Stability assessment of pharmaceuticals using isothermal calorimetry

Pharmaceuticals are formulated to be stable products and hence studying their stability using conventional techniques can be difficult and time consuming. Isothermal calorimetry has the potential to study 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), followed by model systems with increasing complexity. Degradation involving parallel processes - binary mixtures of para bens was studied. Using kinetic models, rate constants and reaction enthalpies were determined for individual processes. 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 were demonstrated. Finally the use of IC in the preformulation stages of drug development are 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 to those obtained using conventional chromatographic techniques.EThOS - Electronic Theses Online ServiceGBUnited Kingdo