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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
02 January 2013 1Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 2
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
• Tg -Glass transition temperature02 January 2013 3Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 4
Common Thermal Analysis Methods and the Properties Measured
02 January 2013 5Goa College of Pharmacy, Goa.
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.
02 January 2013 6Goa College of Pharmacy, Goa.
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.
02 January 2013 7Goa College of Pharmacy, Goa.
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.
02 January 2013 8Goa College of Pharmacy, Goa.
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.
02 January 2013 9Goa College of Pharmacy, Goa.
Basic Principles of Thermal Analysis
02 January 2013 10Goa College of Pharmacy, Goa.
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.
02 January 2013 11Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 12
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.
02 January 2013 13Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 14
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.
02 January 2013 15Goa College of Pharmacy, Goa.
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.
02 January 2013 16Goa College of Pharmacy, Goa.
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.
02 January 2013 17Goa College of Pharmacy, Goa.
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."
02 January 2013 18Goa College of Pharmacy, Goa.
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.
02 January 2013 19Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 20
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.
02 January 2013 21Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 22
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.
02 January 2013 23Goa College of Pharmacy, Goa.
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. 24
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 25Goa College of Pharmacy, Goa.
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. 26
Thermal Analysis Techniques
02 January 2013 27Goa College of Pharmacy, Goa.
IUPAC: International Union of Pure and Applied Chemistry
Thermal Analysis
• Differential Scanning
Calorimetry (DSC)
– Measure heat absorbed or
liberated during heating or
cooling
• Thermal Gravimetric
Analysis (TGA)
– Measure change in
weight during heating or
cooling
• Thermomechanical
Analysis (TMA)
– Measure change in
dimensions during
heating or cooling
• Differential Thermal
Analysis (DTA)
• They are use for thermal
investigation where thermal
change can be observed and
characterised
02 January 2013 28Goa College of Pharmacy, Goa.
THERMOGAVIMETRIC ANALYSIS
(TGA)
02 January 2013 29Goa College of Pharmacy, Goa.
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.
02 January 2013 30Goa College of Pharmacy, Goa.
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’.
02 January 2013 31Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 32
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
02 January 2013 33Goa College of Pharmacy, Goa.
Differential Thermal Analysis
02 January 2013 34Goa College of Pharmacy, Goa.
Thermogravimetric Analysis
(TGA)
02 January 2013 35Goa College of Pharmacy, Goa.
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.
02 January 2013 36Goa College of Pharmacy, Goa.
TGA Curve of Calcium Oxalate
02 January 2013 37Goa College of Pharmacy, Goa.
Examples of TGA Curves
02 January 2013 38Goa College of Pharmacy, Goa.
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.
02 January 2013 39Goa College of Pharmacy, Goa.
Experimental Conditions
• Heating Rate
• Purge gas
02 January 2013 40Goa College of Pharmacy, Goa.
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.
02 January 2013 41Goa College of Pharmacy, Goa.
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.
02 January 2013 42Goa College of Pharmacy, Goa.
Miscellaneous
02 January 2013 43Goa College of Pharmacy, Goa.
Calibration
• Blank test
• Calibration of mass changes
• Calibration of temperature
02 January 2013 44Goa College of Pharmacy, Goa.
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.
02 January 2013 45Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 46
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.
02 January 2013 47Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 48
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.
02 January 2013 49Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 50
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 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.
02 January 2013 51Goa College of Pharmacy, Goa.
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.
02 January 2013 52Goa College of Pharmacy, Goa.
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.
02 January 2013 53Goa College of Pharmacy, Goa.
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.
02 January 2013 54Goa College of Pharmacy, Goa.
TGA+Spectroscopy/Chromatography
Combination
TGA IR or MS or GC
Gases, vapors
02 January 2013 55Goa College of Pharmacy, Goa.
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.
02 January 2013 56Goa College of Pharmacy, Goa.
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.
02 January 2013 57Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 58
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
02 January 2013 59Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 60
Summary of Pharmaceutically Relevant
information Derivation from TGA Analysis
02 January 2013 61Goa College of Pharmacy, Goa.
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)
02 January 2013 62Goa College of Pharmacy, Goa.
DIFFERENTIAL SCANNING CALORIMETRY
(DSC)
02 January 2013 63Goa College of Pharmacy, Goa.
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.
02 January 2013 64Goa College of Pharmacy, Goa.
Definitions
• A calorimetermeasures 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.
• Endothermicheat flows into the sample.
• Exothermicheat flows out of the sample.
