Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms
Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms
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DOI：
10.1002/jps.24003
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发表时间：
2014-09-01
影响因子：
3.8
通讯作者：
Jones, William
中科院分区：
文献类型：
--
作者：
Eddleston, Mark D.;Madusanka, Nadeesh;Jones, William
以前的研究表明，由于两个共晶体分子的溶解度不同，特别是当这些分子可以形成水合物时，共晶体在高湿度下容易解离。然而，与之形成对比的是，与草酸共结晶降低了药用活性化合物咖啡因水合物形成的倾向。在这里，通过使用咖啡因水合物和草酸二水合物的水溶液，从热力学的角度研究了咖啡因的草酸共晶体的稳定性。在此条件下发生了向无水咖啡因-草酸共晶体的转化，证实了这种形式在水环境中热力学上是稳定的。浆料方法被进一步发展为筛选在高湿度下不容易解离的共晶的一般方法。通过这种方式，水合物形成分子茶碱、卡马西平和吡罗昔康的共晶体被鉴定出来，这些分子在高湿度下稳定，无限期地避免水合物的形成。(C)2014年威利期刊公司和美国药剂师协会
previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by cocrystallization with oxalic acid. Here, the stability of the oxalic acid cocrystal of caffeine is investigated from a thermodynamic perspective through the use of aqueous slurries of caffeine hydrate and oxalic acid dihydrate. Conversion to the anhydrous caffeine-oxalic acid cocrystal occurred under these conditions confirming that this form is thermodynamically stable in an aqueous environment. The slurry methodology was further developed as a general approach to screening for cocrystals that are not susceptible to dissociation at high humidity. In this manner, cocrystals of the hydrate-forming molecules theophylline, carbamazepine, and piroxicam that are stable at high humidity, indefinitely avoiding hydrate formation, were identified. (C) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association