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) and extent of PioHCl disproportionation.

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.

The stability of theophylline cocrystals composed of acidic (glutaric acid), basic (isonicotinamide), or neutral (benzamide) coformers was evaluated in the presence of several excipients. Tablets of theophylline-glutaric acid (TG) and theophylline-isonicotinamide (TINT) cocrystals were stable “as is” (no excipient) after storage at 40 °C/75% RH for 1 week. However, TG and TINT cocrystals dissociated rapidly in the presence of basic and acidic excipients, respectively. The dissociation reaction was water-mediated, and theophylline, the reaction product, was identified by powder X-ray diffractometry. In the case of theophylline-benzamide cocrystal, storage of tablets with and without excipients at 40 °C/75% RH for 1 week resulted in a cocrystal polymorphic transformation. Thus, the potential for excipient-induced cocrystal dissociation exists for cocrystals composed of acidic and basic coformers. Moreover, if the coformer renders the cocrystal highly water-soluble, even in the presence of neutral excipients, there is a propensity for dissociation.

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Disproportionation of pioglitazone hydrochloride (PioHCl), leading to the free base formation, was observed in tablet formulations containing basic excipients such as magnesium stearate (Koranne et al, Mol. Pharmaceutics, 2017, 14, 1133−1144. The nature and concentration of excipients, by modulating the microenvironmental acidity (measured as pH eq ), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pH eq , can stabilize PioHCl. Powder blends containing PioHCl, magnesium stearate and each oxalic, maleic, tartaric, fumaric, and glutaric acid were stored at 40 °C/75% RH for 15 days. The concentration of crystalline free base, a product of the disproportionation reaction, was quantified using synchrotron radiation. The pH eq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pH eq of the formulation blend and more effective it was in stabilizing PioHCl and preventing disproportionation. Thus, controlling the microenvironmental acidity in a rational and systematic way provided an avenue to mitigate excipient-induced salt disproportionation. Even when the lattice of PioHCl was activated by milling, it remained stable in the presence of acid. The amount of water sorbed during tablet storage provided an indirect measure of the disproportionation.