02 January 2013 65Goa College of Pharmacy, Goa.
Differential Scanning Calorimetry (DSC)
ExothermaldQ/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
02 January 2013 66Goa College of Pharmacy, Goa.
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)
02 January 2013 67Goa College of Pharmacy, Goa.
Sample containers and sampling
02 January 2013 68Goa College of Pharmacy, Goa.
Differential Scanning Calorimeter
02 January 2013 69Goa College of Pharmacy, Goa.
Conventional DSC
Metal
1
Metal
2
Metal
1
Metal
2
Sample Empty
Sample
Temperature
Reference
Temperature
Temperature
Difference =
Heat Flow
02 January 2013 70Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 71
Variants of DSC
02 January 2013 72Goa College of Pharmacy, Goa.
Differential Scanning Calorimetry
(DSC)
02 January 2013 73Goa College of Pharmacy, Goa.
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
02 January 2013 74Goa College of Pharmacy, Goa.
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)
02 January 2013 75Goa College of Pharmacy, Goa.
DSC- Principle
• Heat Flow Rate is expressed in a variety of units
which can also be normalized for the weight of
sample used
02 January 2013 76Goa College of Pharmacy, Goa.
Principle Of DSC
02 January 2013 Goa College of Pharmacy, Goa. 77
Typical DSC Curve
02 January 2013 Goa College of Pharmacy, Goa. 78
6
DSC Thermogram
Temperature
HeatFlow->exothermic
Glass
Transition
Crystallisation
Melting
Cross-Linking
(Cure)
Oxidation
02 January 2013 79Goa College of Pharmacy, Goa.
Transitions in a DSC Curve
02 January 2013 80Goa College of Pharmacy, Goa.
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
02 January 2013 81Goa College of Pharmacy, Goa.
DSC
02 January 2013 Goa College of Pharmacy, Goa. 82
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).
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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 ΔT between the sample and reference.
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Heat Flux Type DSC
02 January 2013 Goa College of Pharmacy, Goa. 85
Heat Flux and DSC
02 January 2013 86Goa College of Pharmacy, Goa.
Heat Flux Type DSC
02 January 2013 Goa College of Pharmacy, Goa. 87
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.
02 January 2013 88Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 89
Power Compensation DSC Cell
Design
02 January 2013 90Goa College of Pharmacy, Goa.
Power Compensated DSC
02 January 2013 91Goa College of Pharmacy, Goa.
Principles of DSC Analysis
02 January 2013 92Goa College of Pharmacy, Goa.
Sample Preparation
• Sample Shape
• Sample Pans
• Sample Weight
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Sample Preparation
02 January 2013 94Goa College of Pharmacy, Goa.
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.
02 January 2013 95Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 96
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.
02 January 2013 97Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 98
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.
02 January 2013 99Goa College of Pharmacy, Goa.
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 10°C/min heating rate the run
should start at least 20°C 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.
02 January 2013 103Goa College of Pharmacy, Goa.
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.
02 January 2013 104Goa College of Pharmacy, Goa.
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
02 January 2013 106Goa College of Pharmacy, Goa.
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.
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DSC curves of Acetophenetidin
02 January 2013 108Goa College of Pharmacy, Goa.
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 20°C/min yielded
the same Tm of 135°C ±1°C.
02 January 2013 Goa College of Pharmacy, Goa. 109
DSC curves of Phenacetin
02 January 2013 110Goa College of Pharmacy, Goa.
Effects of heating rate
• 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.
02 January 2013 111Goa College of Pharmacy, Goa.
Effect of Heating Rate
02 January 2013 112Goa College of Pharmacy, Goa.
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.
02 January 2013 113Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 114
Purge Gases
02 January 2013 115Goa College of Pharmacy, Goa.
Summary of DSC experimental
conditions
02 January 2013 116Goa College of Pharmacy, Goa.
Purity by DSC
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Purity Determination
02 January 2013 118Goa College of Pharmacy, Goa.
Summary of Pharmaceutically Relevant
Information Derived from DSC Analysis
02 January 2013 119Goa College of Pharmacy, Goa.
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
• Negative peak on
thermogram
• Ordered to disordered
transition
• Tm, melting temperature
• Melting happens to
crystalline polymers;
Glassing happens to
amorphous polymers
Temperature, K
Thermogram
dH/dt,mJ/s
Melting
Tm
02 January 2013 123Goa College of Pharmacy, Goa.
Polymorphic Forms
02 January 2013 124Goa College of Pharmacy, Goa.
Pseudopolymorphism
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Amorphous Material
02 January 2013 126Goa College of Pharmacy, Goa.
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.
