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Thermal Analysis
Dr. Basavaraj K. NanjwadeM. Pharm., Ph.D
KLE University College of PharmayBEL!"UM#$%&&'&, Karnata(a, )ndia.
Cell No* &&%'%+-'&&&E#mail* nanjwade/(0gmail.om
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Thermal analysis
Thermal analysis is a branch of materialsscience where the properties of materials arestudied as they change with temperature.
Several methods are commonly used theseare distinguished from one another by theproperty which is measured.
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ABBREVIATIONS
ICTAC - International Confederation for Thermal Analysis and Calorimetry DA- Dielectric Analysis DSC- Differential Scanning Calorimetry T!A- Thermogravimetric Analysis T"A- Thermomechanical Analysis
#$f- $eat of %usion Tm - "elting Temperature& e'trapolated endothermic onset temperature Tp- (ea) "elting endothermic Temperature #$c-$eat of e'othermic Crystalli*ation Tc- Crystalli*ation Temperature& e'trapolated e'othermic onset temperature Tcp- (ea) e'othermic Crystalli*ation temperature #$v - $eat of endothermic +apori*ation Tv - +apori*ation temperature& e'trapolated endothermic onset temperature Tvp - (ea) +apori*ation temperature Tg -!lass transition temperature AST"- American Standards for Testing "aterials
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Thermal analysis
Dielectric thermal analysis ,DA dielectric permittivity and loss factor Differential thermal analysis ,DTA temperature difference
Differential scanning calorimetry (DSC): heat ifference
Dilatometry,DI/ volume
Dynamic mechanical analysis ,D"A mechanical stiffness and damping volved gas analysis ,!A gaseous decomposition products
/aser flash analysis ,/%A thermal diffusivity and thermal conductivity
Thermogra!imetric analysis (T"A): mass
Thermomechanical analysis (T#A): imension Thermo-optical analysis ,T0A optical properties
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Common Thermal Analysis #ethos an the $ro%erties #eas&re
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Intro&ction
Thermal analysis is defined as 1series of techni2ues formeasuring the temperature dependency of a physicalproperty of a certain substance while varying thetemperature of the substance according to a specific
program.3
The substance referred to here includes reactionproducts.
(hysical properties include mass& temperature&enthalpy& dimension& dynamic characteristics& andothers& and depending on the physical properties to bemeasured& the techni2ues of thermal analysis.
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Intro&ction
Introduce thermal analysis at an entry levelchemist or a new function for the e'perienced
pharmaceutical scientist.
This teaching tool describes the introductory useof Differential Scanning Calorimetry ,DSC&
Thermo-"echanical Analysis ,T"A and to somee'tent Thermo-gravimetric Analysis ,T!A forcharacteri*ing pharmaceuticals.
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Basic $rinci%les of Thermal Analysis
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Thermal Analysis Techni'&es
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I$AC: International nion of $&re an A%%lie Chemistry
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Thermal Analysis
Differential ScanningCalorimetry ,DSC "easure heat absorbed or
liberated during heating orcooling
Thermal !ravimetricAnalysis ,T!A "easure change in
weight during heating orcooling
ThermomechanicalAnalysis ,T"A
"easure change indimensions duringheating or cooling
4 Differential ThermalAnalysis ,DTA
4 They are use for thermalinvestigation where thermalchange can be observed andcharacterised
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TER#O"AVI#ETRIC ANA*+SIS(T"A)
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Thermogra!imetric Analysis (T"A)
$rinci%le: T!A measures the amount and the rate ofweight change of a material with respect totemperature or time in controlled environments.
A T!A consists of three ma5or parts a furnace&
6. A microgram balance&
7. An auto sampler and
8. A thermocouple.
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"ENERA* $RINCI$*ES INVO*VED IN
TER#O"RAVI#ETR+
$RINCI$*E Thermogravimetry is a techni2uein which a change in the weight of a substance isrecorded as a function of temperature or time.
Instr&ment: Instrument used forthermogravimetry is 1Thermobalance3. Data
recorded in form of curve )nown as9Thermogram:.
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Thermogra!imetric Analysis
(T"A)
The furnace can raise the temperature as highas 6;;;
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Thermogra!imetric Analysis
(T"A)
A techni2ue that permitsthe continuous weighingof a sample as afunction of temperatureand=or as a function oftime at a desiredtemperature
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Differential Thermal Analysis
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Thermogra!imetric Analysis
(T"A)
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Inter%retation of T" an DT" c&r!es
i. he !am"le un#ergoe! no#ecom"o!i$ion %i$h lo!! of &ola$ile"ro#uc$! o&er $he $em"era$ure range!ho%n 'u$ !oli# "ha!e $ran!forma$ion,mel$ing ,e$c can no$ 'e #e$ec$e# 'yG,
ii. he ra"i# ini$ial ma!! lo!! i!charac$eri!$ic of #e!or"$ion or #rying. (fi$ i! $rue, $hen re)run $he !am"le !houl#re!ul$ in $y"e *i+ cur&e!,
iii. ingle !$age #ecom"o!i$ion,
i&. -ul$i)!$age #ecom"o!i$ion %i$hrela$i&ely !$a'le in$erme#ia$e! "ro&i#einforma$ion on $he $em"era$ure limi$ of!$a'ili$y of reac$an$! an# in$erme#ia$e"ro#uc$! an# al!o !$oichiome$ry,
&. -ul$i)!$age #ecom"o!i$ion %i$h no!$a'le in$erme#ia$e "ro#uc$. /o%e&er
hea$ing)ra$e eec$ mu!$ 'e con!i#ere#.$ lo% hea$ing ra$e, $y"e *&+ re!em'le$y"e *i&+. $ high hea$ing ra$e, $y"e *i&+an# *&+ re!em'le $y"e *iii+ an# lo!e all$he #e$ail!,
&i. Gain in ma!! #ue $o reac$ion %i$ha$mo!"here, e.g. oi#a$ion of me$al!,
&ii. i#a$ion "ro#uc$ #ecom"o!e again a$higher $em"era$ure $hi! i! no$ of$enencoun$ere#.
