Navigating the Waters of Unconventional Crystalline Hydrates.
Navigating the Waters of Unconventional Crystalline Hydrates.
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DOI：
10.1021/acs.molpharmaceut.5b00357
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发表时间：
2015-08-03
影响因子：
4.9
通讯作者：
Reutzel-Edens SM
中科院分区：
文献类型：
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作者：
Braun DE;Koztecki LH;McMahon JA;Price SL;Reutzel-Edens SM
阐明 3-(4-二苯并[b,f][1,4]oxepin-11-yl-哌嗪-1-基)-2,2-二甲基丙酸 (DB7) 的两种两性离子水合物（Hy2 和 HyA）的晶体结构、转化和热力学，合理化了温度、水活度和 pH 值对固体形态稳定性和转化途径的复杂相互作用。 三种中性无水物多晶型物（I型、II°型和III型）。每个 DB7 两性离子 (DB7z) HyA 含有 1.29 至 1.95 个水分子。去除必需的水稳定 HyA 会使其塌陷为无定形相，通常同时使稳定的无水物 I 型和 II° 型成核。 Hy2 是一种化学计量的二水合物，也是唯一已知的 III 型前体，III 型是一种高能无序无水物，无序程度取决于干燥条件。通过精确控制结晶、过滤和干燥条件获得的高度结晶相纯样品的 X 射线晶体学、固态 NMR 和 H/D 交换实验以及计算模型，提供了对该系统的分子水平理解。由于其不同的静态和动态无序以及不同相中的水流动性，许多转化速度缓慢且平衡对精确条件敏感，这意味着用简化的水合物分类来表征 DB7 水合对于开发这种药物来说是不合适的。
Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.