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Thermal Analysis

Dr. Basavaraj K. Nanjwade


M. Pharm., Ph.D

KLE University College of Pharmacy


BELGAUM-590010, Karnataka, India.
Cell No: 00919742431000
E-mail: nanjwadebk@gmail.com
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Thermal analysis
Thermal analysis is a branch of materials
science where the properties of materials are
studied as they change with temperature.
Several methods are commonly used these
are distinguished from one another by the
property which is measured.

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ABBREVIATIONS

ICTAC - International Confederation for Thermal Analysis and Calorimetry


DEA- Dielectric Analysis
DSC- Differential Scanning Calorimetry
TGA- Thermogravimetric Analysis
TMA- Thermomechanical Analysis
Hf- Heat of Fusion
Tm - Melting Temperature, extrapolated endothermic onset temperature
Tp- Peak Melting endothermic Temperature
Hc-Heat of exothermic Crystallization
Tc- Crystallization Temperature, extrapolated exothermic onset temperature
Tcp- Peak exothermic Crystallization temperature
Hv - Heat of endothermic Vaporization
Tv - Vaporization temperature, extrapolated endothermic onset temperature
Tvp - Peak Vaporization temperature
Tg -Glass transition temperature
ASTM- American Standards for Testing Materials

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Thermal analysis

Dielectric thermal analysis (DEA): dielectric permittivity and loss factor


Differential thermal analysis (DTA): temperature difference

Differential scanning calorimetry (DSC): heat difference

Dilatometry (DIL): volume


Dynamic mechanical analysis (DMA) : mechanical stiffness and damping
Evolved gas analysis (EGA) : gaseous decomposition products
Laser flash analysis (LFA): thermal diffusivity and thermal conductivity

Thermogravimetric analysis (TGA): mass


Thermomechanical analysis (TMA): dimension

Thermo-optical analysis (TOA): optical properties

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Common Thermal Analysis Methods and the Properties Measured

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Introduction
Thermal analysis is defined as series of techniques for
measuring the temperature dependency of a physical
property of a certain substance while varying the
temperature of the substance according to a specific
program.
The substance referred to here includes reaction
products.
Physical properties include mass, temperature,
enthalpy, dimension, dynamic characteristics, and
others, and depending on the physical properties to be
measured, the techniques of thermal analysis.
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Introduction
Conventionally thermal analysis has been mainly
employed in measurements for research and
development, but in recent times it is used in many
practical applications, as the testing standards on the
basis of thermal analysis have been established, for
example, in quality control in the production field,
process control, and material acceptance inspection.
It is also applied in wide fields, including polymer,
glass, ceramics, metal, explosives, semiconductors,
medicines, and foods.
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Introduction
Introduce thermal analysis at an entry level
chemist or a new function for the experienced
pharmaceutical scientist.
This teaching tool describes the introductory use
of Differential Scanning Calorimetry (DSC),
Thermo-Mechanical Analysis (TMA) and to some
extent Thermo-gravimetric Analysis (TGA) for
characterizing pharmaceuticals.
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Basic Principles of Thermal Analysis

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Thermal Analysis Techniques

IUPAC: International Union of Pure and Applied Chemistry


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Thermal Analysis
Differential Scanning
Calorimetry (DSC)
Measure heat absorbed or
liberated during heating or
cooling

Differential Thermal
Analysis (DTA)
They are use for thermal
investigation where thermal
change can be observed and
characterised
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Thermal Gravimetric
Analysis (TGA)
Measure change in
weight during heating or
cooling

Thermomechanical
Analysis (TMA)
Measure change in
dimensions during
heating or cooling

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THERMOGAVIMETRIC ANALYSIS
(TGA)

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Thermogravimetric Analysis (TGA)


Principle: TGA measures the amount and the rate of
weight change of a material with respect to
temperature or time in controlled environments.
A TGA consists of three major parts a furnace,
1. A microgram balance,
2. An auto sampler and
3. A thermocouple.

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GENERAL PRINCIPLES INVOLVED IN


THERMOGRAVIMETRY
PRINCIPLE : Thermogravimetry is a technique
in which a change in the weight of a substance is
recorded as a function of temperature or time.

Instrument:
Instrument
used
for
thermogravimetry is Thermobalance. Data
recorded in form of curve known as
Thermogram.

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Thermogravimetric Analysis
(TGA)
The furnace can raise the temperature as high
as 1000C which is made of quartz.
The auto sampler helps to load the samples on
to the microbalance.
The thermocouple sits right above the sample.
Care should be taken at all times that the
thermocouple is not in touch with the sample
which is in a platinum pan.
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Thermogravimetric Analysis
(TGA)
A technique that permits
the continuous weighing
of a sample as a
function of temperature
and/or as a function of
time at a desired
temperature

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Differential Thermal Analysis

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Thermogravimetric Analysis
(TGA)

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Interpretation of TG and DTG curves


The
sample
undergoes
no
decomposition with loss of volatile
products over the temperature range
shown but solid phase transformation,
melting ,etc can not be detected by
TG,
ii. The
rapid
initial
mass
loss
is
characteristic of desorption or drying. If
it is true, then re-run the sample should
result in type (i) curves,
iii. Single stage decomposition,
iv. Multi-stage
decomposition
with
relatively stable intermediates : provide
information on the temperature limit of
stability of reactants and intermediate
products and also stoichiometry,
v. Multi-stage decomposition with no
stable intermediate product. However
heating-rate effect must be considered.
At low heating rate, type (v) resemble
type (iv). At high heating rate, type (iv)
and (v) resemble type (iii) and lose all
the details,
vi. Gain in mass due to reaction with
atmosphere, e.g. oxidation of metals,
vii. Oxidation product decompose again at
higher temperature; this is not often
encountered.
i.

