Nichola 1995 Modulated Temperature Differential Scanning Calorimetry

8/14/2019 Nichola 1995 Modulated Temperature Differential Scanning Calorimetry

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E L S E V I E R Internation al Journa l of Pharm aceutics 135 (1996) 13 29

i n t e r n a t i o n a ljo u r n a l o fp h a r m a c e u t i c s

Invited review

Modulated temperature differential scanning calorimetry: anovel approach to pharmaceut ical thermal analysis

N i c h o l a J . C o l e m a n , D u n c a n Q . M . C r a i g *

Centre .[or Materials" Science, The School of Pharmacy, University of London, 29 -39 Brunswick Square, London W C IN lA X, U

Received 11 Dec emb er 1995; accepted 22 January 1996

A b s t r a c t

Modulated temperature different ial scanning calorimetry (MTDSC) is a novel therrnoanalyt ical technique winvolves the applicat ion of a s inusoidal heat ing programme to a sample and the resolut ion of the responsereversing and non-reversing signals , thereby enabling the deconv olut ion o f com plex and ov erlapping theprocesses. This represents an important advance on conventional different ial scanning calorimetry (DSC), winvolves the use of a l inear heating pro gram me , and does not al low the separat ion o f the s ignal into com poresponses. In this review, the principles and current uses of convention al D SC will be discussed and com par

th 'ose of MTDSC, part icular ly with a view to emphasising the comparat ive advantages of the new techniquerespect to exist ing methods. A discussion wil l be given of how this technique may be applicable to a ranpharmaceutical systems.

Ke) ,words : Modulated temperature different ial scanning calorimetry; Polymers; Thermal analysis

1 . I n t r o d u c t i o n

D i f f e r e n t i a l s c a n n i n g c a l o r i m e t r y ( D S C ) i s aw e l l e s t a b l i s h e d m e t h o d o f t h e r m a l a n a l y s i s w i t h i n

t h e p h a r m a c e u t i c a l s c i e n c e s . T h e t e c h n i q u e m a yb e u s e d t o c h a r a c t e r i s e p h y s i c a l a n d c h e m i c a le v e n t s v i a c h a n g e s i n e i t h e r e n t h a l p y o r h e a tc a p a c i t y o f a s a m p l e . A s v i r t u a l l y a l l p r o c e s s e s o fp h a r m a c e u t i c a l i n t e r e s t a r e a c c o m p a n i e d b y s u c hc h a n g e s , t h e t e c h n i q u e h a s f o u n d w i d e a p p l i c a t i o n

* Corresponding author.

w i t h in t he f i e l d . I n p a r t i cu l a r, a p p l i c a t i ons i nc l u d et h e d e t e ct i o n o f p o l y m o r p h i s m , m e a s u r e m e n t o fr e a c t i o n a n d d e c o m p o s i t i o n k i n e t i c s , a s s e s s m e n to f t h e c o m p a t i b i li t y o f d o s a g e f r o m c o n s ti t u en t s ,p u r i t y d e t e r m i n a t i o n a n d g l as s tr a n s it i o n t e m p e r a -t u r e s t u d i e s . N u m e r o u s t e x t s a r e a v a i l a b l e i nw h i c h t h e t h e o r y, p r i n c i p l e s , i n s t r u m e n t a t i o n a n da p p l i c a ti o n s o f D S C a r e d is c u ss e d ( W e n d l a n d t ,1 97 4 ; F o r d a n d T i m m i n s , 1 9 8 9; W u n d e r l i c h , 1 99 0;H a ine s , 1 995 ) .

M o d u l a t e d t e m p e r a t u r e d i f f e r e n t i a l s c a n n i n gc a l o r i m e t r y, M T D S C , i s a r e c e n t l y d e v e l o p e d e x -t e n s i o n o f D S C i n w h i c h a s in e w a v e m o d u l a t i o n

0378-5173/96/$15.00 1996 Elsevier Science B.V . All righ ts reservedP II S0378-5173(95)04463-8


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14 N.J. Coleman, D .Q.M . C raig / International Journal of Pharmaceuties 135 (1996) 13- 29

is applied to the standard, linear temperatureprogramme, as shown in Fig. 1. A discreteFourier Transform algorithm is applied to theresultant data to deconvolute the sample responseto the underlying (linear) and modu lated tempera-ture programmes (Read ing et al., 1994). The re-

sponse to the underlying signal is essentiallyindistinguishable from the signal yielded by con-ventional DSC. However, in addition, the methodoffers a number of advantages which will be de-scribed in detail later and include the separationof overlapping phenomena and deconvolution ofcomplex transitions, greater resolution withoutloss of sensitivity, the detection of metastablemelting phenomena, and greater ease of collectionof heat capacity data.

In this review, an overview will be given of the

principles and some of the general pharmaceuticaluses of conventional DSC. A number of texts,particularly that of Ford and Timmins (1989),have already discussed pharmaceutical applica-tions of DSC in detail, hence the purpose of thesummary given here is to provide a suitable con-text for discussion of the MTDSC technique. Theprinciples underlying the types of measurementthat may be made using DSC will be outlinedrather t han a detailed discussion of actual thermalstudies that have been conducted in the pharma-

ceutical field. A discussion of the principles ofMTDSC will then be given, along with an outlineof some of the considerations pertinent to makingMTDSC measurements and the advantages anddisadvantages of MTDSC compared to those ofconventional DSC. The systems to which theMTDSC technique has been applied to date willbe reviewed and the potential uses of the tech-nique within the pharmaceutical sciences will bediscussed.

It should be noted that references involving a

number of DSC methods in which a periodicperturbation (usually a sine wave) is applied tothe standard linear or isothermal temperatureprogramme have recently appeared in the litera-ture (e.g. Sauerbrunn et al., 1993; Sauerbrunn andGill, 1993; Alden et al., 1995; Song et al., 1995;Wulff and Alden, 1995 a; Wulff and Alden,1995b). Various terms such as oscillating, alter-nating, cyclic, and modulated DSC have been

used to distinguish these approaches from thoseof conventional DSC, although the basic princi-ples of these approaches are similar. It has re-cently been suggested by Dr. Mike Reading, whohas pioneered this approach, that the generic termmodulated temperature DSC (MTDSC) should be

used to describe these techniques as a group,while the individual terms cited above should beused to identify the different models available. Atthis early stage in the development of the tech-nique within the pharmaceutical sciences, wewould strongly suggest that this nomenclature isadopted, as otherwise considerable confusion willrapidly develop within the literature. While thereare differences between the various MTDSC tech-niques, the principles outlined here will be verylargely applicable to all the methods. It should,

however, be stated that the review is based on ourexperience with the TA Ins truments model, whichwas developed by Dr. Reading and consequentlyuses the data deconvolution techniques outlinedin his published work; the data analysis used byother models may not exactly be the same hencecare should be taken in extrapolating v e r b a t i m theinformation given here to other models.

7Q

~ 6a .

T ~ ( ~ )

Fig. 1. The comparison of an MTDSC temperature profile(depicted by the unbroken line) and constant heating rateramp (depicted by the dotted line). Heating rate 2C rain ~,modulation amplitude 0.3C and period 30s. (After Seferis etal., 1992).


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N.J. Coleman, D.Q.M. Craig/ Internationa l Journal of Pharmaceutics 135 (1996) 13-29 15

~ .-4.

5 o t d e i z d e - - a ~ e ~ d e

T ~ ( 'C )

F i g . 2 . C o n v e n t i o n a l D S C t h e r m o a n a l y t i c a l c u r v e o f P E Ts h o w i n g : ( a ) a g l a s s t r a n s i t i o n ( w i t h a s s o c i a t e d e n t h a l p i c r e l a x -a t i o n ) , ( b ) a c o l d c r y s t a l l i s a t i o n e x o t h e r m , a n d ( c ) a m e l t i n ge n d o t h e r m .