02 January 2013 127Goa College of Pharmacy, Goa.
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.
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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
02 January 2013 132Goa College of Pharmacy, Goa.
Example of a MTDSC Curve
02 January 2013 133Goa College of Pharmacy, Goa.
Fast Scan DSC, Rapid Scanning DSC
02 January 2013 134Goa College of Pharmacy, Goa.
Fast Scan DSC, Rapid Scanning DSC
02 January 2013 135Goa College of Pharmacy, Goa.
‘Hyper’ DSC
02 January 2013 136Goa College of Pharmacy, Goa.
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.
02 January 2013 137Goa College of Pharmacy, Goa.
DSC Calibration curve of indium
02 January 2013 138Goa College of Pharmacy, Goa.
DSC – Applications
• Glass Transition Temperature (Tg)
• Glass Transition Size (ΔCp)
• Crystallization temperature (Tc)
• Crystallinity (based on J/g and adjusted to %)
• Polymorphic Transitions.
02 January 2013 139Goa College of Pharmacy, Goa.
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.
02 January 2013 140Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 141
Glass Transition
• Step in thermogram
• Transition from
disordered solid to
liquid
• Observed in glassy
solids, e.g., polymers
• Tg glass transition
temperature
Temperature, K
Thermogram
dH/dt,mJ/s
Glass transition
Tg
02 January 2013 142Goa College of Pharmacy, Goa.
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.
02 January 2013 143Goa College of Pharmacy, Goa.
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
02 January 2013 144Goa College of Pharmacy, Goa.
Crystallization
• Sharp positive peak
• Disordered to ordered
transition
• Material can crystallize!
• Observed in glassy
solids, e.g., polymers
• Tc crystallization
temperature
Temperature, K
Thermogram
dH/dt,mJ/s
Crystallization
Tc
02 January 2013 145Goa College of Pharmacy, Goa.
Analysis
• Sharp positive peak
• Disordered to ordered
transition
• Observed in glassy
solids, e.g., polymers
• Tc crystallization
temperature
Temperature, K
dH/dt,mJ/s
Crystallization
Tc
02 January 2013 146Goa College of Pharmacy, Goa.
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.
02 January 2013 147Goa College of Pharmacy, Goa.
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
02 January 2013 148Goa College of Pharmacy, Goa.
DSC curves of Sulfanilamide
Polymorphs
02 January 2013 149Goa College of Pharmacy, Goa.
DSC of Polymorphs of Tolbutamide:
Tolbutamide A (Form 1) and B (Form 3)
02 January 2013 150Goa College of Pharmacy, Goa.
SEM of Tolbutamide polymorphs
02 January 2013 Goa College of Pharmacy, Goa. 151
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
02 January 2013 154Goa College of Pharmacy, Goa.
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
02 January 2013 155Goa College of Pharmacy, Goa.
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
02 January 2013 156Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 157
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.
02 January 2013 158Goa College of Pharmacy, Goa.
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
02 January 2013 159Goa College of Pharmacy, Goa.
Typical TGA and DSC Results
for Various Transitions
02 January 2013 Goa College of Pharmacy, Goa. 160
Lactose monohydrate
02 January 2013 161Goa College of Pharmacy, Goa.
Hyphenated Thermal Equipment
02 January 2013 162Goa College of Pharmacy, Goa.
Temperature Scales
02 January 2013 163Goa College of Pharmacy, Goa.
Maxwell-Boltzmann Distribution
02 January 2013 164Goa College of Pharmacy, Goa.
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
02 January 2013 Goa College of Pharmacy, Goa. 165
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
02 January 2013 167Goa College of Pharmacy, Goa.
Physical Forms of Solids
02 January 2013 168Goa College of Pharmacy, Goa.
Importance of Solid State Forms in Pharma
02 January 2013 169Goa College of Pharmacy, Goa.
Compatibility Studies
02 January 2013 170Goa College of Pharmacy, Goa.
DSC in Polymer Analysis
Main transitions which can be studied by DSC:
• Melting
• Freezing
• Glass transition
02 January 2013 171Goa College of Pharmacy, Goa.
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
02 January 2013 172Goa College of Pharmacy, Goa.
THERMOMECHANICAL ANALYSIS
(TMA)
02 January 2013 173Goa College of Pharmacy, Goa.
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.
02 January 2013 174Goa College of Pharmacy, Goa.
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
02 January 2013 175Goa College of Pharmacy, Goa.
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.