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TGA Curve of Calcium Oxalate

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Examples of TGA Curves

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Sample Preparation
Sample preparation has a significant effect in obtaining
good data.
It is suggested that maximizing the surface area of the
sample in a TGA pan improves resolution and
reproducibility of weight loss temperatures.
The sample weight affects the accuracy of weight loss
measurements.
Typically 10-20mg of sample is preferred in most
applications.
Whereas, if the sample has volatiles 50-100mg of sample is
considered adequate.
It is to be noted that most TGA instruments have baseline
drift of 0.025mg which is 0.25% of a 10mg sample.
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Experimental Conditions
Heating Rate
Purge gas

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Experimental Conditions -Heating Rate


Samples are heated at a rate of 10 or 20C/min in
most cases.
Lowering the heating rates is known to improve the
resolution of overlapping weight losses.
Advances in the technology have made it possible for
variable heating rates (High Resolution TGA) to
improve resolution by automatically reducing the
heating rate during periods of weight loss.

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Experimental Conditions -Purge gas


Nitrogen is the most common gas used to purge samples
in TGA due to its inert nature.
Whereas, helium provides the best baseline.
Air is known to improve resolution because of a
difference in the oxidative stability of components in
the sample.
Vacuum may be used where the sample contains volatile
components, which helps improve separation from the
onset of decomposition since the volatiles come off at
lower temperatures in vacuum.
e.g. oil in a rubber tire product.
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Miscellaneous

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Calibration
Blank test
Calibration of mass changes
Calibration of temperature

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Calibration- Blank test


Without sample, air is passed at 20 ml/mm, and the
temperature is raised up to 1000 C at heating rate of 10C
min-1.
By this blank test, the general condition of the apparatus
can be known.
The TGA curve can drift slightly as the temperature is
increased.
This is owing to the changes in the buoyancy and
convection.
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Calibration- Blank test


When noise appears in the TG curve, the possible
cause may include contact between sample dish and
thermocouple, contact between quartz suspension
wire and purge gas feed pipe, and contact between
weight pan and arid glass cap.
Vibration and shock may also cause noise.
When the sample pan or suspension wire is
contaminated with deposit of decomposition product
or the like, the TGA curve shows a slight decreasing
curve.
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Calibration- Calibration of mass


changes
Since the TGA is usually measured by the rate of
the weight change to the sample weight,
calibration of absolute value of weight is hardly
necessary.
A weight of 20 mg is read to a precision of 10
microgms by a precision balance, and the mean
(So) is determined.
The furnace is put on, and when the TGA signal is
stabilized, the instrument balance control is
adjusted to set the automatic zero.
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Calibration- Calibration of mass


changes
Then the furnace is put into place and the furnace is set again,
and the TGA signal value is read. This value is S1.
Repeating the same operation several times, the mean of S1 is
obtained as S.
In this operation it is known that a signal corresponding to S1
mg is delivered with the weight of So mg is placed on the
balance.
The measuring precision of TGA is within 1 % of the range.
When calibrating the apparatus, the calibration function is
utilized.

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Calibration-Calibration of
temperature
The temperature of the TGA may be calibrated in two
manners:
The method of making use of the melting point of a
pure metal, and the method of utilizing the Curie point
temperature.
In the former method, one of the metals processed in a
ribbon shape, and it is suspended on the TGA
suspension wire, and a weight of about 100mg is
attached at its tip.
When the pure metal is fused by heating, the weight
drops, and a weight drop appears on the TGA curve.
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Calibration-Calibration of
temperature
In the latter method, the standard substance
verified by International Congress on
Thermal Analysis, ICTA, is measured. The
standard substances are Ferromagnets, and
have different Curie temperatures.
It is intended to calibrate by measuring the
apparent weight change appearing in steps at
Curie temperatures by making use of a
permanent magnet.
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Calibration-Calibration of
temperature
Based on the TGA data, thermal stability of materials and
their compositions can be predicted depending on the
weight changes caused by evaporation, dehydration,
oxidation and decomposition, up to temperatures as high
as 1000C.
A typical example is the TGA of calcium oxalate hydrate,
heated to 1000C which shows three steps in its
decomposition curve.
The weight loss data is recorded every half second
throughout the run time.
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Applications of TGA
There is a wide range of applications of TGA, e.g,
Composition of multi-component system
Thermal stability of materials
Oxidative stability of materials
Estimated lifetime of a product
Decomposition Kinetics of materials
The effect of reactive or corrosive atmosphere on
materials
Moisture and volatiles contents on materials.
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Applications of TGA
Evaporation of free (unbound) water begins at room
temperature due to dry gas flowing over the sample.

Dehydration/Desolvation of bound water almost always


begins at temperatures above room temperature and
typically 125C.
Decomposition can have multiple stages (weight losses)
but the presence of multiple weight loss steps can also
indicate the presence of multiple components in the
sample.
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Applications of TGA
Determination of the bound and unbound water in the
suspension of Milk of Magnesia (MoM), used as a laxative.
Comparison of the generic and a brand MoM.
In an overview of thermal analysis testing it is always
preferable to do a TGA experiment on unknown samples before
doing a DSC experiment (especially for pharmaceuticals).
Decomposition of pharmaceuticals renders products which are
insoluble and generally sticky on the inside of a DSC cell.
These products will lower the life use of a DSC cell.
Therefore, know the decomposition temperatures of all drugs
and heat in a DSC evaluation to 50C below those
temperatures.
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TGA+Spectroscopy/Chromatography
Combination
Gases, vapors
TGA

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IR or MS or GC

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Thermogravimetry thermal analysis