2. Basic principles of conventional D SC

T h e r m a l m e t h o d s o f a n a ly s i s i n v o l v e t h e m a -n i p u l a t io n o f t e m p e r a t u r e t o p r o d u c e a m e a s u r e dp a r a m e t e r , f r o m w h i c h i n f o r m a t i o n c o n c e r n i n gt h e s t r u c t u re a n d b e h a v i o u r o f a m a t e r i a l m a y b ed e r i v e d . In p a r t i c u l a r, D S C h a s b e e n w i d e l y u s e di n a n u m b e r o f fi e ld s a n d i n v o l v e s t h e i n d i r e c tm e a s u r e m e n t o f d i ff e r e n t ia l p o w e r ( i. e. h e a t f lo w,u s u a l l y e x p r e s s e d i n r o W ) d u r i n g a t h e r m a l e v e n t .

To d a t e , D S C h a s a l m o s t i n v a r i a b l y i n v o l v e d t h ea p p l i c a t io n o f a l i n e ar o r i s o t h e r m a l t e m p e r a t u r ep r o g r a m m e t o a s a m p l e s y s te m a n d t h e c o n t i n u -o u s m e a s u r e m e n t o f h e at f lo w a s a f u n c t i o n o ft e m p e r a t u r e o r t i m e , r e s p e c t i v e l y.

T h e r m a l e v e n t s w h i c h a r e d e t e c ti b l e b y D S Cm a y b e e n d o t h e r m i c ( e . g . m e l t i n g , d e h y d r a t i o n ) ,e x o t h e r m i c ( e . g . c r y s t a l l i s a t i o n ) o r m a y i n v o l v e ac h a n g e i n t h e h e a t c a p a c i t y o f a s a m p l e ( e . g . g l as st r a n s i t i o n p h e n o m e n a ) . T h e s e e v e n t s a r e d e p i c t e di n F i g . 2 , w h i c h s h o w s t h e D S C t r a c e f o r

p o l y e t h y l e n e t e r e p h t h a l a t e ( P E T ) , f o r w h i c h a l lt h r e e m a j o r t y p e s o f th e r m a l e v e n t m a y b e o b -s e r v e d . T h e r e m a i n d e r o f t h i s s e c t io n d e s c r i b e s th et w o r e c o g n i s ed f o r m s o f D S C a n d t h e i r m o d e s o fi n d i re c t h e a t f lo w m e a s u r e m e n t .

H e a t , f l u x D S C is th e m o s t c o m m o n f o r m o f th et e c h n i q u e a n d c o n s i s t s o f a s a m p l e a n d r e f e r e n c ep o s i t i o n e d s y m m e t r i c a ll y in a f u r n a c e. T h e s a m p l ea n d r e fe r e n c e p a n s a r e h e a t e d f r o m t h e s a m e

s o u r c e a n d t h e d i f f e r e n t i a l t e m p e r a t u r e i s m e a -s u r e d . T h e r e s u l t a n t s i g n a l is c o n v e r t e d t o h e a tf l o w u s i n g t h e f o l l o w i n g r e l a t i o n s h i p ( w h i c h i sd e r iv e d f ro m N e w t o n ' s l aw o f c o o l in g a n d m a y b ec o n s i d e r e d a s a t h e r m a l a n a l o g u e o f O h m ' s l aw ) :

A Q = ( 7 ~ , - T, ) / R r (1 )

wh ere Q ( J ) i s hea t , R v (K J ~), the t her m alr e s i s ta n c e o f th e c e l l, Ts ( K ) , t h e t e m p e r a t u r e o ft h e s a m p l e a n d Tr ( K ) , t h e r e fe r e n c e te m p e r a t u r e .A n a s s u m p t i o n is m a d e t h a t t h e t h e r m a l g r a d i e n t sw i t h i n t h e c o m p o n e n t s o f t h e c el l ( e. g. b e t w e e nt h e s a m p l e , r e f e r e n c e a n d t h e i r h o l d e r s ) a r e n e g li -gible .

P o w e r c o m p e n s a t io n D S C ,c o m p r i s e s a s y s t e mi n w h i c h t h e s a m p l e a n d r e f e r e n c e p a n s a r e p l a c e di n i s o l a t e d f u r n a c e s , a s o p p o s e d t o b o t h p a n sb e i n g h e a t e d I o m t h e s a m e s o u r c e . T h e d i f f e r e n -t ia l te m p e r a t u r e b e t w e e n t h e s a m p l e a n d r e f er e n c ei s ( n o m i n a l l y ) m a i n t a i n e d a t z e r o w h i l s t t h e p o w e r( s u p p l i e d b y t h e d i f f e r e n t i a l h e a t e r s ) , r e q u i r e d t om a i n t a i n t h e s a m e t e m p e r a t u r e i n t h e t w o p a n s , i sm e a s u r e d . A t t h e o n s e t o f a n e n t h a l p i c e v e n t (e .g .f u s i o n , r e c r y s t a l l i s a t i o n , d e c o m p o s i t i o n ) t h e s a m -p l e t e m p e r a t u r e b e g i n s t o d e v i a t e f ro m t h a t o f t h er e f e r e n c e , h e n c e e n e rg y i s s u p p l i e d t o o n e o r o t h e rp a n i n o r d e r t o m a i n t a i n i s o t h e r m a l c o n d i t i o n sb e t w e e n t h e t w o . I n t h e a d v e n t o f a n e n t h a l p i cp r o c e s s p o w e r c o m p e n s a t i o n D S C s u p p l i e s a m e a -s u r e d q u a n t i t y o f h e a t p e r u n i t t im e t o t h e s a m p l e( in t h e c a s e o f e n d o t h e r m i c e v e n t s ) o r to t h er e f er e n c e (d u r i n g e x o t h e r m i c e v e nt s ) t o m a i n t a i n ad i f f e re n t i a l t e m p e r a t u r e o f z e r o . T h e p o w e r d e li v -e r e d b y t h e d i f f e r e n t i a l h e a t e r s i s g i v e n b y t h ef o l l o w i n g e x p r e s s i o n :

P = d Q / d t = I 2 R (2 )

w h e r e P ( W ) i s p o w e r, I ( A ) i s c u r r e n t s u p p l i e d t o

the h ea te r and R (g2) i s the res i s tan ce o f theh e a t e r.D S C d a t a a r e p r e s e n t e d i n C a r t e s i a n f o r m ( a

t h e r m o a n a l y t i c a l c u rv e , f o r m e r l y k n o w n a s a t h er -m o g r a m ) . I r re s p e c t iv e o f t h e t y p e o f i n s t r u m e n t a -t i o n u s e d , d i f f e r e n t i a l p o w e r i s p l o t t e d a g a i n s tt e m p e r a t u r e ( o r t i m e f o r i s o t h e r m a l h e a t i n g p r o -g r a m m e s ) . T h u s f o r a n i d e a l s y s t e m i n w h i c h t h es a m p l e a n d r e f e r e n c e a r e i d e n t i c a l ( i. e. a r e o f t h e


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16 N.J. Coleman, D.Q.M. Craig/International Journal of Pharmaceutics 135 (1996) 13-29

same mass and possess identical heat capacitiesand thermal conductivities) the differential heatflow signal recorded on the ordinate axis would bezero as the heat flow to and from the samplewould perfectly match tha t of the reference. Forsystems in which the heat capacities of the sampleand reference differ a horizontal displacement ofthe baseline is noted. The baseline reading of thethermoanalytical curve is perturbed when an en-thalpic event occurs; exo- and endothermic eventsare registered as peaks and troughs. According toconvention, endotherms usually appear as peaksalthough either method of plotting is acceptable(and may be determined by the particular instru-mentation used). The nature and interpretation ofthe signals arising from changes in heat capacityand enthalpy are treated in subsequent sections.

2. I. Sa m ple preparation an d operating conditions

The data collected from a DSC scan are a resultof the source, pre-treatment and intrinsic natureof the sample and the instrumental conditions(e.g. scan rate, atmosphere, reference system, panconfiguration) under which the investigation isconducted. This section discusses some of theeffects of sample preparat ion and operating condi-

tions, as such considerations become even moreimportant when using MTDSC.

