Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788

Adams, Monica; Sharma, Vijayata; Gokhale, Madhushree; Huang, Yande; Stefanski, Kevin; Su, Ching; Hussain, Munir

doi:10.1016/j.xphs.2015.12.028

Cited by 1 publication

(1 citation statement)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While there is agreement in literature on the pivotal role of microenvironmental acidity and pH max in the context of salt disproportionation, a direct measurement of proton activity in microenvironment of solid systems is challenging. Recently, indicator dyes have been used to probe the microenvironments in pharmaceutical solid compositions. ,− In this method, the acidity is expressed as pH equivalent (pH eq ) and is defined as the “pH of an aqueous solution in which the ratio of the peak absorbance signals of the ionized to the un-ionized forms of the indicator is the same as in the given solid sample” . This method provides a practical means for estimating and rank ordering microenvironmental “acidity”.…”

Section: Results and Discussionmentioning

confidence: 99%

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

2017

View full text Add to dashboard Cite

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.

show abstract