2. Introduction
Thermal Analysis
A number of physical and chemical effects can be produced by
temperature changes, and methods for characterizing these alterations
upon heating or cooling a sample material are referred to as thermal
analysis.
The physical and chemical changes a sample undergoes when heated, are
characteristic of the material being examined. By measuring the
temperature at which such reactions occur and the heat involved in the
reaction, the compounds present in the material can be characterized. The
majority of known inorganic compounds have been so characterized. The
physical and chemical changes that take place when unknown sample is
heated provide the information that enables the identification of the
material. These changes also indicate the temperature at which the
material in question ceases to be stable under normal conditions.
Common methods of thermal analysis are DSC, DTA, TGA, and TMA. 24-12-2015
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3. Sr. no Name of the technique Instrument employed Parameter measured Graph
1 Thermogravimetry (TG) Thermobalance Mass Mass vs temperature
2 Derivative thermogravimetry (DTG) Thermobalance dm/dt dm/dt vs time
3 Differential thermal analysis (DTA) DTA apparatus ∆T ∆T vs temperature
4 Differential scanning calorimetry (DSC) Differential scanning calorimeter dH/dt dH/dt vs temperature
5 Thermometric titrimetry Calorimeter Temperature Temperature vs titrant volume
6 Dynamic reflectance spectroscopy
(DRS)
spectrophotometer Reflectance % reflectance vs temperature
7 Evolved gas detection (EGD) Thermal conductivity cell Thermal conductivity(TC) TC vs temperature
8 Dilatometry (TMA) Dilatometer Volume or length Volume or length vs
temperature
9 Electrical conductivity (EC) Electrometer or Bridget Current(I) or Resistance(R) I or R vs temperature
10 Emanation thermal analysis (ETA) ETA apparatus Radioactivity (E) E vs temperature
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5. Objectives
The main objective to
introduce thermal analysis and
its applications at an entry level
in the pharmaceutical industry.
In the process, instruments
were successfully calibrated
using pharmaceuticals.
Studying the behavior of
pharmaceuticals by different
thermal analysis instruments,
under different conditions and
then compare the results was
another objective.
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Basic Principles of Thermal Analysis
6. Differential Scanning
Calorimetry
6
History
This technique is developed by E.S.Watson and
M.J.O’Neill in 1962.
Introduced commercially at the Pittsburgh
Conference on analytical Chemistry and Applied
Spectroscopy.
First Adiabatic differential scanning calorimeter
that could be used in Biochemistry was
developed by P.L.Privalov in 1964.
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7. Principle
DSC is a thermal analysis apparatus measuring how physical properties of a
sample change along with temperature against time.
In DSC the heat flow is measured and plotted against temperature of furnace or time to get a thermo
gram. This is the basis of Differential Scanning Calorimetry (DSC).
The deviation observed above the base (zero) line is called exothermic transition and below is called
endothermic transition.
The area under the peak is directly proportional to the heat evolved or absorbed by the reaction, and
the height of the curve is directly proportion
to the rate of reaction.
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8. Calorimetry - The study of heat transfer during physical and chemical process.
Calorimeter - A device for measuring the heat transferred.
Differential scanning calorimetry (DSC) is a technique for measuring the energy necessary to
establish a nearly zero temperature difference between a substance and an inert reference material,
as the two specimens are subjected to identical temperature regimes in an environment heated or
cooled at a controlled rate.
It is the most widely used method of thermal analysis in pharmaceutical field.
Thus, when an endothermic transition occurs, the energy absorbed by the sample is compensated by
an increased energy input into the sample in order to maintain a zero temperature difference.
Because this energy input is precisely equivalent magnitude of energy absorbed in transition, direct
calorimetric measurement of transition is obtained from this balancing energy.
On the DSC chart recording, the abscissa indicates the transition temperature and the peak measures
the total energy transfer to or from the sample.
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9. 1. What Does DSC Measure
A DSC measures the difference between heat flow rate (mW= mJsec) between the sample and inert reference as a
function of time and temperature.
DSC measures the amount of energy (heat) absorbed or released by a sample as it is heated, cooled or held at
constant temperature. DSC also performs precise temperature measurements.
2.Used
Melting point
Crystallization
Glass Transition
O.I.T. (Oxidative Induction Time) - It is a standardized test performed in DSC that measures the level of
stabilization of the material tested. The time between melting and onset of decomposition in isothermal
conditions is measured.