To ensure accurate heat flow measurements it isnecessary to minimise thermal gradients withinthe sample; this requires the use of small quanti-ties (generally a few milligrams) of sample. Previ-ous studies (e.g. Craig and Newton, 1991) havesuggested that the particle size of the sample mayhave a profound effect on the thermoanalyticalcurves obtained. It is preferable to fully encapsu-late the sample in a closed pan to achieve opti-

mum thermal conductivity. In the event of highlyenthalpic reactions, an 'inert' diluent may be inti-mately mixed with the sample although its pres-ence may greatly influence the thermal, and henceheat transfer, characteristics of the system. Thereference system usually comprises an empty panof the same type and configuration as that of thesample (and should include a quantity of diluentif it has been included in the sample system).

Aluminium pans are used for most DSC inves-tigations with the exception of systems which arelikely to react with aluminium and those whichrequire a temperature programme exceeding600C. Copper, platinum and gold pans can beheated to at least 700C and may be used forsamples which react with aluminium. Non-her-metic pans are suitable for use with most solidsamples. Lids may be placed or crimped onto thetop of the pans to minimise thermal gradientsthroughout the sample and to ensure good ther-mal contact between the sample and detectionsystem. Open pans are employed if contact be-tween the purge gas and sample is required or ifphenomena such as hydrate desolvation are beingstudied (e.g. Miller and York, 1985; Sawh et al.,1993) in order to observe water losses more

clearly. Some workers advocate the use o f pin-holes in the lids of pans to allow controlledevaporation of volatile materials. Hermetically-sealed pans are required for use with aqueoussolutions, volatile liquids, and sample matterwhich sublimes, since they possess an air tight seal.The resistance to internal pressures which maybuild up during heating of hermetic pans dependson their design and should be considered whenplanning DSC experiments.

The heating rate used in conventional DSC

experiments is typically between 10 and20C min 1. Heating rate influences the nature ofthe thermoanalyt ical curve. In general, low heat-ing rates result in high resolution (between ther-mal events which occur over similar temperatureranges) and low sensitivity, hence smaller eventsmay not be detected. In addition, if the sample isnot heat-stable the longer scanning times mayresult in degradation of the material. The con-verse is true of high heating rates whereby anincrease in sensitivity is obtained at the expense o f

resolution. Fig. 3 demonstrates the effect of heat-ing rate on the nature of a typical endothermicmelting signal. The following explanation is basedon heat flux DSC although the principle is easilyapplied to power compensation DSC.

A sample substance will absorb heat energythrough the melting range. The temperature o f thesample will essentially remain constant through-out the melting process whereas the reference will


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N.J. Coleman, D.Q.M. Craig /International Journal of Pharmaceutics 135 (1996) 13 29 17

c o n t i n u e t o i n c r e a s e i n t e m p e r a t u r e a c c o r d i n g t ot h e p r o g r a m m e d h e a t i n g r a t e . W h e n t h e m e l t i n gp r o c e s s i s c o m p l e t e r e e q u i l i b r a ti o n o f t h e s a m p l et e m p e r a t u r e w i t h t h a t o f t h e re f e re n c e a n d t e m -p e r a t u r e p r o g r a m m e w i l l o c c u r. A t l o w h e a t i n gr a t e s t h e t e m p e r a t u r e l a g o f t h e s a m p l e w i t h r e-s p e c t t o t h a t o f t h e r e f e r e n c e is r e l a ti v e l y s m a ll .T h e a r e a ( r e p re s e n t e d b y A ' in F i g. 3 ) m a p p e d o u tb y t h is d e v i a t i o n o f s a m p l e t e m p e r a t u r e w i t h r e -s p e c t to t h a t o f t h e r e f e r en c e is p r o p o r t i o n a l t ot h e h e a t f l o w d u r i n g t h e m e l t i n g p r o c e s s . A th i g h e r h e a t i n g r a t e s t h e s a m e p r i n c i p l e a p p l i e sa l t h o u g h t h e l ag b e t w e e n t h e t e m p e r a t u r e o f t h es a m p le a n d t h a t o f th e t e m p e r a t u r e p r o g r a m m ea n d r e f e r e n c e i s g r e a t e r a s a c o n s e q u e n c e o f t h eh i g h e r h e a t i n g r a t e . H e n c e , a t t h e p o i n t o f r e e q u i -l i b r a ti o n o f t h e s a m p l e a n d r e f e re n c e t e m p e r a t u r e s

a g r e a t e r a r e a ( r e p r e s e n t e d b y A " ) h a s b e e nm a p p e d o u t , a s s h o w n i n F i g . 3 .

A n e x p l a n a t i o n o f th e l o ss o f r e s o lu t i o n a th i g h e r h e a t in g r a te s m a y b e p r o v i d e d i f t w o t h e r-m a l p r o c e s s e s o f s i m i l a r t e m p e r a t u r e a r e c o n s i d -e r e d . C o n s i d e r t h a t , a t s o m e l o w h e a t i n g r a t e , t h ef i r s t t h e r m a l p r o c e s s w i l l b e c o m p l e t e b e f o r e t h es e c o n d c o m m e n c e s . I n t h i s i n s t a n c e t h e t w o p r o -c e s s e s w i l l b e r e s o l v e d . A t s o m e h i g h e r h e a t i n gr a te , d u e t o t h e i n c r ea s e d t e m p e r a t u r e p r o g r e s s i o no f t h e r e f e r e n c e w i t h r e s p e c t t o t h a t o f t h e s a m p l e ,

i t i s p o s s i b l e t h a t t h e t e m p e r a t u r e r e e q u i l i b r a t i o nf o l l o w i n g t h e f i r s t p r o c e s s w i l l n o t h a v e o c c u r r e db e f o r e t h e o n s e t o f t h e s e c o n d e v e n t . T h e t w op r o c e s s e s w i l l n o t b e r e s o l v e d i n t h i s i n s t a n c e . I ts h o u l d a l s o b e n o t e d t h a t p o o r h e a t t r a n s f e r i s

T~ap.

r ', ~ . ( ~ )

Fig . 3 . The e ff ec t o f hea t in g r a t e o n s igna l s ens i t i v i ty.

a s s o c i a t e d w i t h l a rg e s a m p l e s i z e s w h i c h c o n s e -q u e n t l y p r o l o n g s t h e t e m p e r a t u r e l a g o f t h e s a m -p l e w i t h r e s p e c t to t h a t o f th e r e f e r e n c e . H e n c e ,l a rg e s a m p l e s i z e s a r e a s s o c i a t e d w i t h p o o r r e s o l u -t i o n a n d g o o d s e n s i t i v i t y.

A n i m p o r t a n t c o n s i d e r a t i o n i s t h e c l a s s i f i c a t i o no f t h e r m a l e v e n t s a s r e v e r s i b l e o r i r r e v e r s i b l e p r o -c e s s e s . R e v e r s i b l e p r o c e s s e s a r e t h o s e w h i c h m a yb e r e v e r s e d b y a n i n f i n i t e s i m a l m o d i f i c a t i o n o f av a r i a b l e . A s y s t e m u n d e rg o i n g a r e v e r s i b l e p r o c e s si s c o n s i d e r e d t o b e i n e q u i l i b r i u m w i t h i t s s u r -r o u n d i n g s a t e a c h s t a g e d u r i n g t h a t p r o c e s s . I no t h e r w o r d s , a n i d e a l , r e v e r s i b l e , p r o c e s s ( t a k i n gp l a c e i n a n i d e a l D S C i n s t r u m e n t ) w i l l a b s o r b o rr a d i a te h e a t t o p e r f e c tl y m a t c h t h e t e m p e r a t u r ep r o g r a m m e . T h e h e a t fl o w as s o c i a te d w i t h s u c hp r o c e s s e s i s t h u s d e p e n d e n t o n t h e r a t e a t w h i c h

h e a t i s a p p l i e d t o t h e s a m p l e . I n c o n t r a s t , i r r e -v e r s i b l e p r o c e s s e s a r e n o t i n e q u i l i b r i u m w i t h t h et e m p e r a t u r e p r o g r a m m e a n d t e n d t o b e k i n e t i c a l l yc o n t r o l l e d p r o c e ss e s w h i c h a r e d e p e n d e n t o n a b -s o l u t e t e m p e r a t u r e . I q e n c e, i f a s a m p l e i s s u b j e c t edt o a t h e r m a l c y c l e ( b e g i n n i n g a n d e n d i n g a t t h es a m e t e m p e r a t u r e ) t h e i n t e g r a l o f th e h e a t f l o wa s s o c i a t e d w i t h r e v e r s i b l e p h e n o m e n a w i l l b e z e r o ,t h a t a s s o c i a t e d w i t h i r r e v e r s ib l e e v e n t s w il l b ef ini te (Sefer is e t a l ., 1992).

