Thermal analysis

DIFFERENTIAL SCANNING CALORIMETRY
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.
THERMAL ANALYTICAL METHODS:
S
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 ΔT ΔT 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
K.Sravya, pharmaceutics, NCOP Page 1

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
THERMAL EVENTS:
A(s1) A(s2) phase transition
A(l) melting
A(g) sublimation
B(s) + gases decomposition
gases
A (glass) A (rubber) glass transition
A(s) + B(g) C(s) oxidation, tarnishing
A(s) + B(g) gases combustion, volatilization
A(s) + (gases)1 A(s) + (gases)2 heterogeneous catalysis
A(s) + B(s) AB(s) addition
AB(s) + CD(s) AD(s) + CB(s) double decomposition
WHERE DO WE USE IT ???
 Virtually every area of modern Science and Technology.
 The basic information obtained is needed for the research and development of new
products.
 Increasing use for quality control and assurance
 In academia from basic undergraduate studies to the most sophisticated postgraduate
research.
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 inorder 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.
WHAT DOES DSC MEASURE?
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.
DSC IS USED TO ANALYZE?
 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
forming a bonded joint. The reaction may be initiated by heat, light, UV radiation, water etc.
 Denaturation:

A process pertaining to change in the structure of a protein from regular to irregular
arrangement of polypeptide chains.
WHERE MOSTLY USED ?
 Pharmaceutical industry
 To find the Purity of the compounds.
 Food industry
 For Characterization of fats and oils
 Polymer industry
 To find the Synthetic blends
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
DSC is most often used thermal analysis method, primarily because of its speed, simplicity
and availability.
PRINCIPLE:
The difference in heat supplied to the sample, and the reference material per unit time
is recorded and plotted as dH/dt vs the average temperature to which the sample and
reference to be raised.
COVENTIONAL DSC:

In general an endothermic reaction on a DSC arises from
1) Desolvations
2) Melting
3) Glass transitions and
4) Decompositions.
An exothermic reaction measured by DSC is usually indicative of molecular reorganizations
such as
1) Crystallization
2) Curing
3) Oxidation
The differential heat input is recorded with a sensitivity of +0.1 millicalories per second and
the temperature range over which the instrument operates is -1750c to 7250c.

The heat flow may be of two types:
1) Relative heat flow:
Measured by many DSC instruments.
2) Absolute heat flow:
Used by TA Q 1000 type instruments. Dividing the signal by measured heating rate
converts the heat flow signal into a heat capacity signal.

OUTPUT OF DSC:
Glass Transition
 Step in thermogram
 Transi tion from
disordered solid to
liquid
 Observed in glassy
solids, e.g., polymers
 Tg, glass transition
temperature
Thermogram
Glass transition
Tg
Temperature, K
dH/dt, mJ/s
Melting
 Negative peak on
thermogram
 Ordered to disordered
transition
 Tm, melting temperature
 NB: melting happens
to crystalline polymers;
glassing happens to
amorphous polymers
Thermogram
Melting
Tm
Temperature, K
dH/dt, mJ/s
Crystallization
 Sharp positive peak
 Disordered to ordered
transition
 Material can crystallize!
 Observed in glassy
solids, e.g., polymers
 Tc, crystallization
temperature
Thermogram
Crystallization
Tc
Temperature, K
dH/dt, mJ/s

TYPES OF DSC TECHNOLOGIES:
HEAT FLUX DSC:
It is proposed by Boersma.
The sample and reference cells are heated at a constant rate and thermocouples are used to
detect the temperature differential between sample side and reference side using single, large
mass furnace.
Principle:
The introduction of a controlled heat leak between the sample and reference holders enabled
a quantitative measurement of energy changes to be made. Heat flux can be measured
directly if a sample is surrounded by a thermopile.
The peak area is related to the enthalpy change by a calibration factor which is partially
temperature dependent.
Sample holder: sample and reference holders are connected by a low resistance heat flow
path. The material with which the sample holder is made may be aluminium, stainless steel,
platinum.
Sensors: temperature sensors are thermocouples.
Furnace: same block is used for sample and reference.
Temperature controller: temperature difference between sample and reference is measured.
A metallic disc made of constantan alloy is the primary means of heat transfer. Sample and
reference sit on raised constantan discs.
Differential heat flow to sample and reference is measured by thermocouples which are
connected in series, located at the junction of constantan disc and chromel wafers.
With this, it is possible to achieve heating or cooling rates of 1000c /min to 00c /min
(isothermal).
It needs mathematical equations to get the heat flow.