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T"A C&r!e of Calci&m O,alate
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E,am%les of T"A C&r!es
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Sam%le $re%aration
Sample preparation has a significant effect in obtaininggood data.
It is suggested that ma'imi*ing the surface area of thesample in a T!A pan improves resolution and
reproducibility of weight loss temperatures. The sample weight affects the accuracy of weight lossmeasurements.
Typically 6;-7;mg of sample is preferred in mostapplications.
>hereas& if the sample has volatiles ?;-6;;mg of sample isconsidered ade2uate.
It is to be noted that most T!A instruments have baselinedrift of @;.;7?mg which is @;.7? of a 6;mg sample.
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E,%erimental Conitions
Heating Rate
Purge gas
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E,%erimental Conitions -Heating Rate
Samples are heated at a rate of 6; or 7;
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E,%erimental Conitions -$&rge gas
itrogen is the most common gas used to purge samplesin T!A due to its inert nature.
>hereas& helium provides the best baseline.
Air is )nown to improve resolution because of adifference in the o'idative stability of components inthe sample.
+acuum may be used where the sample contains volatile
components& which helps improve separation from theonset of decomposition since the volatiles come off atlower temperatures in vacuum.
e.g. oil in a rubber tire product.
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#iscellaneo&s
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Cali.ration
Blank test
Calibration of mass changes
Calibration of temperature
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Cali.ration-Blank test
>ithout sample& air is passed at 7; ml=mm& and thetemperature is raised up to 6;;;
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Cali.ration-Blank test
>hen noise appears in the T! curve& the possiblecause may include contact between sample dish andthermocouple& contact between 2uart* suspension
wire and purge gas feed pipe& and contact betweenweight pan and arid glass cap.
+ibration and shoc) may also cause noise.
>hen the sample pan or suspension wire iscontaminated with deposit of decomposition productor the li)e& the T!A curve shows a slight decreasingcurve.
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Cali.ration- Calibration of mass
changes
Since the T!A is usually measured by the rate ofthe weight change to the sample weight&calibration of absolute value of weight is hardly
necessary. A weight of 7; mg is read to a precision of 6;microgms by a precision balance& and the mean,So is determined.
The furnace is put on& and when the T!A signal isstabili*ed& the instrument balance control isad5usted to set the automatic *ero.
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Cali.ration- Calibration of mass
changes
Then the furnace is put into place and the furnace is set again&and the T!A signal value is read. This value is S6.
Bepeating the same operation several times& the mean of S6 isobtained as S.
In this operation it is )nown that a signal corresponding to S6mg is delivered with the weight of So mg is placed on thebalance.
The measuring precision of T!A is within @6 of the range.
>hen calibrating the apparatus& the calibration function isutili*ed.
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Cali.ration-Calibration of
temperature
The temperature of the T!A may be calibrated in twomanners
The method of ma)ing use of the melting point of apure metal& and the method of utili*ing the Curie pointtemperature.
In the former method& one of the metals processed in aribbon shape& and it is suspended on the T!Asuspension wire& and a weight of about 6;;mg isattached at its tip.
>hen the pure metal is fused by heating& the weightdrops& and a weight drop appears on the T!A curve.
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Cali.ration-Calibration of
temperature In the latter method& the standard substance
verified by International Congress onThermal Analysis/ ICTA& is measured. The
standard substances are %erromagnets& andhave different Curie temperatures.
It is intended to calibrate by measuring the
apparent weight change appearing in steps atCurie temperatures by ma)ing use of apermanent magnet.
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Cali.ration-Calibration of
temperature
ased on the T!A data& thermal stability of materials andtheir compositions can be predicted depending on theweight changes caused by evaporation& dehydration&o'idation and decomposition& up to temperatures as high
as 6;;;
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A%%lications of T"A
There is a wide range of applications of T!A& e.g& Composition of multi-component system Thermal stability of materials
0'idative stability of materials stimated lifetime of a product Decomposition Einetics of materials
The effect of reactive or corrosive atmosphere onmaterials
"oisture and volatiles contents on materials.
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A%%lications of T"A
vaporation of free ,unbound water begins at roomtemperature due to dry gas flowing over the sample.
Dehydration=Desolvation of bound water almost alwaysbegins at temperatures above room temperature andtypically 67?
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A%%lications of T"A
Determination of the bound and unbound water in thesuspension of "il) of "agnesia ,"o"& used as a la'ative.
Comparison of the generic and a brand "o".
In an overview of thermal analysis testing it is alwayspreferable to do a T!A e'periment on un)nown samples beforedoing a DSC e'periment ,especially for pharmaceuticals.
Decomposition of pharmaceuticals renders products which areinsoluble and generally stic)y on the inside of a DSC cell.
These products will lower the life use of a DSC cell.
Therefore& )now the decomposition temperatures of all drugsand heat in a DSC evaluation to ?;
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T"A0S%ectrosco%y1Chromatogra%hy
Com.ination
TGA IR or MS or GC
Gases, vapors
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Thermogra!imetry thermal analysis
(T"A) testing
Thermogravimetric ,T!A analysis providesdetermination of endotherms& e'otherms& weight losson heating& cooling& and more.
"aterials analy*ed by T!A include polymers&plastics& composites& laminates& adhesives& food&coatings& pharmaceuticals& organic materials& rubber&
petroleum& chemicals& e'plosives and biologicalsamples.
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T"A materials analysis
Thermogravimetric analysis uses heat to forcereactions and physical changes in materials.
