Western Kentucky University
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Masters Theses & Specialist Projects
Graduate School
8-1-2013
Ionic Conductivity in Non-Ionic Compounds
Usha Kranthi Avala
Western Kentucky University, [email protected]
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Avala, Usha Kranthi, "Ionic Conductivity in Non-Ionic Compounds" (2013). Masters Theses & Specialist Projects. Paper 1279.
http://digitalcommons.wku.edu/theses/1279
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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.
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.
iv
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
v
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
vi
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
vii
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
viii
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
ix
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.
x
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
1
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 nonpolar 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
2
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
3
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
4
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.
5
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
6
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
7
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.
8
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 /min3,4, 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.
9
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
10
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
11
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
12
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
13
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
14
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
15
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
16
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 °C14.
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,
17
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.
Sample: ca ox-veri1
Size: 9.8000 mg
File: E:\TA\Data\TGA\usha\ca ox-veri1.001
Operator: usha
Run Date: 26-Mar-13 10:18
Instrument: 2950 TGA HR V6.0E
TGA
120
0.6
736.58°C
12.2%
(1.19mg)
486.38°C
Weight (%)
165.57°C
0.4
18.6%
(1.82mg)
80
0.2
60
30.1%
(2.95mg)
Deriv. Weight (%/°C)
100
0.0
40
20
0
200
400
600
Temperature (°C)
Figure 7. TGA curve of calcium oxalate
18
800
-0.2
1000
Universal V3.9A TA Instruments
1st Step
CaC2O4.H2O (s)
CaC2O4 (s) + H2O (g).................... (1)
Calcium oxalate monohydrate
Calcium oxalate
2nd step
CaC2O4 (s)
Calcium oxalate
CaCO3 (s) + CO (g)……………….. (2)
Calcium carbonate
3rd Step
CaCO3 (s)
Calcium carbonate
CaO (s) + CO2 (g)……………….. (3)
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
19
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 viseversa, 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
20
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.
21
Where, Xc is percent of crystallinity, ∆H is the heat of fusion of the sample and ∆Ho is
that of the 100% crystalline standard.
22
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
23
Figure 10. Chemical structure of Ketoconazole
Figure 11. Chemical structure of Nifedipine.
24
Table 2. List of drugs studied.
Melting
Drug
Lidocaine
Phase
Solid
Point (◦C)
Source
Functional Category
Sigma
Local anesthetic and
Aldrich
antiarrhythmic
68-70
MP
Antianginal and
Nifedipine
Solid
172-174
Biomedicals,
antihypertensive
LLC
Sigma
Procainamide
Solid
165-168
Antiarrhythmic
Aldrich
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
25
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
26
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.
27
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
28
29
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Exo Up
Heat Flow (W/g)
20
–––––––
––––
––––– ·
––– – –
––– –––
40
indium-5.001
indium-2.001
indium-3.001
indium-4.001
indium-1.001
60
100
Temperature (°C)
120
140
Figure 14. Overlay of 5 DSC runs of indium
80
180
Universal V4.1D TA Instruments
160
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
2nd
3rd
1st
2nd
3rd
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
30
31
Weight (%)
20
40
60
80
100
120
0
400
600
Temperature (°C)
ca ox-veri5.001
ca ox-veri1.001
ca ox-veri2.001
ca ox-veri3.001
ca ox-veri4.001
800
Figure 15. Overlay of TGA curves of Calcium oxalate.
200
–––––––
–––––––
––––– ·
––– – –
––– –––
Universal V3.9A TA Instruments
-0.2
1000
0.0
0.2
0.4
0.6
Deriv. Weight (%/°C)
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 2nd 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 2nd 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.
32
Table 5. Standard deviation of TGA curves of Calcium oxalate monohydrate.
