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

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Investigation of Spatial Heterogeneity of Salt Disproportionation in Tablets by Synchrotron X-ray Diffractometry
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-03-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.6b01052
Sampada Koranne ₁ , Ramprakash Govindarajan ₂ , Raj Suryanarayanan ₁

Affiliation

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.

中文翻译：

同步辐射X射线衍射法研究片剂中盐歧化的空间异质性

制备片剂，其为盐酸吡格列酮（PioHCl）与硬脂酸镁（MgSt），交联羧甲基纤维素钠（CCS），微晶纤维素或乳糖一水合物的二元混合物。使用完整的片剂进行了两组实验。（i）将含有PioHCl（90％w / w）和MgSt的片剂在定制的温湿度箱中暴露于25或40°C和75％RH。通过传输模式同步加速器X射线衍射仪（SXRD；阿贡国家实验室）进行歧化的原位时空映射。从药片的顶部边缘开始沿径向方向扫描药片，并以300μm的增量向中心移动。有证据表明10分钟后（在40°C下）歧化。反应在片剂表面上引发，并向核心方向发展。（ii）储存时间更长（最多15天）的片剂的SXRD能够同时量化反应物和歧化产物，并提供对反应进程的深入了解。研究了吸附水和微环境酸度对歧化反应的影响。在MgSt和CCS的存在下观察到最明显的反应。转化是溶液介导的，歧化中的空间异质性可以用吸附水的迁移来解释。微环境酸度（pH 研究了吸附水和微环境酸度对歧化反应的影响。在MgSt和CCS的存在下观察到最明显的反应。转化是溶液介导的，歧化中的空间异质性可以用吸附水的迁移来解释。微环境酸度（pH 研究了吸附水和微环境酸度对歧化反应的影响。在MgSt和CCS的存在下观察到最明显的反应。转化是溶液介导的，歧化中的空间异质性可以用吸附水的迁移来解释。微环境酸度（pH_eq）和PioHCl歧化程度。

更新日期：2017-03-02

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