T!A provides 2uantitative measurement of masschange in materials associated with transition andthermal degradation.
T!A records change in mass from dehydration&decomposition& and o'idation of a sample with timeand temperature.
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T"A materials analysis
Characteristic thermogravimetric curves are given for
specific materials and chemical compounds due to uni2uese2uence from physicochemical reactions occurring overspecific temperature ranges and heating rates.
These uni2ue characteristics are related to the molecularstructure of the sample.
>hen T!A is used in combination with %TIB& T!A=%TIBis capable of detailed %TIB analysis of evolved gases
produced from the T!A.
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T"A thermogra!imetric ca%a.ilities
Compositional analysis of materials
Decomposition temperatures
Bate of degradation
(roduct lifetimes 0'idative stability
valuation of polymer flammabilities
Thermal stabilities Determination of rancidity of edible oils
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S&mmary of $harmace&tically Rele!ant
information Deri!ation from T"A Analysis
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# 2 iff . t
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#a2or ifference .et3een
T"A an DTA (DSC)
T!A reveals changes of a sample due to weight& whereas DTA andDSC reveal changes not related to the weight ,mainly due to phasetransitions+
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Differencial Scanning Calorimetry
(DSC)
Characteri*ation of pharmaceuticalcompounds and analysis of comple' modernformulations& together with an increasing need
for data to support regulatory submissions&means that the pharmaceutical industry nowdepends on the range of thermal analysis
techni2ues.
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Differential Scanning Calorimetry (DSC)
'othermaldH=dT
Temperature
DSC measures differences in the amount of heat re2uired to increase thetemperature of a sample and a reference as a function of temperature
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Ci it f DSC
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Circ&itry of a DSC
T3o se%arat heating circ&its:4 The a!erage-heating controller
,The temperatures of the sample ,Ts and reference ,Tr are measured and
averaged and the heat output is automatically ad5usted to increase theaverage temperature of the sample and reference in a linear rate
4 Differential-heating circ&it
,"onitor the difference in Ts and Tr& and automatically ad5ust the power toeither the reference or sample chambers to )eep the temperatures e2ual
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Sam%le containers an sam%ling
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Differential Scanning Calorimeter
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Con!entional DSC
"etal6
"etal7
"etal6
"etal7
Sample mpty
SampleTemperature
BeferenceTemperature
TemperatureDifference $eat %low
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+ariants of DSC
$eat flu' 6J?? oersma 6 large ,8; 6;; g furnace
(ower compensated Separate small ,6 g microheaters for sample and reference
$yper DSC +ery fast scan rates ?;;
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Variants of DSC
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DSC Techni'&e
(rinciple $eat %lu' (ower Compensation Sample (reparation - Sample Shape - Sample pans - Sample >eight 'perimental Conditions - Start Temperature - nd Temperature - Beference (an
- $eating Bate - ffects of heating rate (urge !as DSC Calibration
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DSC- $rinci%le
Principle DSC is a thermo-analytical techniue in!hich the difference in the amount of heat reuired toincrease the temperature of a sample and reference ismeasured as a function of temperature"
The differences in heat flow occur with the occurrenceof two ma5or events
6 The heat capacity of the sample which increaseswith temperature ,baseline
7 Transitions that occur in the sample ,eventssuperimposed on the heat capacity baseline
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DSC- $rinci%le
$eat %low Bate is e'pressed in a variety of unitswhich can also be normali*ed for the weight ofsample used
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(rinciple 0f DSC
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Typical DSC Curve
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Transitions in a DSC C&r!e
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Differential Scanning Calorimeter
A DSC consists of a cell& which is the heart of aDSC.
The cell is connected with a gas inlet throughwhich different gases are purged depending on thedata re2uired.
ased on the DSC cells there are two primarytypes 6.Heat #lux $" Po!er Compensation
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DSC
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eat 4l&,
This consists of a large single furnace which acts as aninfinite heat sin) to provide or absorb heat from thesample.
The advantages generally include a better baseline&sensitivity and sampleatmosphere interaction.
The )ey components are the Sample pan ,typically analuminum pan and lid which is combined with theBeference pan ,always the same material as the Sample
pan& aluminum.
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eat 4l&,
The Dynamic sample chamber is the environment of thesample pan compartment and the purge gas.
itrogen is the most common gas& but alternate inert gas is
helium or argon.
>hen using an o'idative atmosphere air or o'ygen are thegases of choice.
The heat flu' DSC is based on the Change in TemperatureLT between the sample and reference.
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eat 4l&, Ty%e DSC
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eat 4l&, an DSC
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eat 4l&, Ty%e DSC
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Po!er Compensation
Small individual furnaces use different amounts of powerto maintain a constant LT between sample and referenceand the advantage here include faster heating and cooling&and better resolution.
This type of cell& with two individually heated withplatinum heaters monitors the difference between thesample and reference.
(latinum resistance thermometers trac) the temperaturevariations for the sample and reference cells.
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Po!er Compensation
$oles in the compartment lids allow the purge gas toenter and contact the sample and reference.
There are physical differences between the heat flu'and power compensated thermal analysis& theresulting fusion and crystalli*ation temperatures arethe same.
The heat of transition is comparable 2uantitatively.
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$o3er Com%ensation DSC Cell
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$o3er Com%ensation DSC Cell
Design
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$o3er Com%ensate DSC
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$rinci%les of DSC Analysis
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Sam%le $re%aration
Sam%le Sha%e
Sam%le $ans
Sam%le 5eight
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Sam%le $re%aration
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Sam%le Sha%e
In most cases lids should always be used in order tomore uniformly heat the sample and to )eep thesample in contact with the bottom of the pan.
In case where o'idation properties of a sample are tobe studied no lid is used and the purge gas is usuallyo'ygen as described in AST" Standard Test "ethods
6M?M& 0'idative Induction Time or AST" 7;;J&0'idation onset temperature.
