The determination of the key physical and chemical properties of a new material is

essential.The melting point, glass transition temperature, the number and identification of

the different phases it may have, and the temperatures at which they are formed are all of

great value, not only in assessing its practical pharmaceutical potential but also as they can

form the basis of many routine QC procedures

Barnes, Philip A.

Charsley, Edward L.

Parkes, Gareth M.B

English

University of Huddersfield Repository

University of Huddersfield RepositoryBarnes, Philip A., Charsley, Edward L. and Parkes, Gareth M.BRecent developments in advanced thermal analysis: sample controlled thermal analysisOriginal CitationBarnes, Philip A., Charsley, Edward L. and Parkes, Gareth M.B (2006) Recent developments in advanced thermal analysis: sample controlled thermal analysis. European Pharmaceutical Review, 11 (4). pp. 83-98. ISSN 1360-8606This version is available at http://eprints.hud.ac.uk/569/The University Repository is a digital collection of the research output of theUniversity, available on Open Access. Copyright and Moral Rights for the itemson this site are retained by the individual author and/or other copyright owners.Users may access full items free of charge; copies of full text items generallycan be reproduced, displayed or performed and given to third parties in anyformat or medium for personal research or study, educational or not-for-profitpurposes without prior permission or charge, provided:• The authors, title and full bibliographic details is credited in any copy;• A hyperlink and/or URL is included for the original metadata page; and• The content is not changed in any way.For more information, including our policy and submission procedure, pleasecontact the Repository Team at: E.mailbox@hud.ac.uk.http://eprints.hud.ac.uk/SCTA for pharmaProf. P.A. Barnes, School of Applied Sciences, Prof. E. L. Charsley, Head of the Centre for Thermal Studies andDr G. M. B. Parkes, Senior Lecturer in Analytical Science, University of HuddersfieldThe determination of the key physical and chemical properties of a new material isessential.The melting point, glass transition temperature, the number and identification ofthe different phases it may have, and the temperatures at which they are formed are all ofgreat value, not only in assessing its practical pharmaceutical potential but also as they canform the basis of many routine QC procedures.Further information can be obtained from drying/desolvation,dehydration and decomposition studies. An excellent overviewof the more common Thermal Analysis techniques and theirmany applications in the pharmaceutical industry has beengiven recently by Royall1. However, the need for the maximumamount of useful information constantly leads to a demandfor both new types of informationand increased sensitivity andresolution and this is where the newapproach of Sample ControlledThermal Analysis has great potential.As yet there are relatively fewapplications of SCTA in the field ofpharmaceuticals and so this articlewill concentrate on the principles and illustrate the advantages of thisnew family of techniques usingexamples of the types of reactionwhich are widely studied in thepharmaceutical industry.Conventional thermal analysistechniques are capable of furtherdevelopment to improve sensitivityand resolution and provide new typesof information on materials. Asignificant new approach, developedindependently by Rouquerol2,3, inFrance and the Pauliks4,5, in Hungary,was designed to address the limitations of conventionalThermal Analysis. Now termed ‘Sample Controlled ThermalAnalysis, SCTA’, this has developed into a range of relatedtechniques6 which confer many additional advantages inaddition to minimising the problems alluded to below and some of which techniques are now available from several manufacturers.Principles of SCTAThe essence of the SCTA approach is to recognise that inconventional thermal analysis, because heat is being appliedto continually raise the temperature, significant temperaturegradients will be produced throughout the sample (Figure 1a).These gradients arise because the exterior surfaces of thesample, through which the heat enters the bulk of thematerial being studied, are hotter than the interior. Thus anythermally induced process will be initiated at the surface ofthe sample and a complex reaction front will then travel tothe centre of the sample which will gradually reach thetemperature originally found at the exterior. Meanwhile thetemperature of the exterior surface has continued to rise.www.russellpublishing.com/pharmaceutical 83THERMAL ANALYSISFigure 1a illustrates the temperature gradients that exist across the sample as aconsequence of conventional temperature programmed heating at say 10 K min-1 andFigure 1b shows schematically the concentration gradients which can exist in a sampleundergoing a gas-solid process.Consider the effect this will have on a material with twoclosely spaced processes, for example dehydration followed bymelting. The dehydration will start at the relatively hotexternal surface of the sample and will progress slowlyinwards, depending on ability of the sample to conduct heat.Meanwhile, the exterior has already reached a highertemperature and has started to melt before the interior hascompletely dehydrated. As the two processes are occurringsimultaneously in different parts