02 January 2013 176Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 177
Types of TMA probes
and resulting measured properties
02 January 2013 178Goa College of Pharmacy, Goa.
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.
02 January 2013 179Goa College of Pharmacy, Goa.
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.
02 January 2013 180Goa College of Pharmacy, Goa.
Experimental Conditions
• 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.
02 January 2013 181Goa College of Pharmacy, Goa.
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.
02 January 2013 182Goa College of Pharmacy, Goa.
TMA Curve of Indium
02 January 2013 183Goa College of Pharmacy, Goa.
TMA Applications
• TMA is used to obtain the melting
temperature, softening temperature, coefficient
of thermal expansion (CTE) and glass
transitions (Tg) of materials.
02 January 2013 184Goa College of Pharmacy, Goa.
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.
02 January 2013 Goa College of Pharmacy, Goa. 185
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
02 January 2013 Goa College of Pharmacy, Goa. 186
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.
02 January 2013 187Goa College of Pharmacy, Goa.
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
02 January 2013 188Goa College of Pharmacy, Goa.
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
02 January 2013 189Goa College of Pharmacy, Goa.
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
02 January 2013 190Goa College of Pharmacy, Goa.
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
02 January 2013 191Goa College of Pharmacy, Goa.
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/
02 January 2013 192Goa College of Pharmacy, Goa.
‘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 .
02 January 2013 193Goa College of Pharmacy, Goa.
‘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 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.
02 January 2013 Goa College of Pharmacy, Goa. 194
‘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.
02 January 2013 Goa College of Pharmacy, Goa. 195
THANK YOU
02 January 2013 196Goa College of Pharmacy, Goa.
Cell No: 00919742431000
E-mail: nanjwadebk@gmail.com

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Thermal analysis

  • 1. 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 1Goa College of Pharmacy, Goa.
  • 2. 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. 02 January 2013 Goa College of Pharmacy, Goa. 2
  • 3. 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 • Tg -Glass transition temperature02 January 2013 3Goa College of Pharmacy, Goa.
  • 4. 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 02 January 2013 Goa College of Pharmacy, Goa. 4
  • 5. Common Thermal Analysis Methods and the Properties Measured 02 January 2013 5Goa College of Pharmacy, Goa.
  • 6. 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. 02 January 2013 6Goa College of Pharmacy, Goa.
  • 7. 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. 02 January 2013 7Goa College of Pharmacy, Goa.
  • 8. 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. 02 January 2013 8Goa College of Pharmacy, Goa.
  • 9. 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. 02 January 2013 9Goa College of Pharmacy, Goa.
  • 10. Basic Principles of Thermal Analysis 02 January 2013 10Goa College of Pharmacy, Goa.
  • 11. 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. 02 January 2013 11Goa College of Pharmacy, Goa.
  • 12. 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. 02 January 2013 Goa College of Pharmacy, Goa. 12
  • 13. 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. 02 January 2013 13Goa College of Pharmacy, Goa.
  • 14. 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 02 January 2013 Goa College of Pharmacy, Goa. 14
  • 15. 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. 02 January 2013 15Goa College of Pharmacy, Goa.
  • 16. 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. 02 January 2013 16Goa College of Pharmacy, Goa.
  • 17. 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. 02 January 2013 17Goa College of Pharmacy, Goa.
  • 18. 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." 02 January 2013 18Goa College of Pharmacy, Goa.
  • 19. 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. 02 January 2013 19Goa College of Pharmacy, Goa.
  • 20. 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. 02 January 2013 Goa College of Pharmacy, Goa. 20
  • 21. 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. 02 January 2013 21Goa College of Pharmacy, Goa.
  • 22. 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. 02 January 2013 Goa College of Pharmacy, Goa. 22
  • 23. 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. 02 January 2013 23Goa College of Pharmacy, Goa.
  • 24. 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. 24
  • 25. 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 25Goa College of Pharmacy, Goa.
  • 26. 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. 26
  • 27. Thermal Analysis Techniques 02 January 2013 27Goa College of Pharmacy, Goa. IUPAC: International Union of Pure and Applied Chemistry
  • 28. Thermal Analysis • Differential Scanning Calorimetry (DSC) – Measure heat absorbed or liberated during heating or cooling • Thermal Gravimetric Analysis (TGA) – Measure change in weight during heating or cooling • Thermomechanical Analysis (TMA) – Measure change in dimensions during heating or cooling • Differential Thermal Analysis (DTA) • They are use for thermal investigation where thermal change can be observed and characterised 02 January 2013 28Goa College of Pharmacy, Goa.