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Sample Pans
/ightest& flattest pans are )nown to have the leasteffect on the results obtained from a DSC.
Crimped pans on the other hand provide the highestsensitivity and resolution.
$ermetic pans are used where the sample is e'pectedto have some volatile content.
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Sample Pans
These pans prevent evaporation.
Two main reasons for the use of these pans are The
Tg of a polymer or amorphous material shifts withvolatile content.
vaporation pea)s loo) 5ust li)e melting endotherm.
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Sample %eight
Though ? to 6; mg is considered to be an appropriatesample weight for a DSC test& selection of theoptimum weight is dependent on a number of factorsthe sample to be analy*ed must be representative ofthe total sample and the change in heat flow due tothe transition of interest should be in the range of ;.6- 6;m>
A recommendation for metal or chemical meltingsample is N ?mg.
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S l i h
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Sample %eight
%or polymer glass transition Tg or melting sample themass should be O 6;mg.
(olymer composites or blends the sample mass isK6;mg.
The accuracy of the analytical balance used tomeasure the sample weight should be accurate to @6.
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E i l C i i
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E,%erimental Conitions
Start Tem%erat&re
En Tem%erat&re
Reference $an
eating Rate
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Start Tem%erat&re
!enerally& the baseline should have 7 minutesto completely stabili*e prior to the transition ofinterest.
Therefore& at 6;
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En Tem%erat&re
Allowing a 7-minute baseline after thetransition of interest is considered appropriatein order to correctly select integration or
analysis limits.
Care should be ta)en not to decompose
samples in the DSCP it not only affects thebaseline performance but the cell life.
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R f $
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Reference $an
A reference pan of the same type used toprepare the sample should be used at all times.
A material in the reference pan that has atransition in the temperature range of interestshould never be used.
02 January 2013 87Goa College of Pharmacy, Goa.
ti R t
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eating Rate
$eating the samples at low heating ratesincreases resolution by providing more time atany temperature.
Transitions due to )inetic processes ,such ascrystalli*ation are shifted to lower
temperature at highest cooling rates or highertemperatures at high heating rates.
02 January 2013 88Goa College of Pharmacy, Goa.
ti R t
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eating Rate
02 January 2013 89Goa College of Pharmacy, Goa.
Eff t f h ti t
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Effects of heating rate
DSC curves of Acetophenetidin and (henacetin.
The Acetophenetidin DSC at ;.?
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DSC c&r!es of Aceto%henetiin
02 January 2013 91Goa College of Pharmacy, Goa.
Eff t f h ti t
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Effects of heating rate
The melting temperature of pure drugs orchemicals will have the same e'trapolatedonset temperature or the melting point as seen
at two varying heating rates.
The DSC Curve for (henacetin viewed at
heating rates of 6.;& ?.; and 7;
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DSC c&r!es of $henacetin
02 January 2013 93Goa College of Pharmacy, Goa.
Eff t f h ti t
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Effects of heating rate
If you use multiple heating rates then start with 6.;and 6;
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Effect of eating Rate
02 January 2013 95Goa College of Pharmacy, Goa.
P &
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Purge &as
itrogen being a relatively poor thermalconductor increases sensitivity whereas heliumwhich is a good conductor of heat to or from
the sample increases resolution.
DSC is used in studying the melting&
crystalli*ation& glass transition& o'idation anddecomposition of pharmaceuticals.
02 January 2013 96Goa College of Pharmacy, Goa.
Purge &as
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Purge &as
y selecting different parameters useful datasuch as the purity& polymorphic transitions canbe obtained.
A typical DSC curve could give glasstransition temperature& melting temperature&
crystalli*ation temperature and decompositiontemperatures.
02 January 2013 Goa College of Pharmacy, Goa. 97
$&rge "ases
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$&rge "ases
02 January 2013 98Goa College of Pharmacy, Goa.
S&mmary of DSC e,%erimental
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y %
conitions
02 January 2013 99Goa College of Pharmacy, Goa.
$&rity .y DSC
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$&rity .y DSC
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$&rity Determination
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$&rity Determination
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S&mmary of $harmace&tically Rele!ant
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Information Deri!e from DSC Analysis
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#elting $oint
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#elting $oint
02 January 2013 104Goa College of Pharmacy, Goa.
#elting $rocess .y DSC
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#elting $rocess .y DSC
02 January 2013 105Goa College of Pharmacy, Goa.
#elting
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#elting
egative pea) onthermogram
0rdered to disordered
transition Tm& melting temperature
"elting happens tocrystalline polymersP!lassing happens toamorphous polymers
Temperature, K
Thermogram
dH/dt,mJ/s
Meltig
Tm
02 January 2013 106Goa College of Pharmacy, Goa.
$olymor%hic 4orms
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$olymor%hic 4orms
02 January 2013 107Goa College of Pharmacy, Goa.
$se&o%olymor%hism
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$se&o%olymor%hism
02 January 2013 108Goa College of Pharmacy, Goa.
Amor%ho&s #aterial
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Amor%ho&s #aterial
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#o&late Tem%erat&re 6 DSC
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(#T-DSC)
"ost transitions detected by DSC will appear as pea)s& wherea change ,e'othermic or endothermic is detected and thenthere 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 e2uilibriumstate.
!lass transitions& on the other hand& are neither first-order norsecond-order transitions since neither the glassy state nor the
viscous state is an e2uilibrium state. Typical DSC thermograms will reveal glass transitions as step-
wise increases in the heat capacity ,Cp of the sample.
02 January 2013 110Goa College of Pharmacy, Goa.
#o&late Tem%erat&re 6 DSC
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(#T-DSC)
This is due primarily to the increase in molecular motionof the sample above the Tg.