Sample ID
(Calcium
Oxalate)
Weight Loss (%)
DTG peak (°C) at weight loss
1st
2nd
3rd
1st
2nd
3rd
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
1st Weight
Temperature
2nd Weight
Temperature
Residue
ID
Loss (%)
(°C)
Loss (%)
(°C)
(mg)
Lidocaine
100
212
-
-
0
Nifidipine
97
283
3.0
-
0
Ketoconazole
53
355
48
571
0
Procainamide
50
295
27
376
0
33
34
Weight (%)
-20
0
20
40
60
80
100
120
0
Sample: lidocaine
Size: 10.3480 mg
200
400
600
Temperature (°C)
99.6%
(10.3mg)
800
-1
1000
Universal V3.9A TA Instruments
Residue 0%
0
1
2
3
File: E:...\TGA\usha\lidocaine 20121005.001
Operator: usha
Run Date: 5-Oct-12 16:42
Instrument: 2950 TGA HR V6.0E
Figure 16. TGA curve of Lidocaine
212.98°C
TGA
Deriv. Weight (%/°C)
35
Weight (%)
-20
0
20
40
60
80
100
120
0
Sample: Nifedipine
Size: 9.4350 mg
200
400
600
Temperature (°C)
97.6%
(9.21mg)
800
0
Universal V3.9A TA Instruments
-1
1000
Residue 0%
2.69%
(0.254mg)
1
2
3
4
File: E:...\TGA\usha\Nifedipine 20121007.001
Operator: usha
Run Date: 7-Oct-12 18:21
Instrument: 2950 TGA HR V6.0E
Figure 17. TGA curve of Nifedipine
282.5°C
TGA
Deriv. Weight (%/°C)
36
Weight (%)
-20
0
20
40
60
80
100
120
0
Sample: ketoconazole
Size: 9.4450 mg
200
400
600
571.°C
Temperature (°C)
52.8%
(5.0mg)
800
0.0
Universal V4.3A TA Instruments
-0.5
1000
Residue 0%
47.6%
(4.5mg)
0.5
1.0
1.5
File: E:...\TGA\ketoconazole r-1 20121022.001
Operator: usha
Run Date: 22-Oct-2012 15:39
Instrument: 2950 TGA HR V6.0E
Figure 18. TGA curve of Ketoconazole
355.°C
TGA
Deriv. Weight Change (%/°C)
37
Weight (%)
-20
0
20
40
60
80
100
120
0
Sample: procainamide
Size: 6.4530 mg
400
26.7%
(1.7mg)
578.°C
600
Temperature (°C)
376.°C
50.2%
(3.2mg)
Figure 19. TGA curve of Procainamide
200
295.°C
TGA
23.5%
(1.5mg)
800
Universal V4.3A TA Instruments
-0.2
1000
0.0
0.2
0.4
0.6
0.8
1.0
File: E:...\TGA\procainamide 20121005.001
Operator: usha
Run Date: 05-Oct-2012 22:37
Instrument: 2950 TGA HR V6.0E
Deriv. Weight Change (%/°C)
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.
38
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
39
40
Exo Up
-2.0
-100
-1.5
-1.0
-0.5
0.0
0.5
Sample: nifedipine
Size: 8.5500 mg
Heat Flow (W/g)
-50
50
Temperature (°C)
150
200
Universal V4.3A TA Instruments
173.°C
155.°C
773.J/g
File: E:\research\DSC\nifedipine r-1.001
Operator: usha
Run Date: 11-Apr-2013 09:52
Instrument: 2920 MDSC V2.4F
100
Figure 20. DSC curve of Nifedipine
0
56.°C(H)
DSC
41
Exo Up
-4
-100
-3
-2
-1
0
1
Sample: ketoconazole
Size: 8.8500 mg
Heat Flow (W/g)
-50
50
100
Temperature (°C)
150
152.°C
148.°C
107.J/g
Figure 21. DSC curve of Ketoconazole
0
46.°C(H)
DSC
200
300
Universal V4.3A TA Instruments
250
File: E:...\DSC\ketoconazole 20121027.001
Operator: usha
Run Date: 27-Oct-2012 17:12
Instrument: 2920 MDSC V2.4F
42
Exo Up
-4
-100
-3
-2
-1
0
1
Sample: procainamide
Size: 9.2200 mg
Heat Flow (W/g)
-50
50
100
Temperature (°C)
Figure 22. DSC curve of Procainamide
0
44.°C(H)
DSC
150
169.°C
102.J/g
172.°C
200
Universal V4.3A TA Instruments
250
File: E:...\DSC\procainamide 20121022.001
Operator: usha
Run Date: 22-Oct-2012 15:55
Instrument: 2920 MDSC V2.4F
43
Exo Up
-4
-2
0
2
4
6
8
10
-80
-60
Sample: lidocaine r-1
Size: 8.5500 mg
Heat Flow (W/g)
-20
0
20
Temperature (°C)
Figure 23. DSC curve of Lidocaine
-40
DSC
40
60
67.°C
1565.J/g
100
Universal V4.3A TA Instruments
80
70.°C
File: E:\research\DSC\lidocaine r-1.001
Operator: usha
Run Date: 10-Apr-2013 12:58
Instrument: 2920 MDSC V2.4F
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 (1030 ◦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.