DSC HEAT FLOW EQUATION:
dH/dt = Cp dT/dt + f(T,t)
dH/dt = DSC heat flow signal
Cp = sample heat capacity = sample specific heat x sample weight
dT/dt = heating rate
f(T,t) = heat flow that is a function of time at an absolute temperature (kinetic)
POWER COMPENSATED DSC:
It is developed by Perkin Elmer, USA. It directly measures heat flow between sample side
and reference side using two separate, low mass furnaces.
Principle: An exothermic or endothermic change occurs in the sample, when the sample is
heated, power (energy) is applied or removed from the furnace to compensate for the energy
change occurring in the sample is measured.
The system is maintained in “Thermal Null” state all the times.
The amount of power required to maintain the system in equilibrium is directly proportional
to the energy changes.
Sample holder: it is made up of aluminium, platinum or stainless steel.
Sensors: platinum resistant sensors are generally used. Separate sensors are used for are used
for sample and reference cells.
Furnace: separate blocks of furnace are used for sample and reference cells.
Temperature controller: differential thermal power is supplied to heaters to maintain the
temperature of the sample and reference at the programmed value.

COMPARISION OF DTA AND DSC:
The basic difference between DSC and DTA is that DSC is a calorimetric method in which
differences in energy are measured. In contrast, in DTA, differences in temperature are
recorded. The temperature programs for the two methods are similar. DSC is considered to be
a quantitative technique, in contrast to DTA.
The exact distinction between DSC and DTA instrumentation was the subject of
controversy for many years; it is eventually resolved by Mackenzie. In conventional
(classical) DTA, ΔT is the difference between TS(sample temperature) and
TR(reference temperature).
The junction of difference thermocouple are located in the centre of the sample and
reference specimens. In this arrangement, ΔT cannot be directly related to the
enthalpy change, thus the peak area cannot be reliably converted to energy units.
Classical DTA can provide useful qualitative information, but it can never be more
than semi quantitative.
Quite different from DTA is the power compensation DSC which makes a direct
measurement of the enthalpy change.
S 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
2
nd
order phase
transition
It can be observed with a
sample of 200mg
It is not observed
5 Specific heat
measurement
accurate Not accurate

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 (ΔH 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
Brush gently both sensors and cell if necessary

Be careful with TzeroTM thermocouple
Blow out any particles remaining, if any
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.
DONOT DECOMPOSE THE SAMPLES IN DSC CELL
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
Composite materials – 15 to 20 mg
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 ΔT 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.
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.
Typical 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 heating rate will decrease the sensitivity but will increase the resolution.
Good starting point is 100c/min.
FACTORS AFFECTING THERMOGRAM:
1) Sample shape:
The shape of the sample has little effect on the quantitative aspect of DSC but more effect on
the qualitative aspects. However, samples in the form of a disc film or powder spread on the
pan are preferred. In the case of polymeric sheets, a disc cut with a cork-borer gives good
results.
2) Sample size:
About 0.5 to 10mg is usually sufficient. Smaller samples enable faster scanning, give better
shaped peaks with good resolution and provide better contact with the gaseous environment.
With larger samples, smaller heats of transitions may be measured with greater precision.
3) Heating rates
4) 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 and mass of the compound, the particle size distribution, packaging and porosity,
pre-treatment and dilution of the sample. It is used for purity analysis of above 98% pure
compounds.
DSC: Main Sources of 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
MODULATED DSC:
It is introduced in 1993and also developed by TA instruments. It uses heat flux DSC design
but a different furnace heating profile.
Modulate +/- 0.42 °C every 40 seconds
Ramp 4.00 °C/min to 290.00 °C
Note that temperature is not decreasing during
Modulation i.e. no cooling
62
60
58
56
54
52
Modulated Temperature (°C)
62
60
58
56
54
52
Temperature (°C)
13.0 13.5 14.0 14.5 15.0
Time (min)
In MDSC, a sinusoidal function is superimposed on the overall temperature program to
produce a micro heating and cooling cycle as the overall temperature is steadily increased or
decreased. Using Fourier transformation methods, the overall signal is mathematically
deconvoluted into two parts, a reversing heat flow and a nonreversing heat flow signal. The
reversing heat flow signal is associated with the heat capacity component of the thermogram
and the nonreversing heat flow is related to kinetic processes. Usually step transitions such as
the glass transition, appear only in the reversing heat flow signal and exothermic or
endothermic events may appear either or in both the signals.
A sinusoidal oscillation (a square wave or saw tooth) or oscillation is overlaid on the
traditional linear heating ramp to yield a heating profile in which the sample temperature still
increases with time but not in a linear fashion. The overall effect of this heating profile on the
sample is the same as if two simultaneous experiments were performed. This produces a slow
underlying heating rate (improving resolution) as well as a faster instantaneous heating rate
(improving resolution).
Total heat flow signal contains all the thermal transitions as that of standard DSC.