Polymorphism
Purity
Specific Heat
Kinetic Studies
Curing Reactions - The process in which an adhesive undergoes a chemical reaction and becomes a solid by
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10. COVENTIONAL DSC
In general an endothermic reaction on a DSC arises from
Desolvations
Melting
Glass transitions and
Decompositions. 24-12-2015
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11. An exothermic reaction measured by DSC is usually indicative of molecular
reorganizations such as
1) Crystallization
2) Curing
3) Oxidation
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15. Types of DSC Technologies
1.Heat Flux DSC
2. Power compensation DSC
DSC Heat Flow Equation
dH/dt=DSC heat flow signal
Cp= Sample heat capacity
= Sample specific heat. Sample weight
F(t,t) - Heat Flow That Is A Function Of Time At An Absolute Temperature (Kinetic)
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Dh/Dt = Cp Dt/Dt + F(t,t)
17. DSC Curve
•The result of a DSC experiment is a curve of heat flux v/s temperature or v/s time. There are two different
conventions: exothermic reactions in the sample shown with a positive or negative peak, depending on the
kind of a technology used in the experiment.
•This curve can be used to calculate enthalpies of transitions, which is done by integrating the peak
corresponding to a given transition. The enthalpy of transition can be expressed using equation:
ΔH=KA
Where ΔH is the enthalpy of transition,
K is the calorimetric constant,
A is the area under the peak.
•The calorimetric constant varies from instrument to instrument, and can be determined by analyzing a
well-characterized material of known enthalpies of transition.
•Area under the peak is directly proportional to heat absorbed or evolved by the reaction.
•Height of the peak is directly proportional to the rate of reaction.
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18. Instrumentation
This instrument works on the temperature control of two similar specimen holders.
It consists of two circuits
1. Left half - differential temperature control circuit
2. Right half - average temperature control circuit
In the average temperature control circuit an electrical signal which is proportional to the dialled
temperature of the sample and reference holders, is generated through the programmer.
In the differential temperature control circuit, signals representing the temperature of sample and
reference are compared. If no reaction taking place in the sample, the differential power input to the
sample and reference heater is almost zero. If a reaction is taking place (∆H is not zero) a differential
power is fed to heaters. A signal proportional to this differential power along with the sign is
transmitted to the recorder pen. The integral of the peak so obtained gives the internal energy change
of the sample.
Cleaning The Sample Cell
If the cell gets dirty – Clean it with brush
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20. Sample Preparation
It is possible to use materials which creep, froth or boil if sealed sample sample containers are used to
ensure no damage occurs to the sample holder assembly.
Accurately weighed samples (approx 3 to 20 mg) are encapsulated in the metal pans of high thermal
conductivity. Small pans of inert treated materials (aluminium, platinum, stainless steel) are used. Pan
configurations may be open, pinhole or hermetically sealed. Same pan material and configuration for both
sample and reference.
Material should entirely cover the bottom of the pan to ensure thermal contact. Avoid overfilling of the pan
to minimize the thermal lag from the bulk of the material to the sensor. Small sample masses and low
heating rates improve resolution but at the expense of sensitivity. [Do not Decompose The Samples In
DSC Cell]
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21. Sample Shape
Cut the sample to uniform shape, do not crush the sample. If the sample to be taken is pellet, cross
section is to be taken. If the sample material is powder then, it is spread uniformly over the bottom of
the sample pan.
Using Sample Press
When using crimped pans, the pans should not be over crimped. The bottom of the pans should remain
flat, even after crimping. When using hermetic pans, a little more pressure is required to crimp the
pans. Hermetic pans are sealed by forming a cold wield on the aluminium pans.
Sample Size
Smaller samples will increase the resolution but will decrease the sensitivity.
Larger samples will decrease the resolution but will increase the sensitivity.
Sample size depends on the type of material being measured
If the sample is
Extremely reactive in nature - very small samples (<1 mg) are to be taken.
Pure organics or pharmaceuticals - 1 to 5 mg
Polymers - approximately 10 mg
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22. Reference Materials - An inert material like α-alumina is generally used. Empty pan can also be used, if
the sample weight is small. With higher sample weights it is necessary to use a reference material, because
the total weight of the sample and its container should be approximately the same as the total weight of the
reference and its container. The reference material should be selected so that it possesses similar thermal
characteristics to the sample.