(TGA) testing
Thermogravimetric (TGA)
analysis
provides
determination of endotherms, exotherms, weight loss
on heating, cooling, and more.
Materials analyzed by TGA include polymers,
plastics, composites, laminates, adhesives, food,
coatings, pharmaceuticals, organic materials, rubber,
petroleum, chemicals, explosives and biological
samples.
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TGA materials analysis


Thermogravimetric analysis uses heat to force
reactions and physical changes in materials.
TGA provides quantitative measurement of mass
change in materials associated with transition and
thermal degradation.
TGA records change in mass from dehydration,
decomposition, and oxidation of a sample with time
and temperature.
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TGA materials analysis


Characteristic thermogravimetric curves are given for
specific materials and chemical compounds due to unique
sequence from physicochemical reactions occurring over
specific temperature ranges and heating rates.
These unique characteristics are related to the molecular
structure of the sample.
When TGA is used in combination with FTIR, TGA/FTIR
is capable of detailed FTIR analysis of evolved gases
produced
from
the
TGA.
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TGA thermogravimetric capabilities

Compositional analysis of materials


Decomposition temperatures
Rate of degradation
Product lifetimes
Oxidative stability
Evaluation of polymer flammabilities
Thermal stabilities
Determination of rancidity of edible oils

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TGA thermogravimetric capabilities

Fingerprinting unknown polymers


Moisture Content
Volatiles content, VOC analysis
Analysis of evolved gases using TGA/FTIR
Competitive product evaluation
Measurement of oil extender content in elastomers
Effects of reactive atmospheres on materials
Determination of inert filler or ash contents
ASTM D6375 Noack Method

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Summary of Pharmaceutically Relevant


information Derivation from TGA Analysis

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Major difference between


TGA and DTA (DSC)

TGA reveals changes of a sample due to weight, whereas DTA and


DSC reveal changes not related to the weight (mainly due to phase
transitions)
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DIFFERENTIAL SCANNING CALORIMETRY


(DSC)

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Differencial Scanning Calorimetry


(DSC)
Characterization
of
pharmaceutical
compounds and analysis of complex modern
formulations, together with an increasing need
for data to support regulatory submissions,
means that the pharmaceutical industry now
depends on the range of thermal analysis
techniques.

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Definitions
A calorimeter measures the heat into or out of a
sample.
A differential calorimeter measures the heat of a
sample relative to a reference.
A differential scanning calorimeter does all of the
above and heats the sample with a linear temperature
ramp.
Endothermic heat flows into the sample.
Exothermic heat flows out of the sample.

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Exothermal dQ/dT

Differential Scanning Calorimetry (DSC)

Temperature

DSC measures differences in the amount of heat required to increase the


temperature of a sample and a reference as a function of temperature
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Circuitry of a DSC
Two separat heating circuits:

The average-heating controller


(The temperatures of the sample (Ts) and reference (Tr) are measured and
averaged and the heat output is automatically adjusted to increase the
average temperature of the sample and reference in a linear rate)

Differential-heating circuit
(Monitor the difference in Ts and Tr, and automatically adjust the power to
either the reference or sample chambers to keep the temperatures equal)

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Sample containers and sampling

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Differential Scanning Calorimeter

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Conventional DSC
Empty

Sample
Metal
1

Sample
Temperature

Metal Metal
2
1

Metal
2

Reference
Temperature

Temperature
Difference =
Heat Flow

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Variants of DSC
Heat flux
1955 Boersma
1 large (30 100 g) furnace

Power compensated
Separate small (1 g) microheaters for sample and reference

Hyper DSC
Very fast scan rates 500C/min
Mimic processing conditions

StepScan DSC
Short dynamic and isothermal scan steps
Separate reversible and irreversible effects
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Variants of DSC

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Differential Scanning Calorimetry


(DSC)

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DSC Technique

Principle
Heat Flux
Power Compensation
Sample Preparation
- Sample Shape
- Sample pans
- Sample Weight
Experimental Conditions
- Start Temperature
- End Temperature
- Reference Pan
- Heating Rate
- Effects of heating rate
Purge Gas
DSC Calibration

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DSC- Principle
Principle DSC is a thermo-analytical technique in
which the difference in the amount of heat required to
increase the temperature of a sample and reference is
measured as a function of temperature.

The differences in heat flow occur with the occurrence


of two major events:
1) The heat capacity of the sample which increases
with temperature (baseline)
2) Transitions that occur in the sample (events
superimposed on the heat capacity baseline)
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DSC- Principle
Heat Flow Rate is expressed in a variety of units
which can also be normalized for the weight of
sample used

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Principle Of DSC

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Typical DSC Curve

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Heat Flow -> exothermic

DSC Thermogram
Cross-Linking
(Cure)

Crystallisation

Oxidation

Glass
Transition

Melting

Temperature
6
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Transitions in a DSC Curve

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Differential Scanning Calorimeter


A DSC consists of a cell, which is the heart of a
DSC.
The cell is connected with a gas inlet through
which different gases are purged depending on the
data required.
Based on the DSC cells there are two primary
types: 1. Heat Flux 2. Power Compensation
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DSC

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Heat Flux
This consists of a large single furnace which acts as an
infinite heat sink to provide or absorb heat from the
sample.
The advantages generally include a better baseline,
sensitivity and sampleatmosphere interaction.
The key components are the Sample pan (typically an
aluminum pan and lid) which is combined with the
Reference pan (always the same material as the Sample
pan, aluminum).
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Heat Flux
The Dynamic sample chamber is the environment of the
sample pan compartment and the purge gas.
Nitrogen is the most common gas, but alternate inert gas is
helium or argon.
When using an oxidative atmosphere air or oxygen are the
gases of choice.
The heat flux DSC is based on the Change in Temperature
T between the sample and reference.
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Heat Flux Type DSC