In some cases& the determination of Tg is relativelystraightforward but this wor) can be some of the most
challenging done with DSC. "ore on detecting and determining Tg:s will be presented
in the applications section of this review but glasstransitions are mentioned here because this applicationhas help drive the development of modulated-temperatureDSC instruments and methods.
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#o&late DSC (#DSC)
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#o&late DSC (#DSC)
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#o&late Tem%erat&re DSC
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(#TDSC)
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#DSC for $olymor%h
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Characteri7ation
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Variants of #TDSC
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Variants of #TDSC
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E,am%le of a #TDSC C&r!e
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E,am%le of a #TDSC C&r!e
02 January 2013 116Goa College of Pharmacy, Goa.
4ast Scan DSC/ Ra%i Scanning DSC
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4ast Scan DSC/ Ra%i Scanning DSC
02 January 2013 117Goa College of Pharmacy, Goa.
4ast Scan DSC/ Ra%i Scanning DSC
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4ast Scan DSC/ Ra%i Scanning DSC
02 January 2013 118Goa College of Pharmacy, Goa.
8y%er9 DSC
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y%er DSC
02 January 2013 119Goa College of Pharmacy, Goa.
DSC Cali.ration
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DSC Cali.ration
Calibration of DSC is done using Indium metal. Calibrating an instrument with a metal when
pharmaceuticals are to be studied appears to be notappropriate.
To overcome this& an effort has been made to calibrateDSC with pharmaceuticals.
The true melting temperature of indium metal is6?F.G
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DSC Cali.ration c&r!e of ini&m
02 January 2013 121Goa College of Pharmacy, Goa.
DSC 6 A%%lications
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DSC A%%lications
&lass 'ransition 'emperature ('g)
&lass 'ransition Si*e (+Cp)
Crystalli*ation temperature ('c)
Crystallinity (based on ,g and ad.usted to /)
Polymorphic 'ransitions"
02 January 2013 122Goa College of Pharmacy, Goa.
"lass Transition Tem%erat&re
(T )
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(Tg)
The glass transition is due to the presence ofamorphous structures in the sample.
It is detected by DSC based on a step-change inmolecular mobility that results in a step increasein heat capacity and heat flow rate.
Amorphous materials flow& they do not melt andhence no DSC melt pea).
The physical and reactive properties ofamorphous structure are different than crystallinestructure.
02 January 2013 123Goa College of Pharmacy, Goa.
"lass Transition Tem%erat&re
(T )
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(Tg)
The physical and reactive properties ofamorphous structure are significantly different attemperatures above and below Tg.
The glass transition temperature& Tg& is a secondorder pseudo transition.
It constitutes a parameter of high interest in the
study of amorphous and semi-crystalline drugssince amorphous drugs are more bio availableand soluble.
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!lass Transition
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!lass Transition
Step in thermogram Transition from
disordered solid toli2uid
0bserved in glassysolids& e.g.& polymers
Tgglass transition
temperature
Temperature, K
Thermogram
dH/dt,m
J/s Glass trasitio
Tg
02 January 2013 125Goa College of Pharmacy, Goa.
&lass 'ransition Si*e (+Cp)
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&lass ansition Si*e ( Cp)
The LCp at Tg is a measure of the fle'ibilityassociated with the Tg.
A larger value implies a more rubbery material& e.g.&polybutadiene.
Stiffer polymers li)e polystyrene have a lower value.
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Crystalli*ation
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y
Sharp positive pea) Disordered to ordered
transition
"aterial can crystalli*eR 0bserved in glassy
solids& e.g.& polymers
Tccrystalli*ationtemperature
Temperature, K
Thermogram
dH/dt,m
J/s
Cr!stalli"atio
T#
02 January 2013 128Goa College of Pharmacy, Goa.
Analysis
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y
Sharp positive pea)
Disordered to ordered
transition
0bserved in glassysolids& e.g.& polymers
Tccrystalli*ationtemperature
Temperature, K
dH/dt,m
J/s
Cr!stalli"atio
T#
02 January 2013 129Goa College of Pharmacy, Goa.
Crystallinity (based on ,g and
d. t d t /)
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ad.usted to /)
The Crystallinity measured by comparing successive heatand cool DSC runs on a drug will yield the change incrystallinity by comparing the $eat of Crystalli*ation tothe $eat of %usion '6;;.
This crystallinity by this method was GM forAcetophenetidin& 7; for Sulfapyradine and ; for/idocaine.
This implies that /idocaine remains amorphous for aperiod of time.
02 January 2013 130Goa College of Pharmacy, Goa.
Polymorphic 'ransitions"
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y p
Sulfanilamide (olymorphs It was observed thatsulfanilamide polymorphs are stable and do not showtransition among its forms at heating rates between 6 and6;hen tolbutamide polymorphs wereobserved by DSC a significant difference was seen in their
behavior. The difference is due to their structures which
were observed by scanning electron microscope ,S". The DSC curves are shown below along with the S"
02 January 2013 131Goa College of Pharmacy, Goa.
DSC c&r!es of S&lfanilamie
$olymor%hs
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$olymor%hs
02 January 2013 132Goa College of Pharmacy, Goa.
DSC of $olymor%hs of Tol.&tamie:
Tol.&tamie A (4orm ) an B (4orm ;)
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Tol.&tamie A (4orm ) an B (4orm ;)
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SE# of Tol.&tamie %olymor%hs