T h e t e r m s u s e d t o d e s c r i b e t h e t h e r m o d y n a m i c

r e v e r s ib i l i ty o f p r o c e s s e s s h o u l d n o t b e c o n f u s e dw i t h t h o s e t e r m s u s e d t o d e s c r i b e c h e m i c a l r e -vers ib i l i ty, e .g . a wea k e lec t ro ly te d i ssoc ia t ing re -v e r s i b l y i n t o c o n s t i t u e n t i o n s . T h i s i s a ni m p o r t a n t d i s ti n c ti o n , a s t h e c o n c e p t s o f t h e r m o -d y n a m i c r e v e rs i b il it y a r e f u n d a m e n t a l t o a n u n -d e r s t a n d i n g o f M T D S C a n d w i ll b e d i sc u s s ed i nm o r e d e t a i l l a t e r. A u s e f u l t e x t o n t h e s u b j e c t o ft h e r m o d y n a m i c r e v e r s i b il i ty i s A t k i n s ( 1 97 8 ) .

2 . 2 . H e a t c a p a c i t y m e a s u r e m e n t s

H e a t c a p a c i t y m e a s u r e m e n t s a r e n o t c u r r e n t l yw i d e l y u s e d p h a r m a c e u t i c a l l y. H o w e v e r , a sM T D S C p r o v i d es a s im p l e a n d r a p i d m e a n s o fa s s es s in g h e a t c a p a c i t i e s , t h e p r i n c i p l e o f h o wt h e s e m e a s u r e m e n t s a r e m a d e u s i n g c o n v e n t i o n a lD S C w il l b e o u t l i n e d h e r e f o r c o m p a r a t i v e p u r -poses .


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18 N.J. Coleman, D .Q.M . Craig /Interna tional Journal oJ" Pharmaceutics 135 (1996) 13-2 9

The energy required to raise the temperature ofa substance by 1 K is a measure of its heatcapacity (or specific heat capacity when unit massof sample is considered). Heat capacity may berepresented as the following:

Cp = (6Q/6T)p (3)where Cp (JK 1) is the heat capacity, Q (J) the(heat) energy and T (K) the temperature. Thismay also be expressed in an alternative form as inEq. (4), where c~Q/&tis the heat flow and 6t/ i~T isthe reciprocal heating rate:

Cp = ( b Q / ~ t ) p x ( 6 t / 6 r ) p ( 4 )

Since the baseline value is a measure of differ-ential heat flow (i.e. 6 Q / 6 t ) then, for a givenheating rate, the difference in baseline values ob-

tained in the presence and absence of samplematerial is proportional to the heat capacity ac-cording to:

Cp = K A Y/b (5)

where the constant of proportionality, K, is thecalorimetric sensitivity, A Y is the difference inbaseline values obtained in the presence and ab-sence of sample material, and b is the heating rate,6 T / 6 t . The calorimetric sensitivity may be foundby calibration with a substance of well established

heat capacity (usually pure, industrially manufac-tured sapphire, A1203). It should be noted thatheat capacity is a function of temperature andthat tables of Cp against T for sapphire are avail-able.

The procedure for heat capacity determinationinvolves three DSC scans; baseline measurementsin the presence and absence of a sample of knownmass and then a similar scan for a known mass ofcalibrant. An 'empty pan' baseline measurementis made by loading the cell with empty sample andreference pans and scanning over the requiredtemperature range (at the desired heating rate).Isothermal portions should be included at thebeginning and end o f each scan. At the beginningof a run a baseline deflection from the initialequilibrium point may be seen. This deflectiondepends upon and is proportional to the differ-ence in heat capacity of the sample and referencepan systems.

This procedure is then repeated under identicalconditions with an accurately weighed calibrantmaterial (e.g. pure, crystall ine sapphire). Thecalorimetric sensitivity, K, may then be estimatedby substit ution into Eq. (5). The A Y value is thedifference in baseline measurements between the

'empty pan' baseline and the 'sapphire' baseline atthe temperature of interest. The procedure is thenrepeated for an accurately weighed sample mate-rial to obtain a 'sample' baseline. The differencebetween the 'empty pan' baseline and the 'sample'baseline (i.e. A Y) may then be substituted intoEq. (5) to obtain a value for the heat capacity ofthe sample. The specific heat capacity may then becalculated by dividing the heat capacity by themass of the sample.

2.3. Quantitative concentration an d enthalp ydeterminations

The area under a signal peak is directly propor-tional to the heat evolved or absorbed during theevent from which it arose and also to the mass ofsample substance present. Similarly, the height ofthe curve (for any given system) is directly pro-portional to the rate of reaction. The peak area(A) is related to enthalpy change by the followingrelationship:

A = k ' m ( - A H ) (6)

where k' is a calorimetric sensitivity (an electricalconversion factor rather than one based uponsample characteristics as in differential thermalanalysis, DTA), m is the mass of the sample and- A H is the enthalpy change. Strictly speaking,enthalpy changes are heat exchanges with thesurroundings at constant pressure (e.g. those oc-curring in open pans). Heat exchanges which takeplace at constant volume (e.g. those in hermeti-cally sealed pans) are referred to as internal en-ergy changes. However, for simplicity, this reviewrefers to all heat exchanges as changes in en-thalpy. The relationship described by Eq. (6) isapplicable to systems of a given sample type andheating rate. The end of an enthalpic event isdenoted by the reestablishment of the baseline(unlike DTA where the reaction may terminatesome time before). Quant itative analysis requires


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N.J. C oleman, D.Q .M . C raig / International Journal of Pharmaeeuties 135 (1996) 13 29 19

dq/dt(arb)

dq/dt(arb)

Y

Temperature (arb)

( b ) i

' T e n ~ r e ( a m )

l a c k o f d e f i n i t i o n o f a t r u e b a s e l i n e a c r o s s t h ep e a k r e g i o n p r e s e n t s a p r o b l e m i n t h e e s t i m a t i o no f p e a k a r e a a n d a n u m b e r o f m e t h o d s a r e a v a il -a b l e i n o r d e r t o o v e r c o m e t h i s d i f f i c u l t y, a l l o fw h i c h i n v o l v e c e r t a in a s s u m p t i o n s . A p e a k a r e ac a l c u l a ti o n b a s e d u p o n t h e e n c l o s u r e o f th e s i g n alb y a ta n g e n t d r a w n f r o m t h e o n s e t t o a p o i n t a tw h i c h t h e b a s e l i n e i n r e e s t a b l i s h e d ( a s s h o w n i nF i g . 4 a ) g e n e r a l l y r e s u l t s i n a n o v e r e s t i m a t i o n o fp e a k a r e a . T h e c o n s t r u c t i o n o f a s t e p p e d ( F ig . 4 b )o r s i g m o i d a l ( F i g . 4 c ) b a s e l i n e a c r o s s t h e p e a k a r ea l s o e m p l o y e d t o c o m p e n s a t e f o r t h e b a s e l i n ed e v i a t i o n a l t h o u g h n o s t a n d a r d p r o c e d u r e e x i s t s .H o w e v e r , p r o v i d i n g t h a t s u i t a b l e c a l i b r a t i o n h a sb e e n e x e c u t e d , m e l t i n g p o i n t s , h e a t s o f fu s i o n ,e n t h a l p i e s o f c r y s t a l l i sa t i o n , r e a c t i o n t e m p e r a t u r e sa n d e n t h a l p i e s f o r n u m e r o u s o t h e r p r o c e s s e s m a y

b e d e t e r m i n e d f a i r l y a c c u r a t e l y b y D S C . Q u a n t i -t a t i v e c o n c e n t r a t i o n m e a s u r e m e n t s m a y a l s o b em a d e o n t h e b a s i s t h a t t h e m a s s o f a s a m p l e ( a sa p p e a r s i n E q . ( 6 ) ) i s r e l a t e d t o c o n c e n t r a t i o n .