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Heat Flux and DSC

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Heat Flux Type DSC

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Power Compensation
Small individual furnaces use different amounts of power
to maintain a constant T between sample and reference
and the advantage here include faster heating and cooling,
and better resolution.
This type of cell, with two individually heated with
platinum heaters monitors the difference between the
sample and reference.
Platinum resistance thermometers track the temperature
variations for the sample and reference cells.
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Power Compensation
Holes in the compartment lids allow the purge gas to
enter and contact the sample and reference.
There are physical differences between the heat flux
and power compensated thermal analysis, the
resulting fusion and crystallization temperatures are
the same.
The heat of transition is comparable quantitatively.
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Power Compensation DSC Cell


Design

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Power Compensated DSC

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Principles of DSC Analysis

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Sample Preparation
Sample Shape
Sample Pans
Sample Weight

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Sample Preparation

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Sample Shape
It is recommended that the sample is as thin as
possible and covers as much of the pan bottom as
possible.
Samples in the form of cakes (as in case of polymers)
must preferably be cut rather than crushed to obtain a
thin sample.
Crushing the sample, whether in crystalline form or a
polymer, induces a stress, which can in turn affect the
results.
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Sample Shape
In most cases lids should always be used in order to
more uniformly heat the sample and to keep the
sample in contact with the bottom of the pan.
In case where oxidation properties of a sample are to
be studied no lid is used and the purge gas is usually
oxygen as described in ASTM Standard Test Methods
E1858, Oxidative Induction Time or ASTM E2009,
Oxidation onset temperature.
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Sample Pans
Lightest, flattest pans are known to have the least
effect on the results obtained from a DSC.
Crimped pans on the other hand provide the highest
sensitivity and resolution.
Hermetic pans are used where the sample is expected
to have some volatile content.

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Sample Pans
These pans prevent evaporation.
Two main reasons for the use of these pans are: The
Tg of a polymer or amorphous material shifts with
volatile content.
Evaporation peaks look just like melting endotherm.

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Sample Weight
Though 5 to 10 mg is considered to be an appropriate
sample weight for a DSC test, selection of the
optimum weight is dependent on a number of factors:
the sample to be analyzed must be representative of
the total sample and the change in heat flow due to
the transition of interest should be in the range of 0.1
- 10mW
A recommendation for metal or chemical melting
sample is < 5mg.
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Sample Weight
For polymer glass transition Tg or melting sample the
mass should be 10mg.
Polymer composites or blends the sample mass is
>10mg.
The accuracy of the analytical balance used to
measure the sample weight should be accurate to
1%.
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Experimental Conditions
Start Temperature
End Temperature
Reference Pan
Heating Rate
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Start Temperature
Generally, the baseline should have 2 minutes
to completely stabilize prior to the transition of
interest.
Therefore, at 10C/min heating rate the run
should start at least 20C below the transition
onset temperature.

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End Temperature
Allowing a 2-minute baseline after the
transition of interest is considered appropriate
in order to correctly select integration or
analysis limits.
Care should be taken not to decompose
samples in the DSC; it not only affects the
baseline performance but the cell life.
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Reference Pan
A reference pan of the same type used to
prepare the sample should be used at all times.
A material in the reference pan that has a
transition in the temperature range of interest
should never be used.

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Heating Rate
Heating the samples at low heating rates
increases resolution by providing more time at
any temperature.
Transitions due to kinetic processes (such as
crystallization) are shifted to lower
temperature at highest cooling rates or higher
temperatures at high heating rates.
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Heating Rate

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Effects of heating rate


DSC curves of Acetophenetidin and Phenacetin.
The Acetophenetidin DSC at 0.5C/min and
10C/min showed no effect of heating rate.
If there were some minor eutectic in this sample
then they would have been detected at the lower
heating rate.
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DSC curves of Acetophenetidin

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Effects of heating rate


The melting temperature of pure drugs or
chemicals will have the same extrapolated
onset temperature or the melting point as seen
at two varying heating rates.
The DSC Curve for Phenacetin viewed at
heating rates of 1.0, 5.0 and 20C/min yielded
the same Tm of 135C 1C.
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DSC curves of Phenacetin

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Effects of heating rate


If you use multiple heating rates then start with 1.0
and 10C/min.
Melting is a thermodynamic process and the onset of
melting does not change significantly with heating
rate.
Evaporation, desolvation and decomposition are
kinetic processes that will move to higher
temperatures as heating rate increases.
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Effect of Heating Rate

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Purge Gas
Nitrogen being a relatively poor thermal
conductor increases sensitivity whereas helium
which is a good conductor of heat to or from
the sample increases resolution.
DSC is used in studying the melting,
crystallization, glass transition, oxidation and
decomposition of pharmaceuticals.
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Purge Gas
By selecting different parameters useful data
such as the purity, polymorphic transitions can
be obtained.
A typical DSC curve could give glass
transition temperature, melting temperature,
crystallization temperature and decomposition
temperatures.
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Purge Gases

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Summary of DSC experimental


conditions

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Purity by DSC

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Purity Determination

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Summary of Pharmaceutically Relevant


Information Derived from DSC Analysis

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Typical Features of a DSC Trace

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Melting Point

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Melting Process by DSC

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Melting

dH/dt, mJ/s

Negative peak on
thermogram
Ordered to disordered
transition
Tm, melting temperature
Melting happens to
crystalline polymers;
Glassing happens to
amorphous polymers

Thermogram

Melting

Tm

Temperature, K
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Polymorphic Forms