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% y %
02 January 2013 Goa College of Pharmacy, Goa. 134
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$olymor%h Screening an
Ientification
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Ientification
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DSC thermal analysis
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Thermal (hase Change
Thermal !lass Transition Temperature ,Tg Crystalline "elt Temperature
ndothermic ffects
'othermic ffects
Thermal Stability
Thermal %ormulation Stability
0'idative Stability Studies
Transition (henomena Solid State Structure
Analysis of a Diverse Bange of "aterials
02 January 2013 137Goa College of Pharmacy, Goa.
DSC analysis etermines
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Tg !lass Transition Temperature
Temperature ,
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AST" 67FJ-;? Determination Specific $eat Capacity byDSC
- G7M epaling van de 0'idatieve Inductieti5d
IS077GFM Bubber& Determination of the glass transition
temperature by DSC AST" D6?6J-J? Bubber& Determination of "elting Bange
AST" D8Q6M-;8 Transition Temperatures of (olymers yDSC
IS0668?G-Q Determination of Specific $eat Capacity IS0668?G-8 Determination of nthalpy Temperature of "elting
and Crystalli*ation
02 January 2013 139Goa College of Pharmacy, Goa.
So&rces for Errors
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4 Calibration4 Contamination
4 Sample preparation how sample is loaded into a pan
4 Besidual solvents and moisture.4 Thermal lag
4 $eating=Cooling rates
4 Sample mass
4 (rocessing errors
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T"A an DSC
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Thermogravimetric Analysis ,T!A
"ass change of a substance measured as function of
temperature whilst the substance is sub5ected to acontrolled temperature programme.
"ass is lost if the substance contains a volatile
fraction.
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T!A and DSC
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Differential Scanning Calorimetry ,DSC
(rovides information about thermal changes that do
not involve a change in sample mass
"ore commonly used techni2ue than T!A
Two basic types of DSC instruments heat-flu' andpower compensation
02 January 2013 142Goa College of Pharmacy, Goa.
Ty%ical T"A an DSC Res<s
for Vario&s Transitions
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for Vario&s Transitions
02 January 2013 Goa College of Pharmacy, Goa. 143
*actose monohyrate
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02 January 2013 144Goa College of Pharmacy, Goa.
y%henate Thermal E'&i%ment
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02 January 2013 145Goa College of Pharmacy, Goa.
Tem%erat&re Scales
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02 January 2013 146Goa College of Pharmacy, Goa.
#a,3ell-Bolt7mann Distri.&tion
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02 January 2013 147Goa College of Pharmacy, Goa.
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DSC A%%lications In
$harmace&tical In&stry
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$harmace&tical In&stry
%ast and reliable research tool. DSC allows fast evaluation of possible
incompatibilities& because it shows change in theappearance& shift or disappearance of melting&endosperms and e'otherms or variations in thecorresponding enthalpies of reaction.
Bapid analysis& easy handling& high significance
for research& development and 2uality control.
02 January 2013 Goa College of Pharmacy, Goa. 149
Characteri7ation for $harma
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02 January 2013 150Goa College of Pharmacy, Goa.
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Im%ortance of Soli State 4orms in $harma
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02 January 2013 152Goa College of Pharmacy, Goa.
Com%ati.ility St&ies
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02 January 2013 153Goa College of Pharmacy, Goa.
DSC in (olymer Analysis
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"ain transitions which can be studied by DSC
"elting
%ree*ing
!lass transition
02 January 2013 154Goa College of Pharmacy, Goa.
$olymer DSC Analysis Ca%a.ilities
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"elting point = "elting Bange $eat Capacity
Crystalli*ation
!lass Transition Identification
Thermal stability
Decomposition Temperature
0'idative Induction Times ,0IT by DSC
(urity
02 January 2013 155Goa College of Pharmacy, Goa.
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TER#O#ECANICA* ANA*+SIS
(T#A)
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Thermo-#echanical Analysis
(T#A)
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(T#A)
Thermo-mechanical analysis ,T"A providesdimensional properties data for materials.
"aterials tested by thermo-mechanical anlaysisinclude polymers& composites& laminates&adhesives& coatings& pharmaceuticals& metals&
glass& ceramics& fibres and other materials.
02 January 2013 157Goa College of Pharmacy, Goa.
Thermo-#echanical Analysis (T#A)
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"easurement of Dimensional Change
Coefficient of /inear Thermal 'pansion
Determination of "aterial Anisotropy
Softening Temperatures and !lass Transition
/inear Thermal 'pansion
02 January 2013 158Goa College of Pharmacy, Goa.
Thermomechanical Analysis
(T#A)
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(T#A)
T"A is a thermal analysis techni2ue used to measurechanges in the physical dimensions ,length or volumeof a sample as a function of temperature and time undera non oscillatory load.
This techni2ue is widely applicable to variety ofmaterials such as pharmaceuticals& polymers& ceramicsand metals etc.
T"A has been used in pharmaceutical analysis. +ariables considered while performing the thermal
mechanical analysis are applied load& gas environment&temperature range and heating rate as well as T"Aprobe type.
02 January 2013 159Goa College of Pharmacy, Goa.
Thermomechanical Analysis
(T#A)
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(T#A)
The tests are run in a heating mode at a desiredheating rate and temperature range of interest.
(robe displacement profiles are subse2uentlyanaly*ed in terms of coefficient of thermal e'pansion&softening and melting temperatures& and glasstransition temperatures.
The different T"A probe types and recorded as afunction of temperature.
02 January 2013 Goa College of Pharmacy, Goa. 160
Ty%es of T#A %ro.es
an res<ing meas&re %ro%erties
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g % %
02 January 2013 161Goa College of Pharmacy, Goa.
Thermomechanical Analysis
(T#A)
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(T#A)
T"A consists of a 2uart* stage& a 2uart* probe&furnace which sits on top of the stage&e2uipped with inlet for purge gas&
thermocouple ad5acent to the stage and a/+DT ,linear variable differential transformerattached to the probe& which measures thedifference in the dimensions caused under theprobe.
02 January 2013 162Goa College of Pharmacy, Goa.
Sam%le %re%aration
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The use of T"A in the pharmaceuticalindustry is limited to polymers.