  • 29. THERMOGAVIMETRIC ANALYSIS (TGA) 02 January 2013 29Goa College of Pharmacy, Goa.
  • 30. 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. 02 January 2013 30Goa College of Pharmacy, Goa.
  • 31. 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’. 02 January 2013 31Goa College of Pharmacy, Goa.
  • 32. 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. 02 January 2013 Goa College of Pharmacy, Goa. 32
  • 33. 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 02 January 2013 33Goa College of Pharmacy, Goa.
  • 34. Differential Thermal Analysis 02 January 2013 34Goa College of Pharmacy, Goa.
  • 35. Thermogravimetric Analysis (TGA) 02 January 2013 35Goa College of Pharmacy, Goa.
  • 36. 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. 02 January 2013 36Goa College of Pharmacy, Goa.
  • 37. TGA Curve of Calcium Oxalate 02 January 2013 37Goa College of Pharmacy, Goa.
  • 38. Examples of TGA Curves 02 January 2013 38Goa College of Pharmacy, Goa.
  • 39. 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. 02 January 2013 39Goa College of Pharmacy, Goa.
  • 40. Experimental Conditions • Heating Rate • Purge gas 02 January 2013 40Goa College of Pharmacy, Goa.
  • 41. 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. 02 January 2013 41Goa College of Pharmacy, Goa.
  • 42. 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. 02 January 2013 42Goa College of Pharmacy, Goa.
  • 43. Miscellaneous 02 January 2013 43Goa College of Pharmacy, Goa.
  • 44. Calibration • Blank test • Calibration of mass changes • Calibration of temperature 02 January 2013 44Goa College of Pharmacy, Goa.
  • 45. 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. 02 January 2013 45Goa College of Pharmacy, Goa.
  • 46. 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. 02 January 2013 Goa College of Pharmacy, Goa. 46
  • 47. 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. 02 January 2013 47Goa College of Pharmacy, Goa.
  • 48. 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. 02 January 2013 Goa College of Pharmacy, Goa. 48
  • 49. 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. 02 January 2013 49Goa College of Pharmacy, Goa.
  • 50. 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. 02 January 2013 Goa College of Pharmacy, Goa. 50
  • 51. 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 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. 02 January 2013 51Goa College of Pharmacy, Goa.
  • 52. 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. 02 January 2013 52Goa College of Pharmacy, Goa.
  • 53. 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. 02 January 2013 53Goa College of Pharmacy, Goa.
  • 54. 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. 02 January 2013 54Goa College of Pharmacy, Goa.
  • 55. TGA+Spectroscopy/Chromatography Combination TGA IR or MS or GC Gases, vapors 02 January 2013 55Goa College of Pharmacy, Goa.
  • 56. 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. 02 January 2013 56Goa College of Pharmacy, Goa.
  • 57. 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. 02 January 2013 57Goa College of Pharmacy, Goa.
  • 58. 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. 02 January 2013 Goa College of Pharmacy, Goa. 58
  • 59. 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 02 January 2013 59Goa College of Pharmacy, Goa.
  • 60. 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 02 January 2013 Goa College of Pharmacy, Goa. 60
  • 61. Summary of Pharmaceutically Relevant information Derivation from TGA Analysis 02 January 2013 61Goa College of Pharmacy, Goa.
  • 62. 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) 02 January 2013 62Goa College of Pharmacy, Goa.
  • 63. DIFFERENTIAL SCANNING CALORIMETRY (DSC) 02 January 2013 63Goa College of Pharmacy, Goa.
  • 64. 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. 02 January 2013 64Goa College of Pharmacy, Goa.
  • 65. Definitions • A calorimetermeasures 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. • Endothermicheat flows into the sample. • Exothermicheat flows out of the sample. 02 January 2013 65Goa College of Pharmacy, Goa.
  • 66. Differential Scanning Calorimetry (DSC) ExothermaldQ/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 02 January 2013 66Goa College of Pharmacy, Goa.
  • 67. 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) 02 January 2013 67Goa College of Pharmacy, Goa.
  • 68. Sample containers and sampling 02 January 2013 68Goa College of Pharmacy, Goa.
  • 69. Differential Scanning Calorimeter 02 January 2013 69Goa College of Pharmacy, Goa.
  • 71. 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 02 January 2013 Goa College of Pharmacy, Goa. 71
  • 72. Variants of DSC 02 January 2013 72Goa College of Pharmacy, Goa.
  • 73. Differential Scanning Calorimetry (DSC) 02 January 2013 73Goa College of Pharmacy, Goa.