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Pseudopolymorphism

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Amorphous Material

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Modulated Temperature DSC


(MT-DSC)
Most transitions detected by DSC will appear as peaks, where
a change (exothermic or endothermic) is detected and then
there is a return of the heat flow to a baseline.
These results are typical of first-order or second-order
thermodynamic phase transitions, which are in an equilibrium
state.
Glass transitions, on the other hand, are neither first-order nor
second-order transitions since neither the glassy state nor the
viscous state is an equilibrium state.
Typical DSC thermograms will reveal glass transitions as stepwise increases in the heat capacity (Cp) of the sample.
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Modulated Temperature DSC


(MT-DSC)
This is due primarily to the increase in molecular motion
of the sample above the Tg.
In some cases, the determination of Tg is relatively
straightforward but this work can be some of the most
challenging done with DSC.
More on detecting and determining Tgs will be presented
in the applications section of this review but glass
transitions are mentioned here because this application
has help drive the development of modulated-temperature
DSC instruments and methods.
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Modulated DSC (MDSC)

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Modulated Temperature DSC


(MTDSC)

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MDSC for Polymorph


Characterization

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Variants of MTDSC

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Example of a MTDSC Curve

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Fast Scan DSC, Rapid Scanning DSC

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Fast Scan DSC, Rapid Scanning DSC

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Hyper DSC

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DSC Calibration
Calibration of DSC is done using Indium metal.
Calibrating an instrument with a metal when
pharmaceuticals are to be studied appears to be not
appropriate.
To overcome this, an effort has been made to calibrate
DSC with pharmaceuticals.
The true melting temperature of indium metal is
156.7C and the observed in calibration is 157.4C.
It is 0.7C high and the instrument values must be
adjusted down to accommodate the true melting
temperature.
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DSC Calibration curve of indium

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DSC Applications

Glass Transition Temperature (Tg)


Glass Transition Size (Cp)
Crystallization temperature (Tc)
Crystallinity (based on J/g and adjusted to %)
Polymorphic Transitions.

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Glass Transition Temperature


(Tg)
The glass transition is due to the presence of
amorphous structures in the sample.
It is detected by DSC based on a step-change in
molecular mobility that results in a step increase
in heat capacity and heat flow rate.
Amorphous materials flow, they do not melt and
hence no DSC melt peak.
The physical and reactive properties of
amorphous structure are different than crystalline
structure.
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Glass Transition Temperature


(Tg)
The physical and reactive properties of
amorphous structure are significantly different at
temperatures above and below Tg.
The glass transition temperature, Tg, is a second
order pseudo transition.
It constitutes a parameter of high interest in the
study of amorphous and semi-crystalline drugs
since amorphous drugs are more bio available
and soluble.
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Glass Transition

dH/dt, mJ/s

Step in thermogram
Transition from
disordered solid to
liquid
Observed in glassy
solids, e.g., polymers
Tg glass transition
temperature

Thermogram

Glass transition

Tg

Temperature, K
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Glass Transition Size (Cp)


The Cp at Tg is a measure of the flexibility
associated with the Tg.
A larger value implies a more rubbery material, e.g.,
polybutadiene.
Stiffer polymers like polystyrene have a lower value.

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Crystallization temperature (Tc)


The Tc of many drugs has been determined in our lab
based on a DSC that can program heat and cool.
The difference in Tm to determine the Tc is a measure
of super cooling, e.g. Vanillin has a 50C super
cooling temperature while indium melts and
crystallizes at the same temperature or super cooling
is zero C

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Crystallization

Crystallization
dH/dt, mJ/s

Sharp positive peak


Disordered to ordered
transition
Material can crystallize!
Observed in glassy
solids, e.g., polymers
Tc crystallization
temperature

Thermogram

Tc

Temperature, K
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Analysis
Crystallization

Disordered to ordered
transition
Observed in glassy
solids, e.g., polymers
Tc crystallization
temperature

dH/dt, mJ/s

Sharp positive peak

Tc

Temperature, K
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Crystallinity (based on J/g and


adjusted to %)
The Crystallinity measured by comparing successive heat
and cool DSC runs on a drug will yield the change in
crystallinity by comparing the Heat of Crystallization to
the Heat of Fusion x100.
This % crystallinity by this method was 78% for
Acetophenetidin, 20% for Sulfapyradine and 0% for
Lidocaine.
This implies that Lidocaine remains amorphous for a
period of time.
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Polymorphic Transitions.
Sulfanilamide Polymorphs: It was observed that
sulfanilamide polymorphs are stable and do not show
transition among its forms at heating rates between 1 and
10C/min.
DSC of Polymorphs of Tolbutamide: Tolbutamide A (Form
1) and B (Form 3): When tolbutamide polymorphs were
observed by DSC a significant difference was seen in their
behavior. The difference is due to their structures which
were observed by scanning electron microscope (SEM).
The DSC curves are shown below along with the SEM
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DSC curves of Sulfanilamide


Polymorphs

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DSC of Polymorphs of Tolbutamide:


Tolbutamide A (Form 1) and B (Form 3)

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SEM of Tolbutamide polymorphs

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Typical Features of a DSC Trace


(Polymorphic System)

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Polymorph Screening and


Identification

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DSC thermal analysis

Thermal Phase Change


Thermal Glass Transition Temperature (Tg)
Crystalline Melt Temperature
Endothermic Effects
Exothermic Effects
Thermal Stability
Thermal Formulation Stability
Oxidative Stability Studies
Transition Phenomena
Solid State Structure
Analysis of a Diverse Range of Materials

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DSC analysis determines

Tg Glass Transition Temperature


Temperature (C) at which amorphous polymers or an amorphous part of a
crystalline polymer go from a hard brittle state to a soft rubbery state

Tm Melting point
Temperature (C) at which a crystalline polymer melts

Hm Energy Absorbed (joules/gram)


Amount of energy a sample absorbs when melting

Tc Crystallization Point
Temperature at which a polymer crystallizes upon heating or cooling

Hc Energy Released (joules/gram)


Amount of energy a sample releases when crystallizing

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DSC Test Methods


ASTM E1269-05 Determination Specific Heat Capacity by
DSC
NEN-EN 728 Bepaling van de Oxidatieve Inductietijd
ISO22768 Rubber, Determination of the glass transition
temperature by DSC
ASTM D1519-95 Rubber, Determination of Melting Range
ASTM D3418-03 Transition Temperatures of Polymers By
DSC
ISO11357-4 Determination of Specific Heat Capacity
ISO11357-3 Determination of Enthalpy Temperature of Melting
and Crystallization
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Sources for Errors


Calibration

Contamination

Sample preparation how sample is loaded into a pan

Residual solvents and moisture.