ck~dt(arb)

Te m p e r ~ u ~ ( a rb )

Fig. 4. M ethods of d etermining peak are a by the constructionof: (a) tangential baseline, (b) step ped baseline, and (c) sig-mo idal baseline.

c a l i b r a t i o n o f t h e t e m p e r a t u r e s c al e a n d c a l o r i -m e t r i c s e n s it i v it y. A v a r i e t y o f s u b s t a n c e s a r ea v a i l a b l e f o r t h i s p u r p o s e , t h e m o s t w i d e l y u s e d

b e i n g 9 9 . 9 9 9 % p u r e i n d i u m w h o s e m e l t i n g t e m -p e r a t u r e a n d e n t h a l p y o f f u s i o n a r e 1 5 6 . 61 C a n d2 8 . 7 1 J g - i

T h e b a s e l i n e v a l u e s p r e c e d i n g a n d f o l l o w i n ge n t h a l p i c e v e n t s a r e a l m o s t i n v a r i a b l y d i f f e r e n to w i n g t o t h e c h a n g e i n h e a t c a p a c i t y w h i c h a c -c o m p a n i e s p r o c e s s e s i n w h i c h t h e p r o p e r t i e s o ft h e s a m p l e a r e a l t e r e d ( a s i n d i c a t e d i n F i g . 4 ) . T h e

2 .4 . Glass t r ans i t ion t empera tu res

T h e g l a s s t r a n s i t i o n i s n o t a c t u a l l y a t r u e p h a s et r a n s i t i o n b u t i s a p r o c e s s i n w h i c h ' f r o z e n ' s e g -m e n t s ( e .g . p o l y m e r c h a i n s e g m e n t s , s i d e c h a i np e n d a n t g r o u p s e t c .) a r e u n f r o z e n . M a n y s o li d s

( p a r t i c u l a r l y t h e r m o p l a s t i c p o l y m e r s ) f o r m s u p e r -c o o l e d l i q u i d s w h e n r a p i d l y c o o l e d f r o m a b o v et h e ' m e l t ' . E l e c t r o n i c r e p u l s i v e f o r c e s , s u c h a st h o s e b e t w e e n s e g m e n t s o f a p o l y m e r, m a y b e' f r o z e n ' in t o t h e s t r u c t u r e . O n h e a t i n g , e n e rg y iss u p p l i e d t o t h e s a m p l e a n d p a r t i a l s e g m e n t a l r o t a -t i o n b e g i n s s u c h t h a t t h e r e p u l s i v e f o r c e s a r er e l i e v e d . A s t h e s e g m e n t a l m o b i l i t y i n c r e a s e s t h ep o l y m e r c h a n g e s f r o m a g la s sy t o a r u b b e r y s t a te .T h e p o l y m e r m a y b e c o n s id e r e d as a n u m b e r o fs u b - s y s t e m s a ll o f d i f f e r in g s e g m e n t l e n g t h s . T h e

o n s e t t e m p e r a t u r e s o f se g m e n t a l m o b i l i t y f o r e a c ho f t h e s u b - s y s t e m s a r e d i f f e r e n t . T h e o v e r a l l g l as st r a n s i t i o n , T ~, i s a c o n s e q u e n c e o f a ll o f t h ed i f f er e n t s e g m e n t a l m o t i o n s a n d is a c c o m p a n i e db y a n i n c r e a s e i n h e a t c a p a c i t y ( a n d p o s s i b l y as m a l l r e la x a t i o n e n d o t h e r m ) . G l a s s t r a n s it i o n s a r ea s s o c ia t e d w i t h th e a m o r p h o u s r e g i o n s o f th ep o l y m e r a n d t h e t e m p e r a t u r e a t w h i c h th e y o c c u ris in f l u e n ce d b y t h e p o l y m e r p r e p a r a t i o n t e m p e r a -


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20 N.J. Coleman, D.Q.M. Craig / International Journal of Pharmaceutics 135 (1996) 13 29

ture, cooling rate, molecular weight (and distribu-tion), degree of cure and the presence of additives.Many drugs, despite their low molecular weights,exhibit glass transition phenomena. There hasbeen considerable pharmaceutical interest indrugs in the glassy state because their high energystates are thought to contribute to fast dissolutionrates.

Glass transition temperatures and the accompa-nying changes in heat capacity may be determinedby DSC on account of the associated baselinedisplacement (as depicted in Fig. 2). It is notalways possible to detect the glass transition ofpolymers which possess a very small amorphouscontent as the associated change in heat capacitywill also be very small. For example, the glasstransitions of carbon fibre reinforced polyimides

are difficult to determine by conventional DSCsince the signal intensity is very low and thetechnique is insufficiently sensitive to enable theseparation of the signal from the baseline (Seferiset al., 1992). As will be discussed later improveddetection of glass transition phenomena is one ofthe advantages of MTDSC over the conventionaltechnique.

3 . T h e b a s i c p r in c ip l es o f M T D S C

Modulated temperature differential scanningcalorimetry, MTDSC, is an extension of DSC inwhich a sine wave modulation is applied to thestandard, linear, temperature programme, as indi-cated earlier in Fig. 1. A discrete Fourier Trans-form algorithm is applied to the resultant heatflow signal to deconvolute the calorimetric re-sponses to the modulated and underlying (i.e.standard, linear) temperature programmes.MTDSC' is therefore, at present, a software devel-opment rather than a change in the basic DSCequipment. As will be discussed in more detaillater, the use of the modulated signal improvesboth the quality and quantity of informationwhich may be obtained from the hardware, al-though certain disadvantages and areas requiringcaution have been identified which will also beoutlined.

In order to understand the principles ofMTDSC, it is necessary to consider the basictheory of conventional DSC. The heat flow signalof the latter is a combination of 'kinetic' and 'heatcapacity' responses, i.e. the heat flow from thesample (or reference) is a function of both the

heat capacity of the sample and of any kineticheat flow component. Broadly speaking, the oc-currence and rate o f an irreversible 'kinetically'controlled event is dependent on the absolutetemperature, whereas reversible 'heat capacity'phenomena tend to be proportional to the rate ofchange of temperature. The resultant heat flowsignal may be expressed in the following way:

d Q / d t = C p d T / d t + J ( t , T ) (7)

where Q is the (heat) energy, Cp is the 'thermody-namic' heat capacity (i.e. that due to the energystored in vibrations, rotations and translations ofmolecular consti tuents of the sample), T is theabsolute temperature and f ( t , T ) is some functionof the time and temperature which expresses thecalorimetric response of any kinetically controlledchemical or physical phenomena.

During a typical linear heating programme, inthe absence of any physical or chemical reaction,the heat flow signal is dictated by the heat capac-

ity. When the temperature attains a certain valuesuch that a kinetically controlled 'chemical' eventoccurs (e.g. polymer cure, melt or crystal reorgan-isation) the resultant heat flow signal is a combi-nation of the heat flow associated with the heatcapacity and that associated with the chemicalevent. There is a fundamental difference in thenature of the energy arising from the two phe-nomena in that the former is reversible and thelatter is irreversible. MTDSC is capable of sepa-rating these two processes, while conventionalDSC heat flow signal represents the sum of thetwo types of process. The basis of the separationof the two types of heat flow signals is theirdifference in response to the underlying and mod-ulated temperature programmes.