  • 74. 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 02 January 2013 74Goa College of Pharmacy, Goa.
  • 75. 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) 02 January 2013 75Goa College of Pharmacy, Goa.
  • 76. DSC- Principle • Heat Flow Rate is expressed in a variety of units which can also be normalized for the weight of sample used 02 January 2013 76Goa College of Pharmacy, Goa.
  • 77. Principle Of DSC 02 January 2013 Goa College of Pharmacy, Goa. 77
  • 78. Typical DSC Curve 02 January 2013 Goa College of Pharmacy, Goa. 78
  • 80. Transitions in a DSC Curve 02 January 2013 80Goa College of Pharmacy, Goa.
  • 81. 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 02 January 2013 81Goa College of Pharmacy, Goa.
  • 82. DSC 02 January 2013 Goa College of Pharmacy, Goa. 82
  • 83. 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). 02 January 2013 83Goa College of Pharmacy, Goa.
  • 84. 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. 02 January 2013 Goa College of Pharmacy, Goa. 84
  • 85. Heat Flux Type DSC 02 January 2013 Goa College of Pharmacy, Goa. 85
  • 86. Heat Flux and DSC 02 January 2013 86Goa College of Pharmacy, Goa.
  • 87. Heat Flux Type DSC 02 January 2013 Goa College of Pharmacy, Goa. 87
  • 88. 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. 02 January 2013 88Goa College of Pharmacy, Goa.
  • 89. 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. 02 January 2013 Goa College of Pharmacy, Goa. 89
  • 90. Power Compensation DSC Cell Design 02 January 2013 90Goa College of Pharmacy, Goa.
  • 91. Power Compensated DSC 02 January 2013 91Goa College of Pharmacy, Goa.
  • 92. Principles of DSC Analysis 02 January 2013 92Goa College of Pharmacy, Goa.
  • 93. Sample Preparation • Sample Shape • Sample Pans • Sample Weight 02 January 2013 93Goa College of Pharmacy, Goa.
  • 94. Sample Preparation 02 January 2013 94Goa College of Pharmacy, Goa.
  • 95. 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. 02 January 2013 95Goa College of Pharmacy, Goa.
  • 96. 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. 02 January 2013 Goa College of Pharmacy, Goa. 96
  • 97. 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. 02 January 2013 97Goa College of Pharmacy, Goa.
  • 98. 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. 02 January 2013 Goa College of Pharmacy, Goa. 98
  • 99. 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. 02 January 2013 99Goa College of Pharmacy, Goa.
  • 100. 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%. 02 January 2013 Goa College of Pharmacy, Goa. 100
  • 101. Experimental Conditions • Start Temperature • End Temperature • Reference Pan • Heating Rate 02 January 2013 101Goa College of Pharmacy, Goa.
  • 102. 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. 02 January 2013 102Goa College of Pharmacy, Goa.
  • 103. 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. 02 January 2013 103Goa College of Pharmacy, Goa.
  • 104. 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. 02 January 2013 104Goa College of Pharmacy, Goa.
  • 105. 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. 02 January 2013 105Goa College of Pharmacy, Goa.
  • 106. Heating Rate 02 January 2013 106Goa College of Pharmacy, Goa.
  • 107. 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. 02 January 2013 107Goa College of Pharmacy, Goa.
  • 108. DSC curves of Acetophenetidin 02 January 2013 108Goa College of Pharmacy, Goa.
  • 109. 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 20°C/min yielded the same Tm of 135°C ±1°C. 02 January 2013 Goa College of Pharmacy, Goa. 109
  • 110. DSC curves of Phenacetin 02 January 2013 110Goa College of Pharmacy, Goa.
  • 111. Effects of heating rate • 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. 02 January 2013 111Goa College of Pharmacy, Goa.
  • 112. Effect of Heating Rate 02 January 2013 112Goa College of Pharmacy, Goa.
  • 113. 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. 02 January 2013 113Goa College of Pharmacy, Goa.
  • 114. 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. 02 January 2013 Goa College of Pharmacy, Goa. 114
  • 115. Purge Gases 02 January 2013 115Goa College of Pharmacy, Goa.
  • 116. Summary of DSC experimental conditions 02 January 2013 116Goa College of Pharmacy, Goa.
  • 117. Purity by DSC 02 January 2013 117Goa College of Pharmacy, Goa.
  • 118. Purity Determination 02 January 2013 118Goa College of Pharmacy, Goa.