Thermal lag
Heating/Cooling rates
Sample mass

Processing errors

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TGA and DSC


Thermogravimetric Analysis (TGA)
Mass change of a substance measured as function of
temperature whilst the substance is subjected to a
controlled temperature programme.
Mass is lost if the substance contains a volatile
fraction.

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TGA and DSC


Differential Scanning Calorimetry (DSC)
Provides information about thermal changes that do
not involve a change in sample mass
More commonly used technique than TGA
Two basic types of DSC instruments: heat-flux and
power compensation
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Typical TGA and DSC Results


for Various Transitions

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Lactose monohydrate

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Hyphenated Thermal Equipment

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Temperature Scales

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Maxwell-Boltzmann Distribution

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DSC Applications In
Pharmaceutical Industry
Characterization - melting point, heat
of
fusion,
specific heat capacity, water
of
crystallization, etc.
Purity
Polymorphism
Screening Tests For Compatibility
Stability Tests

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DSC Applications In
Pharmaceutical Industry
Fast and reliable research tool.
DSC allows fast evaluation of possible
incompatibilities, because it shows change in the
appearance, shift or disappearance of melting,
endosperms and exotherms or variations in the
corresponding enthalpies of reaction.
Rapid analysis, easy handling, high significance
for research, development and quality control.

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Characterization for Pharma

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Physical Forms of Solids

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Importance of Solid State Forms in Pharma

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Compatibility Studies

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DSC in Polymer Analysis


Main transitions which can be studied by DSC:
Melting
Freezing
Glass transition

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Polymer DSC Analysis Capabilities

Melting point / Melting Range


Heat Capacity
Crystallization
Glass Transition
Identification
Thermal stability
Decomposition Temperature
Oxidative Induction Times (OIT) by DSC
Purity

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THERMOMECHANICAL ANALYSIS
(TMA)

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Thermo-Mechanical Analysis
(TMA)
Thermo-mechanical analysis (TMA) provides
dimensional properties data for materials.
Materials tested by thermo-mechanical anlaysis
include polymers, composites, laminates,
adhesives, coatings, pharmaceuticals, metals,
glass, ceramics, fibres and other materials.

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Thermo-Mechanical Analysis (TMA)

Measurement of Dimensional Change


Coefficient of Linear Thermal Expansion
Determination of Material Anisotropy
Softening Temperatures and Glass Transition
Linear Thermal Expansion
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Thermomechanical Analysis
(TMA)
TMA is a thermal analysis technique used to measure
changes in the physical dimensions (length or volume)
of a sample as a function of temperature and time under
a non oscillatory load.
This technique is widely applicable to variety of
materials such as pharmaceuticals, polymers, ceramics
and metals etc.
TMA has been used in pharmaceutical analysis.
Variables considered while performing the thermal
mechanical analysis are applied load, gas environment,
temperature range and heating rate as well as TMA
probe type.
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Thermomechanical Analysis
(TMA)
The tests are run in a heating mode at a desired
heating rate and temperature range of interest.
Probe displacement profiles are subsequently
analyzed in terms of coefficient of thermal expansion,
softening and melting temperatures, and glass
transition temperatures.
The different TMA probe types and recorded as a
function of temperature.
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Types of TMA probes


and resulting measured properties

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Thermomechanical Analysis
(TMA)
TMA consists of a quartz stage, a quartz probe,
furnace which sits on top of the stage,
equipped with inlet for purge gas,
thermocouple adjacent to the stage and a
LVDT (linear variable differential transformer)
attached to the probe, which measures the
difference in the dimensions caused under the
probe.
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Sample preparation
The use of TMA in the pharmaceutical
industry is limited to polymers.
In order to examine powdered samples, the
sample is packed into a flat DSC pan.
The dimension of the sample is measured by
TMA in millimeters.
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Experimental Conditions
The TMA is operated under the following
conditions and includes the heating rate at
10C /min, applied stress of 0.1 N; flat tip
quartz expansion probe with outer diameter
0.125 mm, gas purge nitrogen at 50 mL/min,
sample in a DSC pan and the probe is applied
onto the packed crystalline powder, and the
sample size in the DSC pan is 100 mgs.
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Calibration
Calibration of TMA is done using an Indium metal.
Calibrating an instrument with a metal when
pharmaceuticals are to be studied does not sound
appropriate.
To overcome this, an effort has been made to calibrate
TMA with pharmaceuticals.

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TMA Curve of Indium

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TMA Applications
TMA is used to obtain the melting
temperature, softening temperature, coefficient
of thermal expansion (CTE) and glass
transitions (Tg) of materials.