of the sample at the sametime the net effect is that of a dramatic reduction in theresolution of two processes. Ofcourse, it is possible to minimisetemperature gradients across asample by using the lowest possiblesample mass and keeping its form asa thin plate rather than a cylinder (asmost heat is transferred thorough thegas-phase, at least at atmosphericpressure). Furthermore, it has longbeen known that the use of very slowheating rates improves resolutionsignificantly, as a result of theconsequent reduction in temperaturegradients across the sample. In factthis is something of a simplificationas one also has to consider thetemperature gradients in theinstrument itself, but these serve onlyto further complicate the situation.Another problem caused by thetemperature gradients is that they cause uncertainty in thetemperatures apparently observed.Similarly, for any process involving a gas or vapour, such a solvent removal or oxidation, concentration gradients alsowill exist across the sample (Figure 1b). The result is thatdifferent vapour pressures will be found throughout thesample, possible leading to different reaction rates forreversible processes and, certainly, different reaction conditions throughout the materialbeing studied. This again reducesresolution and causes significanterrors in the measurement of thetemperature of a process, especiallyfor reversible processes such a dryingor certain decomposition reactions.For instance, the thermaldecomposition temperature ofcalcium carbonate can vary by severalhundreds of degrees, depending onthe pressure of the product CO2 overthe sample.The concentration gradients ofproduct or reactant gas found duringconventional heating regimes areshown in Figure 1b for both areaction involving the evolution of agas (e.g. drying) and the reaction ofthe sample with a gas, typicallyoxidation or reduction.However, as SCTA controls the rate of reaction rather thanthe rate of heating, it is possible to minimise these gradienteffects. As it happens, SCTA also brings other potentialadvantages and it has developed into an extensive family oftechniques, under what has now become a generic title.In essence, SCTA uses a sensor to follow the rate of thereaction. Commonly used systems measure reaction rate viathe sample mass using a thermobalance (TG), the evolved orreacting gases using mass spectroscopy (MS) or dimensionalchanges with dilatometry. The system first detects the start ofTHERMAL ANALYSIS84 European Pharmaceutical Review Issue 4 2006Comparison of conventional TG and SCTG of copper sulphate pentahydrate.Comparison of conventional TA (dotted lines) and SCTA, showing how the latter operates.a process and then an automatic feedback loop comes intooperation to control the rate of reaction of the sample. It isthus the sample itself which controls the rate of process it isundergoing, rather than a pre-determined heating rate, as inconventional Thermal Analysis. One of the most commonlyused variants of SCTA is Constant Rate Thermal Analysis inwhich the system forces the sample to react at a constantrate. This rate can be set at any desired level but it is usuallyheld at a very low value in order to minimise thermal andconcentration gradients across the sample. The principles ofSCTA are illustrated in Figure 2.In the conventional TA experiment, the temperature riseslinearly (1) and the parameter corresponding to the rate ofreaction, in this case a product gas measured by MS, shows asharp peak (2). It should be noted that the vertical axis isdirectly proportional to the reaction rate in the sample whichis seen to vary extremely widely in conventional TA during thecourse of the experiment (2).For the SCTA experiment, the temperature required tomaintain the pre-set reaction rate is shown in red while thereaction rate is in green. Once the SCTA process has beeninduced by the initial linear temperature rise (3), the reactionrate increases (4) to the pre-set target level (5) at which pointthe feedback loop (6) begins to operate. The temperature isthen made to follow whatever path is necessary (7) in orderto keep the reaction rate (8) constant at the target level (5).Once the reaction being studied approaches completion, thereaction can no longer maintain the target rate and sodecreases (9) and the temperature programme then returns tothe set linear heating rate (10).An example of the increase in resolution found usingSample Controlled Thermogravimetry (SCTG) to study atypical dehydration process is given in Figure 3. Thedehydration of copper sulphate pentahydrate occurs in threesteps, with the loss of two, two and one molecules of waterrespectively. The figure shows the results plotted againsttemperature and against time using conventional heatingrates and the proprietary MaxRes® technique of MettlerToledo. It can be seen that the SCTA approach producessignificantly enhanced resolution in less time than a very slowconventional TG run.The determination of free vs. bound water is not alwaysstraight forward as the two processes often overlap inconventional TG. However the use of High Resolution TG (TAInstruments) provides sufficient resolution to separate thesetwo events.Temperature resolved SCTA Of course, once the SCTA system can control the rate ofreaction at a constant level it becomes possible to control it in other ways also. For example, the relatively long run times of a Constant Rate experiment can be a disadvantage in