Physical Stability Of Pharmaceutical Salts And Cocrystals In Drug Product Environment

University of Minnesota Ph.D. dissertation. April 2018. Major: Pharmaceutics. Advisor: Raj Suryanarayanan. 1 computer file (PDF); xvi, 167 pages.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

Investigation of Spatial Heterogeneity of Salt Disproportionation in Tablets by Synchrotron X‑ray Diffractometry

Tablets which were binary mixtures of pioglitazone hydrochloride (PioHCl) with magnesium stearate (MgSt), croscarmellose sodium (CCS), microcrystalline cellulose, or lactose monohydrate were prepared. Two sets of experiments, using intact tablets, were performed. (i) Tablets containing PioHCl (90% w/w) and MgSt were exposed to 25 or 40 °C and 75% RH in a custom-built temperature/humidity chamber. In situ spatiotemporal mapping of disproportionation was performed by transmission-mode synchrotron X-ray diffractometry (SXRD; Argonne National Laboratories). Tablets were scanned in radial direction starting from the top edge of the tablet and moving, in increments of 300 μm, toward the center. There was evidence of disproportionation after 10 min (at 40 °C). The reaction was initiated on the tablet surface and progressed toward the core. (ii) SXRD of tablets stored for a longer time (up to 15 days) enabled the simultaneous quantification of the reactants and products of disproportionation and provided insight into the reaction progression. The influence of sorbed water and microenvironmental acidity on the disproportionation reaction was investigated. The most pronounced reaction was observed in the presence of MgSt followed by CCS. The transformation was solution-mediated, and the spatial heterogeneity in disproportionation could be explained by the migration of sorbed water. There was a good correlation between microenvironmental acidity (pH_eq) and extent of PioHCl disproportionation

Challenges in Transitioning Cocrystals from Bench to Bedside: Dissociation in Prototype Drug Product Environment

Tablets containing a theophylline–glutaric acid (TG) cocrystal dissociated rapidly forming crystalline theophylline (20–30%), following storage at 40 °C/75% RH for 2 weeks. Control tablets of TG cocrystal containing no excipients were stable under the same conditions. The dissociation reaction was water-mediated, and the theophylline concentration (the dissociation product), monitored by synchrotron X-ray diffractometry, was strongly influenced by the formulation composition. Investigation of the binary compacts of the TG cocrystal with each excipient revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, providing mechanistic insights into a dissociation reaction. Ionizable excipients with a strong tendency to sorb water, for example, sodium starch glycolate and croscarmellose sodium, caused pronounced dissociation. Microcrystalline cellulose (MCC), while a neutral but hydrophilic excipient, also enabled solution-mediated cocrystal dissociation in intact tablets. Magnesium stearate, an ionizable but hydrophobic excipient, interacted with the cocrystal to form a hygroscopic product. The interaction is believed to be initiated in the disordered cocrystal–excipient particle interface. In contrast, the cocrystal was stable in the presence of lactose, a neutral excipient with no tendency to sorb water. The risk of unintended cocrystal dissociation can be mitigated by avoiding contact with water both during processing and storage