temperature (°C)

ketoconazole 20121027.001

–––––––

ketoconazole-60 parallel.001

–––––––

ketoconazole-60 single.001

– – – –

Exo Up


Figure 32. Overlay of DSC and DEA curves of Ketoconazole (Green-DEA curve,

Blue-DSC curve)

59

63.24°C

66.65°C

69.65°C

67.45°C

71.4J/g

63.36°C

59.01°C

1

10

100

1000

10000

1.0E5

Ion

ic C

on

du

ctivity (

pm

ho

/cm

)

-4

-2

0

2

4

6

8

10

He

at

Flo

w (

W/g

)

0.01

0.1

1

10

100

1000

10000

Io

nic

Co

nd

uctivity (

pm

ho

/cm

)

-80

-60

-40

-20

0

20

40

60

80

100

Temperature (°C)

Lidocaine-60 parallel.001

lidocaine r-1.001

Lidocaine-60 single.001

Exo Up


Figure 33. Overlay of DSC and DEA curves of Lidocaine (Green-DEA curve, Blue-

DSC curve)

60

168.35°C

172.89°C

171.31°C

21.9J/g

155.29°C

151.54°C

1

10

100

1000

10000

1.0E5

Ion

ic C

on

du

ctivity (

pm

ho

/cm

)

-2.0

-1.5

-1.0

-0.5

0.0

0.5

He

at

Flo

w (

W/g

)

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

Io

nic

Co

nd

uctivity (

pm

ho

/cm

)

-100

-50

0

50

100

150

200

Temperature (°C)

Nifedipine-60 parallel.001

nifedipine r-1.001

Nifedipin-60 single.001

Exo Up


Figure 34. Overlay of DSC and DEA curves of Nifedipine (Green-DEA curve, Blue-

DSC curve)

61

172.38°C

169.04°C

172.16°C

168.50°C

102.3J/g

148.62°C

144.03°C

0.1

1

10

100

1000

10000

1.0E5

1.0E6

1.0E7

Ion

ic C

on

du

ctivity (

pm

ho

/cm

)

-4

-3

-2

-1

0

1

He

at

Flo

w (

W/g

)

0.1

1

10

100

1000

10000

1.0E5

1.0E6

1.0E7

1.0E8

Io

nic

Co

nd

uctivity (

pm

ho

/cm

)

-100

-50

0

50

100

150

200

250

Temperature (°C)

Procainamide-60 parallel.001

–––––––

procainamide 20121022.001

–––––––

Procainamide-60 single.001

–––––––

Exo Up


Figure 35. Overlay of DSC and DEA curves of Procainamide (Green-DEA curve,

Blue-DSC curve)

62

IV. CONCLUSION

This research was done to study the dielectric behavior of drugs under applied

external electric field and comparing the results of parallel plate and single surface

sensors. The results obtained from DEA show that there are unique variations in log ionic

conductivity at pre-melt regions at 15 -20 °C below its melting point. All the drugs show

an increase in log ionic conductivity at pre-melt region.

Increase in log ionic conductivity is seen with single surface sensor as well as

parallel plate sensor, from which it can be concluded that increase in log ionic

conductivity is a bulk phenomenon not just a surface phenomenon. Lidocaine was the

only drug tested that could recrystallize thermally.

63

BIBILOGRAPHY

1. Maheshwaram, M.P.; Mantheni, D.; Singh, S. T.; Perera, I.; Venumuddala, H.;

Riga, A.; Alexander, K.; Kaza, L. Universal standard protocols for temperature

and material characterization calibration with pharmaceuticals by thermal

analysis. ASTM Spec. Tech. Publ. 2010.

2. Cahoon, J.M.; Riga, A.T.; Pialet, J.W. Characterization of Electrorheological

Processes by Dielectric Thermal Analysis. Materials Characterization by Dynamic

and Modulated Thermal Analytical Techniques, ASTM STP 1402. 2001, 139-156.

3. Sorai, M. Thermal Analysis. Comprehensive Handbook of Calorimetry &

Thermal Analysis. 1998, 29-54.

4. Giron, D. Applications of Thermal Analysis and Coupled Techniques in

Pharmaceutical Industry. J. Therm. Anal. Calorim. 2002, 68, 335-357.

