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

Abstract

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.

Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy

“…Even though extensive studies are reported on the disproportionation kinetics in binary or multicomponent tablet formulations, the information obtained is only by bulk measurements and does not reveal either the spatial heterogeneity or the molecular mechanism behind disproportionation. It has been hypothesized that water can act as the medium for proton exchange between Mgst and PIO-HCl. ,,, Visualization of water distribution (measured by fluorescence of rhodamine 6G) was previously used to help explain the spatial heterogeneity of disproportionation across the tablet surface when exposed to stress at 40 °C/75% RH . While these results further confirmed the hypothesis that humidity plays a central role in the disproportionation kinetics, the direct correlation of water and disproportionation of PIO-HCl along with Mgst has yet to be observed.…”

“…This unfortunately leads to decreased predictive power in concentration mapping. To help elucidate the disproportionation mechanism, previous reports formulated binary mixtures to help reduce the spectral interference from the inert excipient. ,,, Thus, for the following experiments, we prepared binary mixtures of the problematic excipient and PIO-HCl. Furthermore, the binary tablets were prepared with the deuterated analog of Mgst to minimize the interference between the peaks of Mgst, stearic acid, PIO-FB, and PIO-HCl for robust data analysis (Table S1, Figure S7).…”

“…A variety of studies have been performed to investigate the roles of excipient chemistry, formulation storage, and stability to reveal influential factors in disproportionation. ,− One commonly used excipient is magnesium stearate (Mgst) which serves as a lubricant that reduces the adhesion between the powder and the processing equipment. However, Mgst is known to induce significant salt disproportionation of acidic APIs, especially at high relative humidity (RH). ,,− Recently, the HCl salt form of pioglitazone (PIO-HCl), which is used for treating type II diabetes, has become a popular model API for proof-of-concept methods to study disproportionation. ,,,, PIO-HCl has a tendency to readily undergo disproportionation to its free base (PIO-FB) due to its low disproportionation pH (pH max ) when interacting with problematic excipients. ,, Although previous studies have suggested that disproportionation is a solution-mediated transformation, the physical and chemical interplay between PIO-HCl, Mgst, and humidity is not well understood. Thus, to assist designs of robust formulations, it is critical to develop a complete mechanistic understanding of salt disproportionation.…”

“…However, the information obtained through these bulk measurements does not reveal the spatial heterogeneity that is present in complex multicomponent tablets. By utilizing high resolution synchrotron X-ray diffractometry (SXRD), Koranne et al have investigated the spatiotemporal mapping of PIO-HCl disproportionation for the first time . The findings provided an in-depth understanding of the spatial heterogeneity of the disproportionation reaction, with the initiation of the reaction occurring at the tablet surface and moving toward the core.…”

Formulation Development of Sublingual Cyclobenzaprine Tablets Empowered by Standardized and Physiologically Relevant Ex Vivo Permeation Studies

“…In solid dosage forms, salt disproportionation is both solution- and excipient-mediated. The increased humidity of 75% and the use of hygroscopic excipients (crospovidone) may have led to the initial moistening of the tablet surface with the formation of an aqueous diffusion layer and its internal migration [ 37 ], resulting in a basic microenvironmental pH due to the use of dibasic phosphate. This may have exceeded the pH of maximum solubility of cyclobenzaprine as a weak base with a pK a of 8.47 and gradually induced the thermodynamically driven crystallization and accumulation of the lipophilic compound (log P OW = 5.2) on the primary packaging material through the tablet surface.…”