Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride
Derisking the Polymorph Landscape: The Complex Polymorphism of Mexiletine Hydrochloride
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DOI：
10.1021/acs.cgd.1c01009
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发表时间：
2021-12-01
影响因子：
3.8
通讯作者：
Steed, Jonathan W.
中科院分区：
文献类型：
--
作者：
Andrews, Jessica L.;Lill, Sten O. Nilsson;Steed, Jonathan W.
这项工作提出了一种针对抗心律失常药物盐酸美西律多态性的最新固体形式发现方法，其中实验和计算技术相结合，提供了该化合物固体形式景观的严格表征。所得固体形式通过粉末和单晶 X 射线衍射、红外光谱、差示扫描量热法和 C-13 固态 NMR 进行表征。该方法揭示了盐酸美西律的五种固体形式。晶型 1、晶型 2 和晶型 3 是相互对映相关的无水多晶型物，晶型 1 是室温稳定晶型，晶型 2 是高温晶型，晶型 3 是 148 至 167 摄氏度之间热力学稳定的晶型。最后两种晶型称为 A 型和 B 型，包含两大类同晶通道溶剂化物，包括与 A 型同构的第四种非溶剂化晶型。 溶剂化物。我们报告了每种溶剂化物的 11 种修饰，其中通道中包含多种溶剂，而不改变药物框架的基本结构。这些实验结果与计算晶体结构预测（使用阿斯利康晶体结构预测方法）密切相关，这共同表明在环境条件下不太可能发现进一步的非溶剂化形式，至少在 Z' = 1 的情况下。
This work presents an updated solid-form discovery approach to the polymorphism of the antiarrhythmic drug mexiletine hydrochloride, in which experimental and computational techniques are combined to provide a rigorous characterization of the solid-form landscape of this compound. The resulting solid forms were characterized by powder and single-crystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and C-13 solid-state NMR. This approach reveals five solid-form types of mexiletine hydrochloride. Forms 1, 2, and 3 are mutually enantiotropically related anhydrous polymorphs, with Form 1 the room temperature stable form, Form 2 the high-temperature form, and Form 3 the thermodynamically stable polymorph between 148 and 167 degrees C. The final two forms termed Types A and B comprise two large families of isomorphous channel solvates, including a fourth nonsolvated form isostructural to the Type A solvates. We report 11 modifications of each solvate, in which a diverse range of solvents are included in the channels, without changing the fundamental structure of the drug framework. These experimental results go hand-in-hand with computational crystal structure prediction (using the AstraZeneca crystal structure prediction approach), which together suggest that it is unlikely further nonsolvated forms, at least with Z' = 1, will be discovered under ambient conditions.