5. Andrew, K. J, J. Appl. Phys.: Appl. Phys, Dielectric Relaxation in Solids, 1999,

32, 57-70.

6. Cui, Y. A material Science Perspective of Pharmaceutical Solids. Int. J. Pharm.

2007, 339, 3-18.

7. Gurunath, S.; Pradeep Kumar, S.; Basavaraj, N.K.; Patil, P. Amorphous Solid

Dispersion Method for Improving Oral Bioavailability of Poorly Water-Soluble

Drugs. J. Pharm. Res. 2013, 6, 476-480.

8. Md Fakhree, A.A.; Delgado, D.R.; Martinez, F.; Jouyban, A. The Importance of

Dielectric Constant for Drug Solubility Prediction in Binary Solvent Mixtures:

64

Electrolytes and Zwitterions in Water + Ethanol. AAPS Pharm. Sci. Tech. 2010,

11, 1726-1729.

9. Patel, A.; Jones, S.A.; Ferro, A.; Patel, N. Pharmaceutical salts: a formulation

trick or a clinical conundrum?. Br. J. Cardiol., 2009, 16, 16:281-6.

10. Bowe, C.L.; Mokhtarzadeh, L.; Venkateshan, P.; babu, S.; Axelrod, H.R.; Sofia,

M. J.; Kakarla, R.; Chan, T.Y.; Kim, J.S.; Lee, H.J.; Amidon, G.L. Design of

compounds that increase the absorption of polar molecules. Proc. Natl. Acad.

Sci..1997, 94, 12218-12223.

11. Mantheni, D.; Maheshwaram, M.P.; Perera, I.; Venumuddala, H.; Riga, A.;

Alexander, K. Characterization of Crystalline and Amorphous Content in

Pharmaceutical Solids by Dielectric Thermal Analysis. J. Therm. Anal.

Calorim..2013, 111, 1998-1987.

12. Riga, A.; Alexander, K. Electrical conductivity analysis/ Dielectric analysis

differentiate physical chemical properties of drugs and excipients. Am. Pharm.

Rev. 2005, 45-51.

13. Perera, I.; Maheshwaram, M.P.; Mantheni, D.; Venumuddala, H.; Riga, A.;

Alexander, K. Solid and Liquid State Studies of a Wide Range of Chemicals by

Iso-Thermal and Scanning Dielectric Thermal Analysis, J. Therm. Anal. Calorim.

2011.

14. Riga, A.; Pan, W. P.; Cahoon, J. Thermal Analysis, J. Therm. Anal. Calorim.305-

337.

65

15. Twombly, B. Simultaneous Dynamic Mechanical Analysis and Dielectric

Analysis of Polymers (DMA-DEA). Instrum Sci. Technol., 1994, 22, 259-271.

16. Riga, A.; Alexander, K. New Thermal Analytical Techniques in Characterizing

Drugs, J. Therm. Anal. Calorim.2010.

17. Riga, A.; Maheshwaram, M.P.; Mantheni, D.; Sobhi, H. F.; Perera, I.; Alexander,

K. Solid State Studies of Drugs and Chemicals by Dielectric and Calorimetric

Analysis, J.Therm. Anal. Calorim.2012, 108, 237-233.

18. Baird, A. J.; Taylor,S. L. Evaluation of Amorphous Solid Dispersion Properties

using Thermal Analysis Techniques, Adv Drug Deliver Rev.2012, 64, 396-421.

19. Zografi, G.; Hancock, B. C.; Shamblin, S. L. Molecular Mobility of Amorphous

Pharmaceutical Solids below Their Glass Transition Temperature. Pharm. Res.

1995, 799–806.

20. Yadav, V.S.; Sahu, D.K.; Singh, Y.; Dhubkarya, D.C. The Effect of Frequency

and Temperature on Dielectric Properties of Pure Poly Vinylidene Fluoride

(PVDF) Thin Films, Proc of the IMECS, 2010, 3, 1-4.

21. Hendrick, K.B. Planar interdigitated dielectric sensor. Soc.Adv.Mater.Pro.Eng. J.

1983, 19, 1-3.

