Thermal Analysis Methods in Pharma

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
02 January 2013 Goa College of Pharmacy, Goa. 1

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.

ABBREVIATIONS
• ICTAC - International Confederation for Thermal Analysis and
Calorimetry
• DEA- Dielectric Analysis
• DSC- Differential Scanning Calorimetry
• TGA- Thermogravimetric Analysis
• TMA- Thermomechanical Analysis
• ÄHf- Heat of Fusion
• Tm - Melting Temperature, extrapolated endothermic onset temperature
• Tp- Peak Melting endothermic Temperature
• ÄHc-Heat of exothermic Crystallization
• Tc- Crystallization Temperature, extrapolated exothermic onset
temperature
• Tcp- Peak exothermic Crystallization temperature
• ÄHv - Heat of endothermic Vaporization
• Tv - Vaporization temperature, extrapolated endothermic onset
temperature
• Tvp - Peak Vaporization temperature
• January
02 Tg -Glass
2013 transition temperature
Goa College of Pharmacy, Goa. 3
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

Common Thermal Analysis Methods and the Properties Measured

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.
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.

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.
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.

Basic Principles of Thermal Analysis

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.

Thermal Analysis of Pharma
Materials
• By using appropriate heating rates,
polymorphic purity can be determined, and
can involve heating rates up to 750°C/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.
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.

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

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.

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.
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.

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."

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.
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.

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.
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.
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.

• 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.
• 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.

• 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.

Thermal Analysis Techniques
IUPAC: International Union of Pure and Applied Chemistry

Thermal Analysis
• Differential Scanning • Thermal Gravimetric
Calorimetry (DSC) Analysis (TGA)
– Measure heat absorbed or – Measure change in
liberated during heating or weight during heating or
cooling
cooling
• Differential Thermal • Thermomechanical
Analysis (DTA) Analysis (TMA)
• They are use for thermal – Measure change in
investigation where thermal dimensions during
change can be observed and heating or cooling
characterised
THERMOGAVIMETRIC ANALYSIS
(TGA)

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.

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’.
Thermogravimetric Analysis
(TGA)
• The furnace can raise the temperature as high
as 1000°C 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.

(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

Differential Thermal Analysis

(TGA)

Interpretation of TG and DTG curves
i. 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.

TGA Curve of Calcium Oxalate

Examples of TGA Curves

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.

Experimental Conditions
• Heating Rate
• Purge gas

Experimental Conditions -Heating Rate
• Samples are heated at a rate of 10 or 20°C/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.

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.
Miscellaneous

Calibration
• Blank test
• Calibration of mass changes
• Calibration of temperature

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
10°C 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.
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.
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.
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.

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.

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.
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 1000°C.
• A typical example is the TGA of calcium oxalate hydrate,

heated to 1000°C which shows three steps in its
decomposition curve.
• The weight loss data is recorded every half second

throughout the run time.

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.
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 125°C.
• 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.

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 50°C below those
temperatures.
TGA+Spectroscopy/Chromatography
Combination
Gases, vapors
TGA IR or MS or GC

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.

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.
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.

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

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
Summary of Pharmaceutically Relevant
information Derivation from TGA Analysis

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)
DIFFERENTIAL SCANNING CALORIMETRY
(DSC)

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.

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.

Differential Scanning Calorimetry (DSC)
Exothermal dQ/dT
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

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)

Sample containers and sampling

Differential Scanning Calorimeter

Conventional DSC
Sample Empty
Metal Metal Metal Metal

1 2 1 2
Sample Reference
Temperature Temperature
Temperature
Difference =
Heat Flow

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 500°C/min
– Mimic processing conditions
• StepScan DSC
– Short dynamic and isothermal scan steps
– Separate reversible and irreversible effects

Variants of DSC

Differential Scanning Calorimetry
(DSC)

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

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)
DSC- Principle
• Heat Flow Rate is expressed in a variety of units
which can also be normalized for the weight of
sample used

Principle Of DSC

Typical DSC Curve

DSC Thermogram
Oxidation
Heat Flow -> exothermic
Crystallisation Cross-Linking
(Cure)
Glass
Transition
Melting
Temperature
6
Transitions in a DSC Curve

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
DSC

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 sample–atmosphere 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).