  • 119. Summary of Pharmaceutically Relevant Information Derived from DSC Analysis 02 January 2013 119Goa College of Pharmacy, Goa.
  • 120. Typical Features of a DSC Trace 02 January 2013 120Goa College of Pharmacy, Goa.
  • 121. Melting Point 02 January 2013 121Goa College of Pharmacy, Goa.
  • 122. Melting Process by DSC 02 January 2013 122Goa College of Pharmacy, Goa.
  • 123. Melting • Negative peak on thermogram • Ordered to disordered transition • Tm, melting temperature • Melting happens to crystalline polymers; Glassing happens to amorphous polymers Temperature, K Thermogram dH/dt,mJ/s Melting Tm 02 January 2013 123Goa College of Pharmacy, Goa.
  • 124. Polymorphic Forms 02 January 2013 124Goa College of Pharmacy, Goa.
  • 125. Pseudopolymorphism 02 January 2013 125Goa College of Pharmacy, Goa.
  • 126. Amorphous Material 02 January 2013 126Goa College of Pharmacy, Goa.
  • 127. 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. 02 January 2013 127Goa College of Pharmacy, Goa.
  • 128. 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. 02 January 2013 Goa College of Pharmacy, Goa. 128
  • 129. Modulated DSC (MDSC) 02 January 2013 129Goa College of Pharmacy, Goa.
  • 130. Modulated Temperature DSC (MTDSC) 02 January 2013 130Goa College of Pharmacy, Goa.
  • 131. MDSC for Polymorph Characterization 02 January 2013 131Goa College of Pharmacy, Goa.
  • 132. Variants of MTDSC 02 January 2013 132Goa College of Pharmacy, Goa.
  • 133. Example of a MTDSC Curve 02 January 2013 133Goa College of Pharmacy, Goa.
  • 134. Fast Scan DSC, Rapid Scanning DSC 02 January 2013 134Goa College of Pharmacy, Goa.
  • 135. Fast Scan DSC, Rapid Scanning DSC 02 January 2013 135Goa College of Pharmacy, Goa.
  • 136. ‘Hyper’ DSC 02 January 2013 136Goa College of Pharmacy, Goa.
  • 137. 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. 02 January 2013 137Goa College of Pharmacy, Goa.
  • 138. DSC Calibration curve of indium 02 January 2013 138Goa College of Pharmacy, Goa.
  • 139. DSC – Applications • Glass Transition Temperature (Tg) • Glass Transition Size (ΔCp) • Crystallization temperature (Tc) • Crystallinity (based on J/g and adjusted to %) • Polymorphic Transitions. 02 January 2013 139Goa College of Pharmacy, Goa.
  • 140. 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. 02 January 2013 140Goa College of Pharmacy, Goa.
  • 141. 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. 02 January 2013 Goa College of Pharmacy, Goa. 141
  • 142. Glass Transition • Step in thermogram • Transition from disordered solid to liquid • Observed in glassy solids, e.g., polymers • Tg glass transition temperature Temperature, K Thermogram dH/dt,mJ/s Glass transition Tg 02 January 2013 142Goa College of Pharmacy, Goa.
  • 143. 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. 02 January 2013 143Goa College of Pharmacy, Goa.
  • 144. 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 02 January 2013 144Goa College of Pharmacy, Goa.
  • 145. Crystallization • Sharp positive peak • Disordered to ordered transition • Material can crystallize! • Observed in glassy solids, e.g., polymers • Tc crystallization temperature Temperature, K Thermogram dH/dt,mJ/s Crystallization Tc 02 January 2013 145Goa College of Pharmacy, Goa.
  • 146. Analysis • Sharp positive peak • Disordered to ordered transition • Observed in glassy solids, e.g., polymers • Tc crystallization temperature Temperature, K dH/dt,mJ/s Crystallization Tc 02 January 2013 146Goa College of Pharmacy, Goa.
  • 147. 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. 02 January 2013 147Goa College of Pharmacy, Goa.
  • 148. 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 02 January 2013 148Goa College of Pharmacy, Goa.
  • 149. DSC curves of Sulfanilamide Polymorphs 02 January 2013 149Goa College of Pharmacy, Goa.
  • 150. DSC of Polymorphs of Tolbutamide: Tolbutamide A (Form 1) and B (Form 3) 02 January 2013 150Goa College of Pharmacy, Goa.
  • 151. SEM of Tolbutamide polymorphs 02 January 2013 Goa College of Pharmacy, Goa. 151
  • 152. Typical Features of a DSC Trace (Polymorphic System) 02 January 2013 152Goa College of Pharmacy, Goa.
