Physical Stability Of Pharmaceutical Salts And Cocrystals In Drug Product Environment

Abstract

A developmental risk associated with pharmaceutical salt and cocrystal forms is their propensity to undergo unintended disproportionation, resulting in reversion to the corresponding free drug and counter-ion (as in a salt) or coformer (as in a cocrystal). This can negate the solubility, stability and bioavailability advantages conferred by salt (or cocrystal) formation. The central goal of this thesis work was to gain a comprehensive mechanistic understanding of the influence of formulation components (specifically excipients) and processing conditions (including storage) on solid-state stability of salts and cocrystals. Disproportionation of pioglitazone HCl in tablets and indomethacin sodium in lyophilized formulations were investigated. In tablets, the disproportionation reaction, mediated by water, was attributed to the microenvironmental acidity “experienced” by the salt. The nature and concentration of the formulation excipients influenced the microenvironmental acidity. The in situ tablet mapping experiments, by synchrotron X-ray diffractometry (SXRD), revealed that the disproportionation reaction was initiated at the tablet surface and progressed towards the tablet core. In lyophilized formulations, disproportionation of a soluble salt (indomethacin sodium) to an insoluble free acid occurred because of selective crystallization of a buffer component and the consequent pH shift during freeze-drying. A complex interplay of the indomethacin sodium and buffer concentrations dictated the salt stability in the final lyophile. The second part of the thesis focused on excipient-induced dissociation of theophylline cocrystals in tablet formulations. In prototype tablets of theophylline-glutaric acid cocrystal, water mediated dissociation reaction occurred rapidly and the theophylline concentration (the dissociation product), monitored by SXRD, was strongly influenced by the formulation composition. Investigation of binary compacts of theophylline-glutaric acid cocrystal with each excipient, revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, thereby providing mechanistic insights into the dissociation reaction. Finally, the role of coformer properties on solid-state stability of theophylline cocrystals highlighted the risk of excipient-induced dissociation in cocrystals comprising of acidic and basic coformers. Furthermore, relative solubilities of the cocrystal and its constituents were important determinants of solid-state cocrystal stability.