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 ΔT between the sample and reference.
Heat Flux Type DSC

Heat Flux and DSC

Heat Flux Type DSC

Power Compensation
• Small individual furnaces use different amounts of power
to maintain a constant ΔT 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.
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.

Power Compensation DSC Cell
Design

Power Compensated DSC

Principles of DSC Analysis

Sample Preparation
• Sample Shape
• Sample Pans
• Sample Weight

Sample Preparation

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.
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.

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.

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.

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.
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%.

• Start Temperature
• End Temperature
• Reference Pan
• Heating Rate

Start Temperature
• Generally, the baseline should have 2 minutes
to completely stabilize prior to the transition of
interest.
• Therefore, at 10°C/min heating rate the run

should start at least 20°C below the transition
onset temperature.

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.

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.

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.

Heating Rate

Effects of heating rate
• DSC curves of Acetophenetidin and
Phenacetin.
• The Acetophenetidin DSC at 0.5°C/min and

10°C/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.
DSC curves of Acetophenetidin

• 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 20°C/min yielded
the same Tm of 135°C ±1°C.

DSC curves of Phenacetin

• If you use multiple heating rates then start with 1.0
and 10°C/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.
Effect of Heating Rate

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.

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.

Purge Gases

Summary of DSC experimental
conditions

Purity by DSC

Purity Determination

Summary of Pharmaceutically Relevant
Information Derived from DSC Analysis

Typical Features of a DSC Trace

Melting Point

Melting Process by DSC

Melting
Thermogram
• Negative peak on
thermogram
• Ordered to disordered
Melting
transition
dH/dt, mJ/s
• Tm, melting temperature
• Melting happens to
crystalline polymers; Tm
Glassing happens to
amorphous polymers
Temperature, K
Polymorphic Forms

Pseudopolymorphism

Amorphous Material

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 step-
wise increases in the heat capacity (Cp) of the sample.

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 Tg’s 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.

Modulated DSC (MDSC)

Modulated Temperature DSC
(MTDSC)

MDSC for Polymorph
Characterization

Variants of MTDSC

Example of a MTDSC Curve

Fast Scan DSC, Rapid Scanning DSC

Fast Scan DSC, Rapid Scanning DSC

‘Hyper’ DSC

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
156.7°C and the observed in calibration is 157.4°C.
• It is 0.7°C high and the instrument values must be
adjusted down to accommodate the true melting
temperature.
DSC Calibration curve of indium

DSC – Applications
• Glass Transition Temperature (Tg)
• Glass Transition Size (ΔCp)
• Crystallization temperature (Tc)
• Crystallinity (based on J/g and adjusted to %)
• Polymorphic Transitions.

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.
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.
Glass Transition
Thermogram
• Step in thermogram
• Transition from
disordered solid to
liquid
dH/dt, mJ/s
Glass transition
• Observed in glassy
solids, e.g., polymers Tg
• Tg glass transition
temperature
Temperature, K
Glass Transition Size (ΔCp)
• The ΔCp 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.

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 50°C
super cooling temperature while indium melts and
crystallizes at the same temperature or super cooling
is zero °C

Crystallization
Thermogram
• Sharp positive peak
• Disordered to ordered
transition Crystallization
dH/dt, mJ/s
• Material can crystallize!
• Observed in glassy
solids, e.g., polymers Tc
• Tc crystallization
temperature
Temperature, K
Analysis
Crystallization
• Sharp positive peak
• Disordered to ordered
dH/dt, mJ/s
transition
• Observed in glassy Tc
solids, e.g., polymers
• Tc crystallization
temperature
Temperature, K
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.
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
10°C/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
DSC curves of Sulfanilamide
Polymorphs

DSC of Polymorphs of Tolbutamide:
Tolbutamide A (Form 1) and B (Form 3)

SEM of Tolbutamide polymorphs

Typical Features of a DSC Trace
(Polymorphic System)

Polymorph Screening and
Identification

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

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
• Δ 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
• Δ Hc Energy Released (joules/gram)

– Amount of energy a sample releases when crystallizing

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
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

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.