44
Table 9. Summary of DEA data with single surface sensor
Sample name
Frequency of 0.1 Hz
Frequency of 1000 Hz
Temperature(°C)
Log ionic
Temperature(°C)
Log ionic
at the onset of
conductivity
at the onset of
conductivity
increase in log
(pmho/cm)
increase in log
(pmho/cm)
ionic
that
ionic
that
conductivity
temperature
conductivity
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
45
Table 10. Summary of DEA data with parallel plate sensor
Frequency of 0.1 Hz
Frequency of 1000 Hz
Temperature(°C)
Log ionic
Temperature(°C)
Log ionic
at the onset of
conductivity
at the onset of
conductivity
increase in log
(pmho/cm)
increase in log
(pmho/cm)
ionic
that
ionic
that
conductivity
temperature
conductivity
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
Sample name
46
47
Ionic Conductivity (pmho/cm)
0.1
1
10
100
1000
10000
1.0E5
1.0E6
20
60
80
Temperature (°C)
100
DEA
120
1000Hz
138.40°C
140
58.69pmho/cm
142.66°C
0.1Hz
180
Universal V4.3A TA Instruments
160
18.40pmho/cm
File: E:...\DEA\ketoconazole-60 single.001
Operator: usha
Run Date: 18-Mar-2013 12:52
Instrument: 2970 DEA V2.1A
Figure 24. DEA curve of Ketoconazole with single surface sensor
(Blue-0.1 Hz, Red-1000 Hz)
40
Sample: ketoconazole-60
Size: 2.5000 mm
48
Ionic Conductivity (pmho/cm)
0.001
0.01
0.1
1
10
100
1000
10000
1.0E5
0
20
40
60
80
100
Temperature (°C)
DEA
120
16.01pmho/cm
1000 Hz
132.37°C
140
180
Universal V4.3A TA Instruments
160
0.1 Hz
0.2465pmho/cm
148.62°C
File: E:...\DEA\ketoconazole-60 parallel.001
Operator: usha
Run Date: 12-Jun-2013 15:36
Instrument: 2970 DEA V2.1A
Figure 25. DEA curve of Ketoconazole with Parallel plate sensor
(Blue-0.1 Hz, Red-1000 Hz)
Sample: ketoonazole-60 parallel
Size: 0.5000 mm
49
Ionic Conductivity (pmho/cm)
0.01
0.1
1
10
100
1000
10000
1.0E5
1.0E6
1.0E7
1.0E8
20
40
60
80
100
120
Temperature (°C)
DEA
140
1000Hz
160
148.41°C
50.02pmho/cm
0.1Hz
159.3pmho/cm
143.41°C
200
Universal V4.3A TA Instruments
180
File: E:...\DEA\Procainamide-60 single.001
Operator: usha
Run Date: 15-Mar-2013 08:23
Instrument: 2970 DEA V2.1A
Figure 26. DEA curve of Procainamide with single plate sensor
(Blue-0.1 Hz, Red-1000 Hz)
Sample: Procainamide-60
Size: 2.5000 mm
50
Ionic Conductivity (pmho/cm)
0.1
1
10
100
1000
10000
1.0E5
1.0E6
1.0E7
1.0E8
20
60
80
100
120
Temperature (°C)
DEA
140
160
200
Universal V4.3A TA Instruments
180
0.1 Hz
1.323pmho/cm
169.67°C
22.62pmho/cm
1000Hz
172.79°C
File: E:...\DEA\Procainamide-60 parallel.001
Operator: usha
Run Date: 13-Jun-2013 13:17
Instrument: 2970 DEA V2.1A
Figure 27. DEA curve of Procainamide with parallel plate sensor
(Blue-0.1 Hz, Red-1000 Hz)
40
Sample: Procainamide-60 parallel
Size: 0.5000 mm
51
Ionic Conductivity (pmho/cm)
0.01
0.1
1
10
100
1000
10000
1.0E5
1.0E6
20
Sample: Lidocaine
Size: 2.5009 mm
60
Temperature (°C)
63.46°C
13.57pmho/cm
0.1Hz
80
Universal V4.3A TA Instruments
100
File: E:\research\DEA\Lidocaine-60 single.001
Operator: usha
Run Date: 06-Mar-2013 14:12
Instrument: 2970 DEA V2.1A
Figure 28. DEA curve of Lidocain with single surface sensor (Blue0.1 Hz, Red-1000 Hz)
40
1000Hz
25.27pmho/cm
59.10°C
DEA
52
Ionic Conductivity (pmho/cm)
0.0001
0.001
0.01
0.1
1
10
100
1000
10000
1.0E5
30
50
60
70
Temperature (°C)
66.75°C
17.04pmho/cm
1000Hz
DEA
80
0.1 Hz
76.22°C
1.660pmho/cm
90
Universal V4.3A TA Instruments
100
File: E:...\DEA\Lidocaine-60 parallel.001
Operator: usha
Run Date: 12-Jun-2013 16:32
Instrument: 2970 DEA V2.1A
