6.1 Thermal Analysis

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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

02 January 2013 1Goa College of Pharmacy, Goa.


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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.

02 January 2013 Goa College of Pharmacy, Goa. 2


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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


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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(T"A)

A techni2ue that permitsthe continuous weighingof a sample as afunction of temperatureand=or as a function oftime at a desiredtemperature

http://upload.wikimedia.org/wikipedia/commons/e/e6/Analyse_thermo_gravimetrique_appareil.svg


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Differential Thermal Analysis



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(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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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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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


# 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


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.


$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.


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.


E i l C i i


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Start Tem%erat&re

En Tem%erat&re

Reference $an

eating Rate


S T


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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.


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.


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.


ti R t


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eating Rate


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


Eff t f h ti t


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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


Eff t f h ti t


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If you use multiple heating rates then start with 6.;and 6;


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Effect of eating Rate


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.


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.


$&rge "ases


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$&rge "ases


S&mmary of DSC e,%erimental


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y %

conitions


$&rity .y DSC


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$&rity .y DSC


$&rity Determination


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$&rity Determination


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


#elting $rocess .y DSC


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#elting $rocess .y DSC


#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


$olymor%hic 4orms


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$olymor%hic 4orms


$se&o%olymor%hism


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$se&o%olymor%hism


Amor%ho&s #aterial


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Amor%ho&s #aterial


#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.


#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.


#o&late DSC (#DSC)


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#o&late DSC (#DSC)


#o&late Tem%erat&re DSC


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(#TDSC)


#DSC for $olymor%h


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Characteri7ation


Variants of #TDSC


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Variants of #TDSC


E,am%le of a #TDSC C&r!e


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E,am%le of a #TDSC C&r!e


4ast Scan DSC/ Ra%i Scanning DSC


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8y%er9 DSC


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y%er DSC


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


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"


"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.


"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.


!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


&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#


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#


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.


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"


DSC c&r!es of S&lfanilamie

$olymor%hs


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$olymor%hs


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 ;)


SE# of Tol.&tamie %olymor%hs


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% y %



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$olymor%h Screening an

Ientification


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Ientification


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


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


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


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.


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


Ty%ical T"A an DSC Res&lts

for Vario&s Transitions


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for Vario&s Transitions


*actose monohyrate


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y%henate Thermal E'&i%ment


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Tem%erat&re Scales


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#a,3ell-Bolt7mann Distri.&tion


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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.


Characteri7ation for $harma


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Im%ortance of Soli State 4orms in $harma


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Com%ati.ility St&ies


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DSC in (olymer Analysis


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"ain transitions which can be studied by DSC

"elting

%ree*ing

!lass transition


$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



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TER#O#ECANICA* ANA*+SIS

(T#A)


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.


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


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.



(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.


Ty%es of T#A %ro.es

an res&lting meas&re %ro%erties


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g % %



(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.


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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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.


T#A C&r!e of Ini&m


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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.


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.


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


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.


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


*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


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


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 .


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.


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.



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12"NK 34U


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.


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.


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.


Thermal Analysis of $olymers


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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


Thermal Analysis #ethos se in

$harmace&tical


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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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$harmace&tical


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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.



$harmace&tical


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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



$harmace&tical


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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.



$harmace&tical


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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.



$harmace&tical


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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.



$harmace&tical


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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.


Techni'&es an A%%lications in the

$harmace&tical Sciences


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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

6.1 Thermal Analysis

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