It also has ability to separate thermal multiple events.
Benefits
• Increased Sensitivity for Detecting Weak (Glass) Transitions
– Eliminates baseline curvature and drift
• Increased Resolution Without Loss of Sensitivity
– Two heating rates (average and instantaneous)
• Ability to Separate Complex Thermal Events and Transitions Into Their Heat
Capacity and Kinetic Components
• Ability to Measure Heat Capacity (Structure) Changes During Reactions and Under
Isothermal Conditions
Disadvantage
• Slow data collection
APPLICATIONS:
1) Determination of crystallinity in a polymer:
DSC evaluation can be used to measure amount of crystallinity in the sample. Let the heat of
crystallization be Hc and total heat given off during melting be Ht.
H=Ht-Hc……(1)
where H is the heat given off by that part of polymer, which was already in crystalline state.
Now by dividing H by Hc (specific heat of melting)
Where Hc is the amount of heat given off when 1gm of polymer is melted.
H/Hc=joules/joules/gram=Mc grams
This is total amount of polymer that was crystalline below Tc, crystallization temperature.
So % crystallinity in polymer sample=Mc/Mt *100
Where Mt is total mass of sample taken.
2) DSC purity analysis:
DSC provides a rapid yet reliable method for determining the purity of materials, particularly
pharmaceuticals. The presence of minor impurities may reduce the effectiveness of the drug
or even cause adverse side effects on the patient.
The purity is readily calculated from DSC curve of a single melting event of a few milligrams
of the substance, without the need for reference standard of drug substances.

The determination of purity by means of DSC is based on the assumption that impurities
depress the melting point of pure material according to the eutectic phase diagram behavior.
It is well known that the higher the concentration of impurity present in the sample, the lower
its melting point and broader its melting range. The obtained by DSC includes the complete
melting curve and the latent heat of fusion (ΔHf) of the sample. The interpretation of the DSC
curve is based on a modified form of Vant Hoff equation:
Ts=To-RTo
2X1/ΔHf x (1/F)
Where, ΔHf = heat of fusion of pure major component (J mol-1)
R = gas constant (8.314 J mol-1K-1)
Ts = sample temperature (K)
T0 = theoretical melting point of the pure compound
X1 = mole fraction of impurity
F = fraction of sample melted at Ts
Figure shows phase diagram of two component mixture with eutectic point:
3) Analysis of spray dried system using DSC:
Spray drying is widely used as a means of converting liquids into powder via atomization
into a hot air stream. The liquid droplets are dried prior to contact with the walls of the