In order to e'amine powdered samples& thesample is pac)ed into a flat DSC pan.
The dimension of the sample is measured byT"A in millimeters.
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E,%erimental Conitions
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The T"A is operated under the followingconditions and includes the heating rate at6;
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Calibration of T"A is done using an Indium metal.
Calibrating an instrument with a metal whenpharmaceuticals are to be studied does not soundappropriate.
To overcome this& an effort has been made to calibrate
T"A with pharmaceuticals.
02 January 2013 165Goa College of Pharmacy, Goa.
T#A C&r!e of Ini&m
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02 January 2013 166Goa College of Pharmacy, Goa.
T"A Applications
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T"A is used to obtain the meltingtemperature& softening temperature& coefficientof thermal e'pansion ,CT and glass
transitions ,Tg of materials.
02 January 2013 167Goa College of Pharmacy, Goa.
DI44ERENTIA* TER#A*
ANA*+SIS
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seful for investigation of solid-solid interactions.
Thermograms are obtained for pure drugs and for mi'turesusing different ratios.
In absence of any interaction thermograms of mi'ture showpattern corresponding to that of individual components.
ut if interactions occur it is indicated in thermograms byappearance of one= more pea)s corresponding to thosecomponents.
02 January 2013 Goa College of Pharmacy, Goa. 168
RO*E O4 TER#A* ANA*+SIS IN
$RE4OR#*AION
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They are uni2ue methods in the field ofpolymer analysis of high value for a solidstate analysis
- They finds wide application in a Study of comple'ation
b Detection of impurity
c Study of polymorphism
02 January 2013 Goa College of Pharmacy, Goa. 169
A$$*ICATION O4 TER#A*
ANA*+SIS IN $RE4OR#*ATION
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Characteri*ation of hydrates and solvates(reformulation studies is to identify the abilityof drug to ta)e up water and characteri*e the
state of this water.
T!A is useful for characteri*ation of hydrates
solvates.
02 January 2013 170Goa College of Pharmacy, Goa.
INNOVATION IN TER#A*
ANA*+SIS
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6 "/TI/"TA/ SCAI!T$B"A/ AA/USIS ,"STA
7 "ICB0T$B"A/ AA/USIS
8 "0D/ATD DSCQ B00TIC SUST"
? %AST SCA DSC
F DUA"IC "C$AICA/ AA/USIS
02 January 2013 171Goa College of Pharmacy, Goa.
*imitations of Thermal Analysis
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6 /ow sensitivity for transitions involving smallenergies.
7 Impurity consisting of molecules of same
si*e&shape& character as those of the ma5orcomponent are not detected by DSC.
8 T!A used to studies hydrates moisture study
are not always reliable.Q Thermal analysis are affected by number of
factors02 January 2013 172Goa College of Pharmacy, Goa.
Thermal analysis ca%a.ilities Thermal (hase Change
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!lass Transition Temperature
Crystalline "elt Temperature ndothermic ffects
'othermic ffects
%lashpoint Testing
/inear Thermal 'pansion Thermal Stability
Thermal %ormulation Stability
0'idative Stability Studies
%lammability Testing of "aterials
"icroscopy of Thermal (rocesses
Thermal Analysis of a diverse range of materials
02 January 2013 173Goa College of Pharmacy, Goa.
Thermal Analysis
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Characteristic: Thermal %ro%erties:
"orphological change "elting points& glass transition ,Tg&crystallinity& thermal history& nucleation&enthalpy of fusion or re-crystallisation&specific heat capacity ,Cp
Dimensional change Coefficient of thermal e'pansion ,C/T&
shrin)age data& anisotropy due to fillers&reinforcing materials& softeningtemperatures
+iscoelastic properties Stiffness and damping properties&molecular phase interactions bymechanical loss
"ass change Thermal stability& thermal o'idativestability& thermal transitions& solvent loss&water = filler content& organicratios& inorganic ratios
02 January 2013 174Goa College of Pharmacy, Goa.
Thermal Analysis Instr&ment
#an&fact&rers
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(er)in lmer Thermal Analysis Systems
htt%:11333
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A new technology 9nanothermal analysis: ,nano-TA&which in con5unction with other techni2ues providesa powerful analytical strategy for characterising nano-and micro-scale heterogeneity in the solid-state
properties of drugpolymer formulations. anothermal analysis is an emerging locali*ed
thermal analysis techni2ue which combines the highresolution imaging capabilities of atomic forcemicroscopy ,A%" with the ability to characteri*e thethermal properties of materials .
02 January 2013 176Goa College of Pharmacy, Goa.
8Nanothermal Analysis9
(Nano-TA)
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( )
It offers significantly enhanced spatial resolutioncompared with its predecessor& scanning thermalmicroscopy.
In nano-TA the conventional silicon based A%" tip isreplaced by a speciali*ed micro fabricated silicon-based probe with a miniature heater that has a
topographic spatial resolution of around ? nm and athermal property measurement resolution of up to7;nm.
02 January 2013 Goa College of Pharmacy, Goa. 177
8Nanothermal Analysis9
(Nano-TA)
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Importantly this probe enables a surface to be studied withthe most widely applied A%" imaging mode& tappingmode& enabling the analysis of softer samples& such aspolymers& without damage from the imaging probe.
As nano-TA can be used to map thermal properties duringimaging& or to carry out local thermal analysis ,/TA atdefined points on a surface.
/TA& where the probe is heated in a temperature cycle not
dissimilar to DSC whilst in contact with the sample& canprovide 2uantitative information on thermally inducedphase transitions.
02 January 2013 Goa College of Pharmacy, Goa. 178
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12"NK 34U
02 January 2013 179Goa College of Pharmacy, Goa.
Cell No: 00919742431000
E-mail: [email protected]
OB>ECTIVES
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The main ob5ective to introduce thermalanalysis and its applications at an entry levelin the pharmaceutical industry.