Figure 29. DEA curve of Lidocaine with parallel plate sensor (Blue0.1 Hz, Red-1000 Hz)
40
Sample: Lidocaine-60 parallel
Size: 0.6124 mm
53
Ionic Conductivity (pmho/cm)
0.1
1
10
100
1000
10000
1.0E5
1.0E6
20
40
60
80
100
120
Temperature (°C)
DEA
140
150.91°C
73.66pmho/cm
1000Hz
160
200
Universal V4.3A TA Instruments
180
23.51pmho/cm
155.50°C
0.1Hz
File: E:\research\DEA\Nifedipin-60 single.001
Operator: usha
Run Date: 07-Mar-2013 12:36
Instrument: 2970 DEA V2.1A
Figure 30. DEA curve of Nifedipine with single plate sensor (Blue0.1 Hz, Red-1000 Hz)
Sample: Nifedipin-60
Size: 2.5000 mm
54
Ionic Conductivity (pmho/cm)
0.0001
0.001
0.01
0.1
1
10
100
1000
10000
20
60
80
100
120
Temperature (°C)
DEA
140
160
200
Universal V4.3A TA Instruments
180
0.1137pmho/cm
175.50°C
0.1Hz
1000Hz
7.123pmho/cm
169.87°C
File: E:...\DEA\Nifedipine-60 parallel.001
Operator: usha
Run Date: 13-Jun-2013 15:29
Instrument: 2970 DEA V2.1A
Figure 31. DEA curve of Nifedipine with parallel plate sensor
(Blue-0.1 Hz, Red-1000 Hz)
40
Sample: Nifedipine-60 parallel
Size: 0.5000 mm
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
55
(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
56
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 (1520 °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 102-105
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 premelt and melt regions.
57
1
––––––– ketoconazole 20121027.001
––––––– ketoconazole-60 parallel.001
––––
ketoconazole-60 single.001
1.0E6
1.0E5
147.74°C
107.8J/g
0
Heat Flow (W/g)
1000
-1
138.40°C
100
142.85°C
10
-2
131.12°C
1
0.1
147.17°C
-3
Ionic Conductivity (pmho/cm)
10000
152.21°C
0.01
-4
-100
Exo Up
-50
0
50
100
Temperature (°C)
150
200
250
0.001
300
Universal V4.3A TA Instruments
Figure 32. Overlay of DSC and DEA curves of Ketoconazole (Green-DEA curve,
Blue-DSC curve)
58
10000
10
1.0E5
8
10000
6
100
1000
10
100
1
10
Ionic Conductivity (pmho/cm)
Ionic Conductivity (pmho/cm)
1000
66.65°C
2
59.01°C
63.36°C
0
63.24°C
0.1
4
Heat Flow (W/g)
Lidocaine-60 parallel.001
lidocaine r-1.001
Lidocaine-60 single.001
67.45°C
71.4J/g
1
-2
69.65°C
0.01
-80
Exo Up
-60
-40
-20
0
20
Temperature (°C)
40
60
80
-4
100
Universal V4.3A TA Instruments
Figure 33. Overlay of DSC and DEA curves of Lidocaine (Green-DEA curve, BlueDSC curve)
59
10000
0.5
Nifedipine-60 parallel.001
nifedipine r-1.001
Nifedipin-60 single.001
1000
1.0E5
171.31°C
21.9J/g
0.0
10
1000
1
100
0.1
10
-0.5
168.35°C
-1.0
151.54°C
Heat Flow (W/g)
10000
Ionic Conductivity (pmho/cm)
Ionic Conductivity (pmho/cm)
100
155.29°C
0.01
-1.5
0.001
1
0.0001
-100
Exo Up
172.89°C
-50
0
50
Temperature (°C)
100
150
-2.0
200
Universal V4.3A TA Instruments
Figure 34. Overlay of DSC and DEA curves of Nifedipine (Green-DEA curve, BlueDSC curve)
60
1.0E8
1.0E6
1.0E5
1.0E5
10000
10000
1000
1000
100
100
10
10
1
1
0
168.50°C
102.3J/g
-1
144.03°C
-2
Heat Flow (W/g)
Ionic Conductivity (pmho/cm)
1.0E6
1.0E7
Ionic Conductivity (pmho/cm)
1.0E7
––––––– Procainamide-60 parallel.001
––––––– procainamide 20121022.001
––––––– Procainamide-60 single.001
148.62°C
172.38°C
1
-3
169.04°C
0.1
172.16°C
0.1
-100
Exo Up
-50
0
50
100
Temperature (°C)
150
200
-4
250
Universal V4.3A TA Instruments
Figure 35. Overlay of DSC and DEA curves of Procainamide (Green-DEA curve,
Blue-DSC curve)
61
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.
62
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