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DIFFERENTIAL THERMAL
ANALYSIS
Useful for investigation of solid-solid interactions.
Thermograms are obtained for pure drugs and for mixtures
using different ratios.
In absence of any interaction thermograms of mixture show
pattern corresponding to that of individual components.
But if interactions occur it is indicated in thermograms by
appearance of one/ more peaks corresponding to those
components.
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ROLE OF THERMAL ANALYSIS IN


PREFORMULAION
They are unique methods in the field of
polymer analysis & of high value for a solid
state analysis
- They finds wide application in
a) Study of complexation
b) Detection of impurity
c) Study of polymorphism
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APPLICATION OF THERMAL
ANALYSIS IN PREFORMULATION
Characterization of hydrates and solvates
Preformulation studies is to identify the ability
of drug to take up water and characterize the
state of this water.
TGA is useful for characterization of hydrates
& solvates.

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INNOVATION IN THERMAL
ANALYSIS
1) MULTIELEMENTAL SCANNING
THERMAL ANALYSIS (MESTA)
2) MICROTHERMAL ANALYSIS
3) MODULATED DSC
4) ROBOTIC SYSTEM
5) FAST SCAN DSC
6) DYNAMIC MECHANICAL ANALYSIS
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Limitations of Thermal Analysis


1) Low sensitivity for transitions involving small
energies.
2) Impurity consisting of molecules of same
size,shape,& character as those of the major
component are not detected by DSC.
3) TGA used to studies hydrates & moisture study
are not always reliable.
4) Thermal analysis are affected by number of
factors
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Thermal analysis capabilities

Thermal Phase Change


Glass Transition Temperature
Crystalline Melt Temperature
Endothermic Effects
Exothermic Effects
Flashpoint Testing
Linear Thermal Expansion
Thermal Stability
Thermal Formulation Stability
Oxidative Stability Studies
Flammability Testing of Materials
Microscopy of Thermal Processes
Thermal Analysis of a diverse range of materials

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Thermal Analysis
Characteristic:

Thermal properties:

Morphological change

Melting points, glass transition (Tg),


crystallinity, thermal history, nucleation,
enthalpy of fusion or re-crystallisation,
specific heat capacity (Cp)

Dimensional change

Coefficient of thermal expansion (CLTE),


shrinkage data, anisotropy due to fillers,
reinforcing materials, softening
temperatures

Viscoelastic properties

Stiffness and damping properties,


molecular phase interactions by
mechanical loss

Mass change

Thermal stability, thermal oxidative


stability, thermal transitions, solvent loss,
water / filler content, organic
ratios, inorganic ratios

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Thermal Analysis Instrument


Manufacturers

Perkin Elmer Thermal Analysis Systems

http://www.perkin-elmer.com/thermal/index.html

TA Instruments

http://www.tainst.com/

Mettler Toledo Thermal Analysis Systems

http://www.mt.com/

Rheometric Scientific

http://www.rheosci.com/

Haake

http://polysort.com/haake/

NETZSCH Instruments

http://www.netzsch.com/ta/

SETARAM Instruments

http://setaram.com/

Instrument Specialists, Inc.

http://www.instrument-specialists.com/
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Nanothermal Analysis
(Nano-TA)
A new technology nanothermal analysis (nano-TA),
which in conjunction with other techniques provides
a powerful analytical strategy for characterising nanoand micro-scale heterogeneity in the solid-state
properties of drugpolymer formulations.
Nanothermal analysis is an emerging localized
thermal analysis technique which combines the high
resolution imaging capabilities of atomic force
microscopy (AFM) with the ability to characterize the
thermal properties of materials .
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Nanothermal Analysis
(Nano-TA)
It offers significantly enhanced spatial resolution
compared with its predecessor, scanning thermal
microscopy.
In nano-TA the conventional silicon based AFM tip is
replaced by a specialized micro fabricated siliconbased probe with a miniature heater that has a
topographic spatial resolution of around 5 nm and a
thermal property measurement resolution of up to
20nm.
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Nanothermal Analysis
(Nano-TA)

Importantly this probe enables a surface to be studied with


the most widely applied AFM imaging mode, tapping
mode, enabling the analysis of softer samples, such as
polymers, without damage from the imaging probe.
As nano-TA can be used to map thermal properties during
imaging, or to carry out local thermal analysis (LTA) at
defined points on a surface.
LTA, where the probe is heated in a temperature cycle not
dissimilar to DSC whilst in contact with the sample, can
provide quantitative information on thermally induced
phase transitions.
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THANK YOU
Cell No: 00919742431000
E-mail: nanjwadebk@gmail.com

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OBJECTIVES
The main objective to introduce thermal
analysis and its applications at an entry level
in the pharmaceutical industry.
In the process, instruments were successfully
calibrated using pharmaceuticals.
Studying the behavior of pharmaceuticals by
different thermal analysis instruments, under
different conditions and then compare the
results was another objective.
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Thermal Analysis of Pharma


Materials
DSC,TG/DTA and TG/DTA-IR are often used for
characterisation of pharma materials.
DSC, alone or in combination with hot-stage
microscopy, is able to differentiate between different
polymorphic structures and, by using different
heating rates, can investigate the transformations
which occur during the polymorphic transformation.

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Thermal Analysis of Pharma


Materials
By
using
appropriate
heating
rates,
polymorphic purity can be determined, and can
involve heating rates up to 750C/min.
TGA is often used to measure residual solvents
and moisture, but can also be used to determine
solubility of pharma materials in solvents.
Analysis of pharma materials is probably the
largest area of application for thermal analysis.
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Thermal Analysis of Polymers


Polymers represent another large area in which
thermal analysis finds strong applications.
Thermoplastic polymers are commonly found in
everyday packaging and household items, but for the
analysis of the raw materials, effects of the many
additive used (including stabilisers and colours) and
fine-tuning of the moulding or extrusion processing
used can be achieved by using DSC.
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Thermal Analysis of Polymers


An example is oxidation induction time (OIT) by DSC which
can determine the amount of oxidation stabiliser present in a
thermoplastic (usually a polyolefin) polymer material.
Compositional analysis is often made using TGA, which can
separate fillers, polymer resin and other additives.
TGA can also give an indication of thermal stability and the
effects of additives such as flame retardants

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Thermal Analysis Methods Used in


Pharmaceutical
Even though most of the thermal analysis methods can
handle samples such as solids, semi-solids or liquids, an
evaluation of the contemporary literature would recommend
that solid-state portrayal could apply to most of the
pharmaceutical research applications.
Common applications used in thermal analysis incorporate the
categorization of the physicochemical attributes of crystalline
solids and the discovery and classification of polymorphic
forms.