In the process& instruments were successfullycalibrated using pharmaceuticals.
Studying the behavior of pharmaceuticals bydifferent thermal analysis instruments& under
different conditions and then compare theresults was another ob5ective.
02 January 2013 180Goa College of Pharmacy, Goa.
Thermal Analysis of $harma
#aterials
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DSC&T!=DTA and T!=DTA-IB are often used forcharacterisation of pharma materials.
DSC& alone or in combination with hot-stagemicroscopy& is able to differentiate between different
polymorphic structures and& by using differentheating rates& can investigate the transformations
which occur during the polymorphic transformation.
02 January 2013 181Goa College of Pharmacy, Goa.
Thermal Analysis of $harma
#aterials
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y using appropriate heating rates&polymorphic purity can be determined& and caninvolve heating rates up to G?;
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(olymers represent another large area in whichthermal analysis finds strong applications.
Thermoplastic polymers are commonly found ineverydaypac)agingand household items& but for theanalysis of the raw materials& effects of the manyadditive used ,including stabilisers and colours and
fine-tuning of the moulding or e'trusion processingused can be achieved by using DSC.
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An e'ample is o'idation induction time ,0IT by DSC whichcan determine the amount of o'idation stabiliser present in athermoplastic ,usually a polyolefin polymer material.
Compositional analysis is often made using T!A& which canseparate fillers& polymer resin and other additives.
T!A can also give an indication of thermal stability and the
effects of additives such as flame retardants
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ven though most of the thermal analysis methods canhandle samples such as solids& semi-solids or li2uids& anevaluation of the contemporary literature would recommendthat solid-state portrayal could apply to most of thepharmaceutical research applications.
Common applications used in thermal analysis incorporate thecategori*ation of the physicochemical attributes of crystallinesolids and the discovery and classification of polymorphicforms.
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If any laboratory - be it a pharmaceuticalindustry or an academic research institute&needs to purchase no more than one piece of
thermal analysis e2uipment& it is most li)ely tobe a DSC.
These instruments can be purchased fromnumerous manufacturers with wide options ofprice and applications.
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The DSC concept was formerly derived from earlierDTA instruments. >hile DTA measures the differencein temperature& DSC grants for the measurement of amodification in enthalpy.
9The International Confederation for ThermalAnalysis and Calorimetry: ,ICTAC has defined DSC
as a techni2ue where 1the heat flow rate differenceinto a sample and reference material is measured.W
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Two types of basic DSC instruments are available todaycommercially - heat-flu' DSC ,hf-DSC and powercompensation DSC ,pc-DSC.
As per the latest audits& both the instruments are e'tremelyversatile and very comparable.
>hile engaging different techni2ues to inspect themeasurement& both the types of instruments are employed tomeasure heat flow and this seems to be certified as DSC underthe ICTAC(International Confederation for Thermal Analysis
and Calorimetry) definition. 0riginally the term heat-flu' DSC was used to illustrate
2uantitative DTA instruments.
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ow& it is universally denoted as a DSC method. This progress was an improvement over DTA& which allowedfor a measurement in the changes in heat flow as compared toonly temperature.
This was reached by the accumulation of a second se2uence ofthermocouples in order to measure the temperature of afurnace and a heat sensitive plate.
y measuring the capacity of the heat sensitive plate as a tas)of temperature during the process of manufacturing& anestimation of the enthalpy of transition can be prepared by theincremental temperature fluctuation.
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(ower-compensation DSC is different from hf-DSC inoperating principle as well as in basic instrumentdesign.
Xust as the name can notes& pc-DSC measures the
change in power or energy essential to preserve thesample and references material at the identicaltemperature all through the heating or cooling cycle.
This is carried out through an instrument designwhich is different than that normally found in hf-DSCinstruments.
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Two individual heaters are used with pc-DSC tocontrol the flow of heat to the sample and referenceholders.
Individual resistance sensors are positioned within
each holder and temperature is measured at the base ofeach.
>hen a phase change ta)es place in a in thermalanalysis and a temperature difference is observed
between the sample and reference& energy is removedor supplied until the temperature difference is lowerthan the threshold.
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The current field of thermal analysis is both diverse anddynamic.
Although not a new field& more advanced instrumentation&techni2ues and applications are constantly appearing on themar)et and in the literature.
Theoretically& almost any substance whether solid& semi-solidor li2uid can be analy*ed and characteri*ed with thermalanalytical techni2ues.
Common materials include foods& pharmaceuticals& electronicmaterials& polymers& ceramics& organic and inorganiccompounds& even biological organisms.
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In theory& all thermal analytical techni2ues simplymeasure the change of a specific property of amaterial as a function of temperature.
This in turn allows researchers access to information
regarding macroscopic theories of matter including&e2uilibrium and irreversible thermodynamics and)inetics.
>hile numerous techni2ues are available& the primarydifferences in the techni2ues are the properties of thematerial being studied.
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In the pharmaceutical sciences& only a handful of thetechni2ues are commonly employed but the informationgained and phenomena that can be e'plored are countless.
The primary wor)horses in the pharmaceutical sciencesinclude& differential scanning calorimetry ,DSC&thermogravimetric analysis ,T!A& differential thermalanalysis ,DTA and thermomechnical analysis ,T"A.
Admittedly& as the needs of the researcher change and newmaterials are identified in formulation development& less
commonly used techni2ues are being utili*ed and developedresulting in a very dynamic and e'citing field of research.
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The first will be thermal analytical methodscommonly used in the pharmaceutical sciences&primarily DSC ,including several speciali*edtechni2ues& T!A and T"A.
The second will focus on applications in thepharmaceutical sciences including solid-state