  • 153. Polymorph Screening and Identification 02 January 2013 153Goa College of Pharmacy, Goa.
  • 154. 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 02 January 2013 154Goa College of Pharmacy, Goa.
  • 155. 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 02 January 2013 155Goa College of Pharmacy, Goa.
  • 156. 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 02 January 2013 156Goa College of Pharmacy, Goa.
  • 157. 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 02 January 2013 Goa College of Pharmacy, Goa. 157
  • 158. 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. 02 January 2013 158Goa College of Pharmacy, Goa.
  • 159. 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 02 January 2013 159Goa College of Pharmacy, Goa.
  • 160. Typical TGA and DSC Results for Various Transitions 02 January 2013 Goa College of Pharmacy, Goa. 160
  • 161. Lactose monohydrate 02 January 2013 161Goa College of Pharmacy, Goa.
  • 162. Hyphenated Thermal Equipment 02 January 2013 162Goa College of Pharmacy, Goa.
  • 163. Temperature Scales 02 January 2013 163Goa College of Pharmacy, Goa.
  • 164. Maxwell-Boltzmann Distribution 02 January 2013 164Goa College of Pharmacy, Goa.
  • 165. 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 02 January 2013 Goa College of Pharmacy, Goa. 165
  • 166. 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. 02 January 2013 Goa College of Pharmacy, Goa. 166
  • 167. Characterization for Pharma 02 January 2013 167Goa College of Pharmacy, Goa.
  • 168. Physical Forms of Solids 02 January 2013 168Goa College of Pharmacy, Goa.
  • 169. Importance of Solid State Forms in Pharma 02 January 2013 169Goa College of Pharmacy, Goa.
  • 170. Compatibility Studies 02 January 2013 170Goa College of Pharmacy, Goa.
  • 171. DSC in Polymer Analysis Main transitions which can be studied by DSC: • Melting • Freezing • Glass transition 02 January 2013 171Goa College of Pharmacy, Goa.
  • 172. 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 02 January 2013 172Goa College of Pharmacy, Goa.
  • 173. THERMOMECHANICAL ANALYSIS (TMA) 02 January 2013 173Goa College of Pharmacy, Goa.
  • 174. 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. 02 January 2013 174Goa College of Pharmacy, Goa.
  • 175. 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 02 January 2013 175Goa College of Pharmacy, Goa.
  • 176. 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. 02 January 2013 176Goa College of Pharmacy, Goa.
  • 177. 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. 02 January 2013 Goa College of Pharmacy, Goa. 177
  • 178. Types of TMA probes and resulting measured properties 02 January 2013 178Goa College of Pharmacy, Goa.
  • 179. 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. 02 January 2013 179Goa College of Pharmacy, Goa.
  • 180. 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. 02 January 2013 180Goa College of Pharmacy, Goa.
  • 181. Experimental Conditions • 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. 02 January 2013 181Goa College of Pharmacy, Goa.
  • 182. 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. 02 January 2013 182Goa College of Pharmacy, Goa.
  • 183. TMA Curve of Indium 02 January 2013 183Goa College of Pharmacy, Goa.
  • 184. TMA Applications • TMA is used to obtain the melting temperature, softening temperature, coefficient of thermal expansion (CTE) and glass transitions (Tg) of materials. 02 January 2013 184Goa College of Pharmacy, Goa.
  • 185. 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. 02 January 2013 Goa College of Pharmacy, Goa. 185
  • 186. 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 02 January 2013 Goa College of Pharmacy, Goa. 186
  • 187. 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. 02 January 2013 187Goa College of Pharmacy, Goa.
  • 188. 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 02 January 2013 188Goa College of Pharmacy, Goa.
  • 189. 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 02 January 2013 189Goa College of Pharmacy, Goa.
  • 190. 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 02 January 2013 190Goa College of Pharmacy, Goa.
  • 191. 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 02 January 2013 191Goa College of Pharmacy, Goa.
  • 192. 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/ 02 January 2013 192Goa College of Pharmacy, Goa.
  • 193. ‘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 . 02 January 2013 193Goa College of Pharmacy, Goa.
  • 194. ‘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 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. 02 January 2013 Goa College of Pharmacy, Goa. 194
  • 195. ‘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. 02 January 2013 Goa College of Pharmacy, Goa. 195
  • 196. THANK YOU 02 January 2013 196Goa College of Pharmacy, Goa. Cell No: 00919742431000 E-mail: nanjwadebk@gmail.com