The modulated temperature programme may beexpressed in the following way:

T = T,, + bt + B sin (o)t) ( 8 )


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N.J. Coleman, D.Q .M. Craig /International Journal of Pharmaceutics 135 (1996) 13 29 21

where To is the initial temperature , ~ is theangular frequency (i.e. 2gf), b is the linear heatingrate and B is the amplitude of the temperaturemodulation. Differentiation of Eq. (8) and substi-tut ion into Eq. (7) yields the following expression:

d Q / d t = C p ( b + B cocos(o~t)) + f ( t , T ) +C sin (cot) (9)

where f ( t , T ) is the average underlying kineticcalorimetric response (after subtraction of the re-sponse to the sine wave modulation), C is theamplitude o f the kinetic response to the sine wavemodula tion and (b + Bco cos (ogt)) is equivalentto d T / d t . Hence the heat flow signal will containa cyclic component which is dependent on thevalues of B, co and C. The kinetic contribution

p ( t , T ) + C sin(cot) only occurs during irre-versible enthalpic processes although the heat ca-pacity contribution, Cv(b + Bm cos(cot)), isalways present. For many kinetically controlledprocesses C may be approxima ted to zero suchthat the response to the cyclic perturbation origi-nates from the thermodynamic heat capacity con-tribution alone (Eq. (10)):

d Q / d t = ~ , ( b + B ~ ocos(cot)) + f ( t , T ) (10)

Discrete Fourier Transform is used to separate

the cyclic (modulating) heat flow compo nent fromthe underlying heat flow signal. The heat capacity,Cp, may be determined since b, B and co aremeasured. The cyclic heat flow component, theproduct of Cp and the underlying heating rate,may then be calculated and is termed the revers-ing heat flow component. The non-reversing heatflow component is obtained by subtraction of thereversing component from the calculated totalheat flow. All noise appears in the non-reversingsignal.

The theory of MTDSC and the interpretationof data obtained from this technique are based onthe following assumptions and requirements:- The use of small, thin, completely encapsulated

samples minimises temperature gradients andmaximises conductivity during the heating andcooling cycles. Goo d thermal con tact must alsobe ensured between the pans and conductingplates.

- Heat flow is measured by an ideal device whichresponds instantaneously (with no lag).

- The heat capacity heat flow contribution dur-ing the heating and cooling cycles is completelyreversible (with no hysteresis).It should be noted that actual calorimeters do

not conform to the ideal specifications cited aboveand that the distinction between heat flows arisingfrom thermodynamic heat capacity and kineticallycontrolled processes, for real samples, is less welldefined than is suggested by the theory outlinedhere. Nonetheless, this model has proven suitableas a first approximation for the explanation ofdata generated from preliminary MTDSC investi-gations.

Fig. 5 shows the total, reversing, and non-re-versing heat flow signals for a sample of quench

cooled polyethylene terephthalate (PET), the mostwidely cited MTDSC 'pilot' substance. The datawas obtained at an underlying heating rate of3C min 1, a modulat ion period of 50 s and amodula tion amplitude of _+ 2C. The glass transi-tion is seen in the reversing heat flow signal,whereas the recrystallisation appears in the non-reversing heat flow signal. Under the operatingconditions selected the melting endotherm ap-pears in both.

3 .1 . M T D S C o p e r a ti n g c o n d it io n s

One of the features of MTDSC compared tothat of conventional DSC is that the number of

A

~ ~ _ ~ , ~ ~ F " ' - ' ~ -

- ~ \ / , - - ' - ' :~

- , \ v/ i " I

.4

Fig. 5. MTDSC thermoanalytical curve of PET showing thetotal, reversing, and non-reversing heat flow signals.


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22 N.J. Coleman, D.Q.M. Craig / International Journal of Pharmaceuties 135 (1996) 13-29

operational variables is considerably greater forthe former. In addition to the sample size, choiceof pans and (underlying) heating rate, the fre-quency and amplitude of modulation must also beconsidered; the choice of these parameters ishighly important, and, if not properly considered,will result in the generation of artefacts.

The underlying heating rate of an MTDSCexperiment is equivalent to the heating rate em-ployed in standard DSC. MTDSC typically in-volves heating rates of 1 -5 C mi n -~ comparedwith the 10-20C min-~ heating rates employedin conventional DSC. This heating rate gives riseto the (underlying) total heat flow signal whichrepresents the sum of all thermal events. Theaccuracy and precision of the total heat flowmeasurement are equivalent for both techniques(for a given heating rate).

DSC sensitivity for most reversible trans itionsis a function of the maximum instantaneous heat-ing rate. Large modulation amplitudes producelarge instantaneous heating rates and hence giverise to increased heat flow sensitivity. Since theunderlying heating rate of an MTDSC experimentis synonymous with the heating rate of a conven-tional DSC experiment, low underlying heatingrates are associated with increased resolution. It isthe combination of a large modulation amplitudeand low underlying heating rate which enables anincrease in sensitivity without the need to sacrificeresolution.

The amplitude of the temperature modulationis typ ically selected from a range _+ 0.1 to _+1.0C. The period time (that time taken for onecomplete oscillation, i.e. reciprocal frequency) ofthe temperature modulation is currently selectedfrom the range 30 80 s to allow sufficient time forheat flow to and from the sample during thetemperature cycles. However, one of the limita-tions imposed on the conditions of operation isthat at least six modulations are requiredthrougho ut the duration of each thermal event (toenable the complete separation of cyclic and un-derlying responses). The comparatively slow un-derlying heating rates used for MTDSCexperiments are chosen to allow this condition tobe satisfied.

The cooling capacity of the cell imposes a re-striction on the modulation amplitude for a givenperiod time (especially small period times). Dis-tortion of the heat flow sine wave (which is likelyto result in misinterpretation of the deconvolutedresults) will occur if the cell is unable to cool

sufficiently during the cooling portion of the mod-ulation cycle. Maximum modulation amplitudesare achieved with small period times when using acell purge gas of high thermal conductivity (e.g.helium as opposed to nitrogen) at a high flowrate. Empty pan runs may be conducted to ensurethat no distortion of the heat flow sine waveoccurs when large modulation amplitudes areused in conjunction with small period times.

It is possible to select modulation amplitudesand period times such that the net heating rate is

always positive i.e. the temperature is continu-ously rising, even though the signal is oscillating.Similarly, for experiments requiring 'continuouscooling' certain values of modulation amplitudeand period times will ensure that the net heatingrate is always negative. These values may also beselected to produce heating and cooling within acycle. Some thermal events may produce differentseparations between the reversing and non-revers-ing heat flow signals depending on whether thesample is exposed to heating and cooling within a

cycle or continuous heating (or cooling) only. Forexample, during the analysis of melting processesit is necessary to select operating parameters suchthat the net heating rate is always positive ifexothermic melt reorganisation of metastablecrystal forms is to be prevented.

The MTDSC cell calibration procedure (i.e.that for baseline correction, temperature scale andcalorimetric sensitivity) does not differ from thatof conventional DSC although an additional cali-bration for heat capacity is required. The heatcapacity calibration constant enables the accuratemeasurement o f sample heat capacities and allowsthe correct separation and calculation of the total,reversing and non-reversing heat flow data. Theheat capacity calibration is carried out by scan-ning a calibrant of know heat capacity (i.e. sap-phire) under the same conditions as those of thesample run (i.e. the same modulation amplitude,period time, and underlying heating rate). The


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N.J . C oleman, D.Q .M. Craig /Interna tional Journal o[ Pharmaceutics 135 (1996) 13 29 23

measured heat capacity of the calibrant is thencompared with the literature value at the tempera-ture of interest. The ratio of the literature tomeasured value is the required heat capacity con-stant. The measurement of sample heat capacitieswill be discussed later.

3.2 . Advantag es and d isadvantages of" M T D S C

As discussed above, the use of MTDSC allowsthe deconvolution of the total heat flow signalinto two components. This provides a number ofadvantages, some of which will be discussed be-low, although a number of concomitantdifficulties have been identified, which will also bediscussed. As most o f the initial work perfo rmedusing MTDSC has been concerned with polymeric

samples, this class of materials will be used tofurnish examples of the features of the technique.

3 .2 .1 . A d va n t age s o f M T D S C

3.2.1.1. The combina t ion o f high resolut ion andhigh sensi t ivi ty.As outlined in the previous sec-tion, the combination of a high modulation am-plitude and low underlying heating rate satisfiesthe conditions for both high resolution and sensi-tivity. This alone means that small and overlap-ping transitions may be seen with greater clarity,

over and above the separation of the total heatflow signal into reversing and non-reversing com-ponents.