a QC laboratory. To overcome this limitation it is possible to heat the sample quickly until the system detects a reaction or process and then to slow the reaction rate to a low level so that it can be completed before the next eventThermallyStimulatedCurrentsTSCII• Polymorphism• Crystalline/amorphous phase quantification(detection level <1%)• Water influence (plasticization)• Active PrincipleExcipient interaction• Detection of very small Tg transitionsUses molecularmobility as a measurementprobe:• Access to structural information that cannot beprovided by any other techniques• Access to ∆H, ∆S, relaxation time τ• Able to make the characterization of your pharmaceutical compounds even more completewww.setaram.com - sales@setaram.comE x c e l l e n c e  i n  t h e r m a l  a n a l y s i s  a n d  c a l o r i m e t r yTHERMAL ANALYSISis found. If the system then detects the end of this process,it automatically and dynamically increases the heating rateuntil the next reaction is detected where, once again, theheating rate is reduced to a low level to aid resolution7.This is known as operating in the temperature domain andgives rise to temperature resolved SCTA, which is by far the most common form of SCTA. It operates by monitoringthe reaction rate and using its first, second and thirddifferentials to detect the beginning and end of the processesbeing studied.Time resolved SCTAWhile Temperature Resolved SCTA is of great value, there areoccasions when it is very useful to maximise the timebetween events so that, for example, the product of the firstprocess can be removed for analysis before the samplereaches the temperature at which the second processcommences. This can be achieved by using the controlalgorithms to cause the sample to be heated rapidly throughevents and very slowly between them resulting in highresolution in the time domain. In practice this means thatwhen the TA curve is plotted against time the two peaks willbe widely separated, even although when plotted againsttemperature the will appear to be close. The theoreticalbackground to the use of complex reaction control methods isdescribed elsewhere by Barnes et al.8.SCTA can be used also to provide an insight into themechanisms of reactions. Figure 49 shows the SCTG andconventional TG curves for the dehydration of strontiumhydroxide octahydrate. The TG experiment appears to reveal asingle stage mass loss, while the SCTG run shows that thesample is initially cooled slightly to about 20°C and held atthis temperature until 7 H2O have been removed. The sampleis then heated to 50°C when the remaining water is lost. Theshape of the mass loss curve for the decomposition of themonohydrate is characteristic of that attributed to amechanism involving nucleation and growth of nuclei.Other SCTA methods include Stepwise Isothermal SCTA,Sorensen10,11, and Rate Perturbation techniques which allowthe measurement of the energetics of the process beingstudied Rouquerol12. Criado13introduced the concept of ‘IncreasingReaction Rate techniques andCharsley et al. have developedSample Controlled thermomicroscopytechniques which will find greatapplication in the study of solid-solidand solid-liquid transitions14.Of necessity, such an extensivefield cannot be covered fully in ashort article and the reader is referredto the definitive reference work onSCTA edited by Rouquerol andSorensen6 and the application ofSCTA to catalysis15.AcknowledgementsWe gratefully acknowledge the kindpermission of Mettler Toledo Ltd andTA Instruments Ltd to use Figures 3and 4 and the EPSRC, ICI Catalco, ICI Synetix and JohnsonMatthey for financial support. ■References1. P. G. Royall, European Pharmacy Review, 4, 79, 20052. J. Rouquerol, Bull. Soc. Chim. Fr. 31, 67, 19643. J. Rouquerol, J. Thermochim. Acta, 144, 209, 19894. L. Erden, F. Paulik, J. Paulik, J. Hungarian patent 152197,1962 5. F. Paulik, J. Paulik Thermochim Acta 23, 100, 19866. O. T. Sorensen, J. Rouquerol (Eds) in Sample ControlledThermal Analysis, Kluwer Academic, 20037. G. M. B. Parkes, P. A. Barnes and E. L. Charsley, AnalyticalChemistry, 2482, 71, 1999.8. G. M. B. Parkes, P. A. Barnes, E. L. Charsley, M. Reading andI. Abrahams, Thermochimica Acta, 39, 354, 2000.9. E. L. Charsley, J. J. Rooney, H. A. White, B. Berger & T. T.Griffiths, Proceedings 31st North American ThermalAnalysis Society Conference, Albuquerque, New Mexico,Ed. M.Rich, NATAS, 133, 200310. O. T. Sorenson, J. Thermal Analysis, 13, 429, 197811. O. T. Sorenson, Thermochim. Acta 50, 163, 1980 12. F. Rouquerol and J. Rouquerol, in H. G. Widemann (Eds.)Thermal Analysis, Vol. 1, Birkhauser, Basel, 373, 197213. A. Ortega, L. A. Perez-Maqueda and J. M. Criado, J.Thermal Anal. 42, 551, 199414. E. L. Charsley, C. Stewart, P. A. Barnes and G. M. B Parkes,J. Therm. Anal. Cal. 1087, 72, 2003.15. E. A. Fesenko, P. A. Barnes, G. M. B. Parkes, E. A. Dawsonand M. J. Tiernan, Topics in Catalysis, 283, 19, 2002.THERMAL ANALYSIS86 European Pharmaceutical Review Issue 4 2006SCTA and conventional TG curves for the dehydration of strontium hydroxide octahydrate.

Hungarian patent 152197,

Rouquerol (Eds) in Sample Controlled Thermal Analysis,

Topics in Catalysis,

Widemann (Eds.) Thermal Analysis,

Recent developments in advanced thermal analysis: sample controlled thermal analysis

Recent developments in advanced thermal analysis: sample controlled thermal analysis

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