22. Laye, P.G. Differential Thermal Analysis and Differential Scanning Calorimetry.

Principles of Thermal Analysis and Calorimetry. Haines, P.J.2002, 55-92.

23. Verdonck, E.; Schaap, K.; Thomas, C. L. A discussion of the Principles and

Applications of Modulated Temperature DSC. Int. J. Pharm.1993, 3-20.

66

24. Gill, P.; Moghadam, T.T.; Ranjibar, B. Differential Scanning Calorimetry

Techniques: Applications in Biology and Nanoscience. J of Biomol Tech. 2010,

21, 167-193

25. Dollimore, D.; Lerdkanchanaporn, S. Thermal Analysis. Anal. Chem.1998, 70,

27R-35R.

26. Yu, L.X.; Lionberger, R. A.; Raw, A.S.; D’Costa, R.; Wu, H.; Hussain, A.S.

Applications of Process Analytical Technology to Crystallization Processes. Adv

Drug Deliver Rev. 2004; 56, 349-369.

27. Hatakeyama, T.; Liu, Z. Thermal Analysis. Handbook of Thermal Analysis. 1998,

3-80.

28. Wojnarowska, Z.; Swiety, P. A.; Grzybowska, K.; Hawelek, L.; Paluch, M.

Fundamentals of Ionic Conductivity Relaxation Gained from Study of Procaine

Hydrochloride and Procainamide Hydrochloride at Ambient and Elevated

Pressure. J. Chem. Phys.2012, 136, 164507.1-164507.6.

29. Yu, L. Amorphous Pharmaceutical Solids: Preparation, Characterization and

Stabilization. Adv Drug Deliver Rev. 2001, 48, 27-42.

30. Xu, H.; Ince, S.; Cebe. P. Development of the Crystallinity and Rigid Amorphous

Fraction in Cold Crystallized Isolactic Polystyrene. J. Polym. Sci., Part B: Polym.

Phys. 2003, 41, 3026- 3036.

31. Laczkovich, J. O.; Szabo, P. R. Amorphizaton of a Crystalline Active

Pharmaceutical Ingredients and Thermo Analytical Measurements on this Glassy

Form. J. Therm. Anal. Calorim. 2010, 102, 243-247.

67

32. Bruno, C.; Hancock.; Zografi, G. Characteristics and Significance of the

Amorphous State in Pharmaceutical Systems. J. Pharm. Sci. 1997, 86, 1-12.

33. Venkatesh, G. M.; Barnett, E. M.; Fordjour, C. O.; Galop, M. Detection of Low

Levels of the Amorphous Phase in Crystalline Pharmaceutical Materials by

Thermally Stimulated Current Spectrometry. Pharm. Res.2001, 18, 98-103.

34. Shah, B.; Kakumanu, V. K.; Bansal, A.K. Analytical Techniques for

Quantification of Amorphous/Crystalline Phases in Pharmaceutical Solids. J.

Pharm. Sci.2006, 95, 1641-1665.

35. Hancock, B.C.; Parks, M. What is the True Solubility Advantage for Amorphous

Pharmaceuticals?. Pharm. Res. 2000, 17, 397-404.

36. Guinot, S.; Leveiller, F. The use of MTDSC to assess the Amorphous Phase

Content of a Micronised Drug Substance. Int. J. Pharm.1999, 192, 63-75.

37. Cahoon, J.M.; Riga, A.T.; Pialet, J.W. Characterization of Electrorheological

Processes by Dielectric Thermal Analysis. Materials Characterization by

Dynamic and Modulated Thermal Analytical Techniques, ASTM STP 1402. 2001,

157-176.

38. Sharma, M.; Yashonath, S. Correlation between Conductivity or Diffusivity and

Activation Energy in Amorphous Solids. J. Chem. Phys. 2008, 129, 144103.1-

144103.10.

39. Cheng, Q.; Pavlinel, V.; Lengalova, A.; Li, C.; Belza, T.; Saha, P.

Electrorheological Proeprties of New mesoporous Material with Conducting

Polypyrrole in Mesoporous Silica. Microporous and Mesoporous Materials.

2006, 94, 193-199.

ionic conductivity in non-ionic compounds

Documents