3.2 .1 .2. The measurem ent o f hea t capac i ty byM T D S C . The measurement of heat capacity byconventional DSC requires three scans and a cer-tain amount of operator expertise in the produc-tion of precise, accurate results. However, thedetermination of heat capacity by MTDSC re-quires a single sample run providing that suitable

heat capacity calibration has been carried out.This opens up the possibility of exploring themeasurement of heat capacity (by MTDSC) as apharmaceutical tool, as changes in physical struc-ture or chemical composition may be reflected bychanges in this property. Knowledge of heat ca-pacities may also be of use in the design ofpharmaceutical manufactu ring processes whichinvolve a heating stage.

Direct heat capacity measurements may bemade by simply running the sample under identi-cal conditions (i.e. same modulation amplitude,period time and underlying heating programme)to those used to obtain the heat capacity calibra-tion constant. A plot of heat capacity againsttemperature (or time) may then be obtained di-rectly (using the standard software which accom-panies MTDSC instrumentation) and the heatcapacity at the temperature of interest observedand reported. Long period times (those of around80 s) and large modulation amplitudes ( _+ 0.5 to_+ 1.0) are recommended for opt imum measure-ments. The use of long period times results inmaximum accuracy whilst large modulation am-plitudes (which are readily available at long pe-riod times) increase the signal-to-noise ratio of the

heat flow modulation. Underlying heating ratehas been found to have a less influential effect onthe accuracy and precision of the heat capacitymeasurement; an underlying heating rate of5C rain ~ is recommended. Along with a three-fold reduction in the number of scans required inthe determination of heat capacity data the noiseand precision of MTDSC heat capacity measure-ments are approximately twice as favourable asthose of conventional DSC (Gill et al., 1993).

3.2.1.3. The dete ction oJ" glass transitio ns byM T D S C . The procedure for the detection andmeasurement of glass transition phenomena byMTDSC is the same as that for conventionalDSC. However, the high instantaneous heatingrate supplied by the sine wave modulation resultsin superior sensitivity. This increased sensitivitypermits the detection of weak transitions (e.g.those of systems containing 'diluents' or possess-ing low amorphous contents) which are not de-tectible by conventional DSC. Furthermore, the

detection and measurement of glass transitions byconventional DSC often requires preconditioningof the sample to reduce (and preferentially re-move) the accompanying volume relaxation en-dotherm. This procedure involves heating andcooling through the glass transition. MTDSC al-lows the separation of the glass transition whichappears in the reversing heat flow signal and therelaxation endotherm which appears in the non-


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24 N.J . Co leman , D .Q .M. Cra ig / In te r na t ion a l Journa l o f Pha rmaceu t i c s 135 (1996 )13 29

- 0 . ~ , o . o

-o .~o .

-=

=

Total Hc~ Flow

E c~ - a . * - . - o . , E

- ~ . a 0 . t ~ . ~ _ ~ a . a s - c N \ - ~ . 5

-0.07~t7114

!t O / . 00 " 3 5 0 , , 4 0 0t o 0 ~ 3 0 0 " 4 1 ~ ' o - " -

Fig. 6. The total , reversing, and non-reversing heat f low signals fo r the high temperature thermoset t ing polyimide, NR -150, showthe measurement of the glass transition in the reversing heat flow signal. (After Seferis et al. , 1992).

reversing signal. This separation eliminates therequirement for sample preconditioning. This ca-pability is especially important in the investigationof thermoset polymer systems as heating abovethe glass transition may advance the cure and

affect results (as noted in the following section).Seferis et al. (1992) observed the glass transitionof carbon fibre reinforced PET and establishedthat the Tg values determined from the total heatflow signals of both conventional DSC andMTDSC increased as the (underlying) heatingrate was increased. However, the glass transitiondetermined from the MTDSC reversing compo-nent exhibited no apparent heating rate depen-dence (over the observed heating rate range of 1to 10Cmin-~). The onset temperature of theenthalpic relaxation associated with the glass tran-sition, as observed in the non-reversing signal,was found to increase as the heating rate in-creased. This implies that the heating rate depen-dence of Tg (as observed by with conventionalDSC) can be attributed to the enthalpic relax-ation. This observation also indicates that therelaxation of the molecules associated with theglass transition is fast compared with that of the

enthalpic relaxation. Obviously, conventionalDSC is not capable of providing such informa-tion.

The detection of the glass transition of the hightemperature thermosetting polyimide, NR-150, is

not possible by conventional DSC as the transi-tion is weak and the technique insufficiently sensi-tive. In the same publication, Seferis et al. (1992)report that it was possible to determine the glasstransition of this substance by analysis of thereversing heat flow signal of the MTDSC thermo-analytical curve (as shown in Fig. 6). The resultswere found to be in excellent agreement withthose of dynamic mechanical analysis (DMA).

A polymer blend may be considered to bemiscible when only one glass transition is ob-served. If the polymer constituents of a binaryblend are immiscible then two Tgs will berecorded. If the difference between the glass tran-sition temperatures of the two polymers is within15C it is almost impossible to assess the extent ofmixing by conventional DSC. The enhanced reso-lution and sensitivity of MTDSC has enabled theanalysis of physical mixtures o f the two polymers,poly(methyl methacrylate) and poly(styrene-co-


13/17


14/17

26 N.J. Coleman, D.Q .M . Craig /Interna tional Journal of Pharmaceutics 135 (1996) 13-2 9

o

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. . - - - - . - - - - - - . . ~ . . ~ . | d J ~ , ,, m | .

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F i g . 9. T h e m e a s u r e m e n t o f i n it i al c ry s t a l li n i t y o f a s a m p l e o f q u e n c h c o o l e d P E T b y M T D S C . ( A f t e r S a u e r b r u n n a n d T h o m1995).

ac ry lon i t r i l e ) whose g l a s s t r ans i t i on t empera tu re sare wi th in 10C (Song e t a l . , 1995) .

3.2.1.4. Th e detection o f hidden phenom ena by

M T D S C . Seferis et al . (1992) invest igated a bi-l a y e r f il m o f p o l y c a r b o n a t e ( P C ) a n d P E T. C o n -v e n t i o n a l D S C is n o t a n a p p r o p r i a t e t e c h n i q u e f o rthe i nves t i ga t i on o f t h i s sy s t em a s t he PC g l a s st r a n s i t i o n a n d t h e P E T c o l d c r y s t a l l i z a t i o n o c c u rin t he s ame t empera tu re r ange . Howeve r,M T D S C a l l o w e d th e s e p a r a t i o n o f th e se o v e r la p -p ing t r ans i t i ons ; t he Tg o f PC and t he co ld c ry s-t a l li z a t io n e x o t h e r m o f P E T w e r e f o u n d t o a p p e a rin t he r eve r s ing and non - r eve r s ing s igna l s r e spec -t ive ly (as show n in F ig . 7). In the sam e publ ica -t i on t he au th o r s a l so r epo r t ed t he r e su l t s o f aninves t i ga t i on i n to t he p rope r t i e s o f a ca rbon - f ib r er e i n f o r c e d b i s m a l e i m i d e l a m i n a t e b y M T D S C .T h e g l a s s t r a n s i t i o n t e m p e r a t u r e c o u l d n o t b eaccu ra t e ly de t e rmined f rom the hea t f l ow s igna l o fc o n v e n t i o n a l D S C a s a c u r e e x o t h e r m w a s o b -se rved wh ich immed ia t e ly fo l l owed the g l a s s t r an -s i ti on . Upo n sepa ra t i o n o f t he t o t a l hea t fl ows igna l i n to i t s componen t s , t he cu re was obse rved

exc lusive ly in t he non - r eve r s ing s igna l and t heg l a s s t r ans i t i on was de t e rmined fo r t he r eve r s ings ignal (as shown in F ig . 8) .

