Skaria, Cyrus Victor; (2007) Stability Assessment Of Pharmaceuticals Using Isothermal Calorimetry. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pharmaceuticals are formulated to be stable products and studying their stability using conventional techniques can be difficult and time consuming. Isothermal calorimetry has the potential to study the stability of pharmaceuticals, as it is sensitive enough to detect extremely small heat flows associated with change (chemical or physical). Its use in the pharmaceutical arena has not been widespread because of the difficulties associated with analysing data recorded from complex processes, since heat is ubiquitous. The work presented in this thesis demonstrates the applicability of isothermal calorimetry in the stability assessment of pharmaceutical model systems. Calorimetric data recorded for complex processes were analysed based on kinetic modelling. Initial studies involved the degradation of simple single-step processes (hydrolysis of aspirin at 25°C returned rate constants of 2.8 x 10-6 and 5.3 x 10-6 s-1 in 0.1 M HCl and citrate buffer respectively), followed by model systems with increasing complexity. Degradation involving parallel processes - binary mixtures of parabens were studied. Using kinetic models, rate constants and reaction enthalpies were determined for individual processes. Rate constants of 2.2 x 10-4 and 0.8 x 10-4 s-1 for methyl and propyl paraben present in a binary mixture were lower than when recorded individually (3.1 x 10-4 and 1.2 x 10-4 s-1). Data recorded for consecutive reactions, commonly encountered in pharmaceuticals can be difficult to analyse if exact mechanisms are unknown. The use of chemometric techniques to analyse calorimetric data recorded for complex processes offers great potential when reaction mechanisms are unknown. The two-step consecutive reaction of potassium hydroxylamine disulfonate was successfully analysed for reaction parameters using kinetic-based models and chemometric analysis. Significant proportions of degradation in pharmaceuticals proceed at a slow rate and can pose difficulty in their assessment. Minimum desirable reaction parameters required to successfully analyse calorimetric data for slow reactions were generated and its use in designing calorimetric experiments was demonstrated. Finally the use of IC in the preformulation stages of drug development is emphasised, particularly its role in purity determination of impure aspirin and drug excipient compatibility. Compatibility between aspirin and magnesium stearate was investigated using IC and reaction parameters obtained were compared with those obtained using conventional chromatographic techniques.

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