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Thermal Analysis Methods Used in


Pharmaceutical
With the usage of solid dispersions and other polymeric dosage
forms in an increased manner, thermal analytical techniques
have been required more frequently to assist researchers with
the characterization and development.
Thermal analytical techniques are also utilized for studying the
results of lyophilization and developing optimal lyophilization
formulations and cycles.
Differential techniques are also used to review kinetics in the
solid-state, which includes accelerated stability, decomposition
and the aging effects on various formulations.
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Thermal Analysis Methods Used in


Pharmaceutical
If any laboratory - be it a pharmaceutical
industry or an academic research institute,
needs to purchase no more than one piece of
thermal analysis equipment, it is most likely to
be a DSC.
These instruments can be purchased from
numerous manufacturers with wide options of
price and applications.
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Thermal Analysis Methods Used in


Pharmaceutical
The DSC concept was formerly derived from earlier
DTA instruments. While DTA measures the difference
in temperature, DSC grants for the measurement of a
modification in enthalpy.
The International Confederation for Thermal
Analysis and Calorimetry (ICTAC) has defined DSC
as a technique where the heat flow rate difference
into a sample and reference material is measured."
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Thermal Analysis Methods Used in


Pharmaceutical
Two types of basic DSC instruments are available today
commercially - heat-flux DSC (hf-DSC) and power
compensation DSC (pc-DSC).
As per the latest audits, both the instruments are extremely
versatile and very comparable.
While engaging different techniques to inspect the
measurement, both the types of instruments are employed to
measure heat flow and this seems to be certified as DSC under
the ICTAC (International Confederation for Thermal Analysis
and Calorimetry) definition.
Originally the term heat-flux DSC was used to illustrate
quantitative DTA instruments.
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Thermal Analysis Methods Used in


Pharmaceutical
Now, it is universally denoted as a DSC method.
This progress was an improvement over DTA, which allowed
for a measurement in the changes in heat flow as compared to
only temperature.
This was reached by the accumulation of a second sequence of
thermocouples in order to measure the temperature of a
furnace and a heat sensitive plate.
By measuring the capacity of the heat sensitive plate as a task
of temperature during the process of manufacturing, an
estimation of the enthalpy of transition can be prepared by the
incremental temperature fluctuation.
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Thermal Analysis Methods Used in


Pharmaceutical
Power-compensation DSC is different from hf-DSC in
operating principle as well as in basic instrument
design.
Just as the name can notes, pc-DSC measures the
change in power or energy essential to preserve the
sample and references material at the identical
temperature all through the heating or cooling cycle.
This is carried out through an instrument design
which is different than that normally found in hf-DSC
instruments.
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Thermal Analysis Methods Used in


Pharmaceutical
Two individual heaters are used with pc-DSC to
control the flow of heat to the sample and reference
holders.
Individual resistance sensors are positioned within
each holder and temperature is measured at the base of
each.
When a phase change takes place in a in thermal
analysis and a temperature difference is observed
between the sample and reference, energy is removed
or supplied until the temperature difference is lower
than the threshold.
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Techniques and Applications in the


Pharmaceutical Sciences
The current field of thermal analysis is both diverse and
dynamic.
Although not a new field, more advanced instrumentation,
techniques and applications are constantly appearing on the
market and in the literature.
Theoretically, almost any substance whether solid, semi-solid
or liquid can be analyzed and characterized with thermal
analytical techniques.
Common materials include foods, pharmaceuticals, electronic
materials, polymers, ceramics, organic and inorganic
compounds, even biological organisms.
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Techniques and Applications in the


Pharmaceutical Sciences

In theory, all thermal analytical techniques simply


measure the change of a specific property of a
material as a function of temperature.
This in turn allows researchers access to information
regarding macroscopic theories of matter including,
equilibrium and irreversible thermodynamics and
kinetics.
While numerous techniques are available, the primary
differences in the techniques are the properties of the
material being studied.
02 January 2013

Goa College of Pharmacy, Goa.

194

Techniques and Applications in the


Pharmaceutical Sciences
In the pharmaceutical sciences, only a handful of the
techniques are commonly employed but the information
gained and phenomena that can be explored are countless.
The primary workhorses in the pharmaceutical sciences
include,
differential
scanning
calorimetry
(DSC),
thermogravimetric analysis (TGA), differential thermal
analysis (DTA) and thermomechnical analysis (TMA).
Admittedly, as the needs of the researcher change and new
materials are identified in formulation development, less
commonly used techniques are being utilized and developed
resulting in a very dynamic and exciting field of research.
02 January 2013

Goa College of Pharmacy, Goa.

195

Techniques and Applications in the


Pharmaceutical Sciences
The first will be thermal analytical methods
commonly used in the pharmaceutical sciences,
primarily DSC (including several specialized
techniques), TGA and TMA.
The second will focus on applications in the
pharmaceutical sciences including solid-state
characterization of polymorphism, solid dispersions
and polymeric dosage forms.
02 January 2013

Goa College of Pharmacy, Goa.

196