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
Typical TGA and DSC Results
for Various Transitions

Lactose monohydrate

Hyphenated Thermal Equipment

Temperature Scales

Maxwell-Boltzmann Distribution

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

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.

Characterization for Pharma

Physical Forms of Solids

Importance of Solid State Forms in Pharma

Compatibility Studies

DSC in Polymer Analysis
Main transitions which can be studied by DSC:
• Melting
• Freezing
• Glass transition

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
THERMOMECHANICAL ANALYSIS
(TMA)

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.

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

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.

(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.
Types of TMA probes
and resulting measured properties

(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.

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.
• The TMA is operated under the following
conditions and includes the heating rate at
10°C /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.

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.

TMA Curve of Indium

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

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.

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

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.

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

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
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

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
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/

‘Nanothermal Analysis’
(Nano-TA)
• A new technology ‘nanothermal analysis’ (nano-TA),
which in conjunction with other techniques provides
a powerful analytical strategy for characterising nano-
and micro-scale heterogeneity in the solid-state
properties of drug–polymer 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 .

(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 silicon-
based 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.
(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.
THANK YOU
Cell No: 00919742431000
E-mail: nanjwadebk@gmail.com

Thermal Analysis Methods in Pharma

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Thermal Analysis

Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D

02 January 2013 Goa College of Pharmacy, Goa. 1

• Thermal analysis is a branch of materials

• Several methods are commonly used – these

02 January 2013 Goa College of Pharmacy, Goa. 2

02 January 2013 Goa College of Pharmacy, Goa. 4

02 January 2013 Goa College of Pharmacy, Goa. 5

• The substance referred to here includes reaction

• Physical properties include mass, temperature,

• It is also applied in wide fields, including polymer,

02 January 2013 Goa College of Pharmacy, Goa. 7

• This teaching tool describes the introductory use

02 January 2013 Goa College of Pharmacy, Goa. 9

02 January 2013 Goa College of Pharmacy, Goa. 10

• DSC, alone or in combination with hot-stage

02 January 2013 Goa College of Pharmacy, Goa. 11

• Thermoplastic polymers are commonly found in

02 January 2013 Goa College of Pharmacy, Goa. 13

• Compositional analysis is often made using TGA, which can

• TGA can also give an indication of thermal stability and the

02 January 2013 Goa College of Pharmacy, Goa. 14

• Common applications used in thermal analysis incorporate the

02 January 2013 Goa College of Pharmacy, Goa. 15

• Thermal analytical techniques are also utilized for studying

• Differential techniques are also used to review kinetics in the

02 January 2013 Goa College of Pharmacy, Goa. 17

• ‘The International Confederation for Thermal

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• The second will focus on applications in the

02 January 2013 Goa College of Pharmacy, Goa. 26

IUPAC: International Union of Pure and Applied Chemistry

02 January 2013 Goa College of Pharmacy, Goa. 29

• A TGA consists of three major parts a furnace,

02 January 2013 Goa College of Pharmacy, Goa. 30

• Instrument: Instrument used for

02 January 2013 Goa College of Pharmacy, Goa. 32

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• Samples are heated at a rate of 10 or 20°C/min in

02 January 2013 Goa College of Pharmacy, Goa. 41

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• By this blank test, the general condition of the apparatus

• The TGA curve can drift slightly as the temperature is

• This is owing to the changes in the buoyancy and

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• A typical example is the TGA of calcium oxalate hydrate,

• The weight loss data is recorded every half second

02 January 2013 Goa College of Pharmacy, Goa. 51

• Decomposition can have multiple stages (weight losses)

02 January 2013 Goa College of Pharmacy, Goa. 53