chamber, hence the solidification process is very rapid & results in the first instance in
spherical or near sphere particles.
Consequently spray drying may result profound changes to the physical properties of the
material compared to the unprocessed solid form, both in terms of morphology & lattice
structure. In particular spray dried products may be partially or completely amorphous or
alternatively may result in the generation of a range of polymorphic forms.
Ex: spray drying of phenobarbitone from ethanolic solution.
Digitoxin (90); diacetylmide camycin (91) & thiazide diuretics (92).
In particular, spray dried products may be partially or completely amorphous or,
alternatively, may result in the generation of a range of polymorphic forms.
Example of the latter include a study on the spray drying of phenobarbitone from ethanolic
solution, reporting the generation of a material that showed characteristics of the Form 111
polymorph after processing in contrast to the commercially available Form 11.
However, the majority of DSC studies on spray-dried systems have focused on the generation
of amorphous material from the process. DSC can be used to study the number and
temperature range of polymorphs, since each polymorphic transition causes an energy change
that may be detected by DSC.
4) Liquid crystals:
DSC is used in the study of liquid crystals. As some forms of matter go from solid to liquid
they go through a third state, which displays properties of both phases.
This anisotropic liquid is known as a liquid crystalline or mesomorphous state. Using DSC, it
is possible to observe the small energy changes that occur as matter transitions from a solid to
a liquid crystal and from a liquid crystal to an isotropic liquid.
5) Screening technique to determine the compatibility of ketoprofen with
excipients:
Differential scanning calorimetry (DSC) was used as a screening technique for assessing the
compatibility of ketoprofen with some excipients currently employed in tablet or capsule
formulations.
The effect of sample treatment (simple blending, cogrinding, compression, kneading) was
also evaluated.

On the basis of DSC results, ketoprofen was found to be compatible with
hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, corn starch, arabic
gum, colloidal silica, veegum, lactose, glucose, sorbitol and mannitol.
Some drug-excipient interaction was observed with palmitic acid, stearic acid and stearyl
alcohol and eutectic formation was found with magnesium stearate.
6) In preparation of synthetic polymer blends:
DSC analysis on a blend of synthetic fibres was an early application and it shows that the
DSC is a versatile technique. Using Perkin-Elmer differential scanning calorimeter, a blend
containing Nylon66, Orlon and Vycron polyester was determined. The ΔH values per gram of
the sample were compared with the corresponding ΔH per gram of each pure component.
Hence the ΔH values for the crystallization peaks of nylon and the polyester were measured
together with a cross-linking exotherm of Orlon.
A quantitative analysis was then made on the fibre blend. For example, the ratio of the ΔH
value for the nylon crystallization peak in the fibre blend over the ΔH value for the pure
nylon multiplied by 100 gives the percentage of nylon in the fibre blend. The total time for
analysis, performed without sample treatment or any separatory procedure, was less than
30min. the repeatability of the experiment was found to be within 5% of the amount of each
component present.
Polymer blends difficult to evaluate by conventional DSC have been successfully analysed by
modulated DSC. For example, a polymer blend containing polyethylene terepthalate (PET)
and acrylonitrile-butadiene-styrene (ABS) has been separated and evaluated using MDSC.
CONCLUSION
Differential scanning calorimetry is extremely versatile and able to address a wide
variety of analytical problems.
It is often used in conjunction with TG to obtain better results.
Widespread study of thermal properties on an extensive range of sample types can be
done.
REFERENCES

1. Gurudeep R.Chatwal, Sham K.Anand, Instrumental Methods of Chemical Analysis,
Thermal Methods, 5th edition. (pg no:2.747-2.753)
2. 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)
3. B.K.Sharma, Instrumental Methods of Chemical Analysis, Thermoanalytical methods,
26th edition, goel publishing house, Meerut,2007. (pg.no.308)
4. Alfred Martin, Physical Pharmacy, Lippincott Williams and Wilkins, USA,B.I
publications, fourth edition, Indian edition.( pg no: 47-48)
5. www.wikipedia.org/wiki/Differential_scanning_calorimetry
6. www.wikipedia.org/wiki/Thermomechanical_analysis
7. www.anasys.co.uk/library/tma1.htm
8. www.ta instruments.com
9. www.setaram.com
CONTENTS

S NO TOPIC PAGE NO
1 Introduction 1
2 Principle 4
3 Output of DSC 7
4 Types of DSC 8
5 Comparison of DSC and DTA 10
6 Instrumentation 11
7 Factors affecting Thermogram 14
8 MDSC 15
9 Applications 16
10 Conclusion 19
11 References 20

Thermal analysis

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