3.2.1.5. The investigation o f initial crystallinity byM T D S C . The te rm ' in i t ia l c rys ta l l in i ty ' re fers tothe ' a m ou n t ' o f c ry s t a l l in i t y a s ample pos se s se s a sr ece ived . Saue rb runn and Thomas (1995) , haverepo r t ed t he r e su l t s o f an i n i t ia l c ry s t a l l i n i ty s t udyo f a n u m b e r o f th e r m o p l a s t i c p o l y m e r s b yM T D S C . C o n v e n t i o n al D S C m e a s u re s th e s um o fa ll t h e r m a l e v e n t s a n d c a n n o t i n d e p e n d e n t l y m e a -s u re t h e c r y s t a l st r u c t u re f o r m a t i o n w h i c h m a y b eo c c u r r in g d u r i n g h e a t i n g . C o m p a r i s o n o f t h e e n-tha lp i e s o f co ld c ry s t a l l i s a t ion (AHcc) and me l t i ng(AHf) o f r a p id l y q u e n c h c o o l e d P E T i n d i c a te dtha t some in i ti a l c ry s t a l l in i t y i s p r e sen t i n t hesamp le ( s ince [AHcc[ :~ [AHf[) . Ho wev er, X -rayd i f f r ac t i on s tud i e s i nd i ca t ed t ha t no i n i t i a l c ry s -t a l l i n i ty was p r e sen t . The non - r eve r s ing MT DS Cs igna l (F ig . 9 ) showed tha t exo the rmic o rde r ing /c rys t a l l i s a t ion beg ins a t t he onse t o f t he co ldc rys t a l l i s a t i on s igna l and con t inues t o occu r up t oand t h rough the me l t i ng p roces s . The r eve r s ing


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N.J. Coleman , D .Q .M . Craig / International Journ al ~?f Pharma ceuties 135 (1996) 1 3 29 27

signal indicated that endothermic melting was oc-curring simultaneously. The sum of the integralsof these two signals was found to be zero whichrepresented the actual initial crystallinity of thesample. The measurement o f initial crystallinity ofother thermoplastic polymer substances by the of

MTDSC where the use of conventional DSC hasfailed to indicate substantial differences in thisproperty is also demonstrated in this publication.

3 .2 .2 . D i s a d va n t a g e s o f M T D S CThere are a number of associated disadvantages

of the MTDSC technique which have been iden-tified thus far. Firstly, to satisfy the requirementfor at least six modulations throughout the dura-tion of each thermal event, low underlying heatingrates are required. These may not always be desir-

able. This restriction is particularly significantwhen analysing sharp transitions. Secondly, it isarguable that DSC is often regarded a routinescreening technique within the pharmaceutical sci-ences (certainly within industry) and many of theexperimental variables and theoretical consider-ations associated with the technique are not ex-plored. While this is due to DSC being used as atool for detecting specific phenomena, it would beunwise to extend this approach to MTDSC, as thetechnique is more complex, involves the use of a

greater number of experimental variables and re-quires a more sophisticated understanding of thetheory of differential calorimetry. Finally, thetechnique suffers the drawback of all novel ap-proaches, namely that all operators are still in theprocess of establishing the capabilities of the tech-nique. The interpretation of MTDSC data is alsorarely simple. While the technique is clearly ofgreat importance and interest (and is being hailedas the most exciting innovation in thermal analy-sis for several decades), such enthusiasm rein-forces the need for rigorous examination ofexperimental parameters and careful interpreta-tion of results.

4. Current and future applications of M T D SC topharmaceutical systems

Sebhatu et al. (1994) compared the results from

microcalorimetry, X-ray diffraction and MTDSCexperiments in an assessment of the degree ofdisorder of various lactose samples. A measure ofthe degree of disorder o f a sample system may bederived from a value of the heat evolution duringcrystallisation. The separation of the total heatflow signal of lactose into its components revealedthat the crystallisation exotherm, as observed byconventional DSC comprised both an endother-mic reversing peak and an exothermic non-revers-ing peak (under the selected conditions). The heatof crystallisation was measured from the non-re-versing exothermic signal and the reversing en-dotherm was attributed to a conversion betweentwo crystalline forms. The degree of disorder cal-culated from this measurement was found to be inclose agreement with the data obtained from X-

ray and microcalorimetric analyses.Alden et al. (1995) have investigated the effect

of variations in modulation frequency, amplitudeand underlying heating rate on the reversing andnon-reversing heat flow signals for the melting ofgriseofulvin and PEG 6000. They have divided theproduct of the modulation frequency and ampli-tude by the underlying heating rate and haveexpressed this combination as the 'degree of oscil-lation'. It is suggested that, if an appropriatedegree of oscillation is used, the ratio A H c / A H is

a measure of the degree of crystallinity of thesystem, where A H ~ is the energy associated withthe reversing component of the melting processand A H is the heat of fusion. However, care isrequired in the use of the degree of oscillation asan experimental parameter as different combina-tions of modulation frequency, amplitude andunderlying heating rate which give the same valueof the degree of oscillation yield different valuesfor A Hc .

Wulff and Alden (1995b) used MTDSC to ex-amine the thermal behaviour of dispersions ofgriseofulvin, PEG 30 00 and various alkali(sodium, potassium and lithium) dodecyl sul-phates (NaDS, KDS and LIDS, respectively).Exothermic reversing and non-reversing compo-nents were observed for each of the melting sig-nals of the dispersions (under the selectedconditions). The melting temperature and en-thalpy of fusion, as measured from the total heat


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28 N.J. Coleman, D .Q.M . C raig / International Journal of Pharmaceutics 135 (1996) 13 29

f low s ignal, o f the PE G 3000/gr iseofulv in so l idd i spe rs ion were s imil a r t o t hose o f t he PE G 3000/gr iseofulv in /LiDS sol id so lu t ion . The so l id so lu-t i ons con ta in ing NaDS and KDS a l so exh ib i t eds imi lar mel t ing tempera tures and entha lp ies offus ion (which were both s l ight ly lower than thoseo f the PE G 3000 /g r is eo fu lvin and P EG 3000/gr iseofulv in /LiDS sys tems) . However, d i fferencesin the entha lpy changes o f the revers ing and non -reve rs ing com ponen t s o f the me l t ing peaks o fthese sys tems were repor ted .

Give n the adva ntages of the technique , i t isposs ib l e t o pos tu l a t e t he ways in wh ich MTDSCcou ld be o f fu tu re bene f i t w i th in t he pha rm aceu t i -cal sciences. One possibi l i ty is the detect ion ofpolymorphism, which of ten proves d i ff icu l t us ingconven t iona l DSC as t he me l t i ng po in t s may be

ve ry s imi l a r and t r ans fo rma t ion fo r one fo rm toano the r may occu r du r ing the me l t i ng p roces s .The ind epend ent opt im isa t ion o f sens i tiv ity andresolu t ion , a long w i th the sep ara t ion of the s ignalin to revers ing and non -revers ing hea t f low com po-nen t s may a l l ow the r e so lu t ion o f such complexand ove r l app ing phenomena . In add i t i on , t heabi l i ty of the technique to de tec t h idden g lasst rans i t ion phenomena has resul ted in in teres t be-ing genera ted for the s tudy of f reeze dr ied prod-ucts (P ikal et al . , 1995). I t is also of interest to

specula te on the impl ica t ions o f d i rec t hea t capac-i t y measu rem en t s i n t erms o f manu fac tu r ing p ro -cesses and as a qual i ty cont ro l tool .

5. Conclusions

MTDSC rep re sen t s a new and po ten t i a l l yh ighly u sefu l app ro ach to pha rmaceu t i ca l t he rma lanalys is as i t a l lows the independent opt imisa t ionof sens i tiv i ty and resolu t ion , the sepa ra t ion of theheat f low s ignal in to revers ing and non-revers ingcom ponen t s and the de t ec t ion o f ' h idden ' phe -nomena. These capabi l i t ies a l low a more sophis t i -ca t ed unde r s t and ing o f va r ious t he rma l even ts .The use of the technique requi res a grea ter under-s tanding o f thermal ana lys is than i s cur rent lyneces sa ry fo r conven t iona l DSC a l though the po -tent ia l rewards are cons iderable .

Acknowledgements

We would l ike to acknowledge f inancia l sup-p o r t f o r N . J . C o l e m a n f r o m L I N K D T I / E P S R Cgran t w i th TA Ins t rumen t s . W e wou ld a l so li ke t othank Dr. Trevo r Leve r o f TA Ins t rumen t s fo r h is

he lpfu l comments and cr i t ic i sm.

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Nichola 1995 Modulated Temperature Differential Scanning Calorimetry