The most widely used reference material is α-alumina, which must be of analytical reagent quality. Before
use, α-alumina should be recalcined and stored over magnesium perchlorate in a dessicator. Kieselguhr is
another reference material normally used when the sample has a fibrous nature. If there is an appreciable
difference between the thermal characteristics of the sample and reference materials, or if values of ∆T are
large, then dilution of the sample with the reference substance is sensible practice. Dilution may be
accomplished by thoroughly mixing suitable proportions of sample and reference material.
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23. Purge Gases - Sample may react with air and may oxidize or burn. The problem is overcomed by using
inert gases.
Inert gases are used to control moisture in the surrounding atmosphere. Commonly used inert gases are
nitrogen, helium, argon etc.
Inert gases should ensure even heating and helps to sweep away the off gases that might be released during
sublimation or decomposition.
Nitrogen - It is the most commonly used inert gas. It increases the sensitivity of the experiment. Typica
flow rate is 50 ml/min.
Helium - It has high thermal conductivity. It increases the resolution of the peaks. The upper temperature
limit for this gas is upto 3500c. Flow rate is 25 ml/min
Air or oxygen - Sometimes it is deliberately used to view oxidative effects of the sample. Flow rate is 50
ml/min
Heating Rate - Faster heating rate will increase the sensitivity but will decrease the resolution. Slow
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24. Factors Affecting Thermogram/ DSC Curve
1) Sample shape:
The shape of the sample has little effect on the quantitative aspect of DSC but more effect on the qualitativ
aspects. However, samples in the form of a disc film or powder spread on the pan are preferred. In the case o
polymeric sheets, a disc cut with a cork-borer gives good results.
1) Sample size:
About 0.5 to 10mg is usually sufficient. Smaller samples enable faster scanning, give better shaped peaks wit
good resolution and provide better contact with the gaseous environment. With larger samples, smaller heats o
transitions may be measured with greater precision.
1) Heating rates
2) Atmosphere and geometry of sample holders
There are a number of variables that affect DSC results includes the type of pan, heating rate, the nature an
mass of the compound, the particle size distribution, packaging and porosity, pre-treatment and dilution of th
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25. 24-12-2015
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Comparision Of DTAAnd DSC
Sr. no ASPECT DSC DTA
1 Size of the sample 2-10 mg 50-20mg
2 Sensitivity of the
measurement
a few J/mole 0.5 KJ/mole
3 Heating and cooling cycles Programmed heating and cooling
possible
Generally programmed heating
4 2nd order phase transition It can be observed with a sample of
200mg
It is not observed
5 Specific heat measurement accurate Not accurate
26. Application
Protein Stability and Folding
Liquid Biopharmaceutical Formulations
Process Development
Protein Engineering
Rank order Binding
Antibody Domain Studies
Characterisation of Membranes, lipids, nucleic acids & micellar systems
Assessment of the effects of structural change on a molecules stability
Measurement of Ultra-light molecular interactions
Assessment of biocompatibility during manufacturing.
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27. DSC In Pharmaceutical Industry
Purity determination of sample directly
Detection of polymorphism
Quantification of polymorph
Detection of metastable polymorph
Detection of isomerism
Stability/ compatibility studies
Percentage crystallinity determination
Lyophilization studies
Lipid/ Protein determination
Finger printing of wax
Amorphous content in excipient
Choosing better solvent 24-12-2015
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28. Reference
Gurudeep R.Chatwal, Sham K.Anand, Instrumental Methods of Chemical Analysis, Thermal Methods,
5th edition. (pg no:2.747-2.753)
J.Mendham,R.C Denny, J.D Barnes,M.J.K Thomas,Vogels text book quantitative chemical analysis,
pearson education, sixth edition.(pg no.503-521)
B.K.Sharma, Instrumental Methods of Chemical Analysis, Thermoanalytical methods, 26th edition, goel
publishing house, Meerut,2007. (pg.no.308)
Alfred Martin, Physical Pharmacy, Lippincott Williams and Wilkins, USA,B.I publications, fourth
edition, Indian edition.( pg no: 47-48)
www.wikipedia.org/wiki/Differential_scanning_calorimetry
, No. 1, pp. 127–142, 2010.ttp://www.tainst.com Mettler Toledo Thermal Analysis System
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![Differential
Scanning
Calorimetry
[DSC]
Ms. Panchal Sanjana Sanjivkumar
[M. Pharm, Pharmaceutics]
Roll no.- 06
24-12-2015
1](https://image.slidesharecdn.com/dscsanjana1-230329053336-11f7a74a/85/Differential-Scanning-Colourimetry-1-320.jpg)
