Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?,Crystal Growth & Design

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Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1021/acs.cgd.7b00842
Doris E. Braun ₁ , Sreenivas R. Lingireddy ₂ , Mark D. Beidelschies ₃ , Rui Guo ₄ , Peter Müller ₅ , Sarah L. Price ₄ , Susan M. Reutzel-Edens ₂

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The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level.

中文翻译：

揭开药用盐固体形式筛选的复杂性：为什么有这么多种形式？为什么这么少？

证明难以建立5-HT 2a拮抗剂3-（4-（4-（苯并[d]异恶唑-3-基）哌嗪-1-基）-2，2-二甲基丙酸盐酸盐（B5HCl）的固态形式。通过固体形式筛选产生了许多晶体材料，但是很少有形式容易生长出高质量的晶体以提供清晰的图像或对固体形式景观的理解。需要仔细控制结晶条件，一系列实验方法，溶剂化物结构的计算模型以及晶体结构预测，才能看到盐以其晶体形式的潜在排列。在无水多晶型物（形式I和II），二水合物和一类与醇的溶剂化物的层结构中，B5HCl固态形式的结构多样性十分明显。醇溶剂化物它提供了与纯净形式和二水合物截然不同的堆积，形成了在B5HCl和溶剂之间具有保守氢键的层，以及芳香环的堆积。醇烃部分在各层之间有效堆积的能力解释了一些溶剂化物晶体生长的困难和其他溶剂化物不能一起结晶的原因。通过实验和计算的组合，已经在分子水平上合理化了B5HCl的结晶问题，形状稳定性和去溶剂化途径。醇烃部分在各层之间有效堆积的能力解释了一些溶剂化物晶体生长的困难和其他溶剂化物不能一起结晶的原因。通过实验和计算的组合，已经在分子水平上合理化了B5HCl的结晶问题，形状稳定性和去溶剂化途径。醇烃部分在各层之间有效堆积的能力解释了一些溶剂化物晶体生长的困难和其他溶剂化物不能一起结晶的原因。通过实验和计算的组合，已经在分子水平上合理化了B5HCl的结晶问题，形状稳定性和去溶剂化途径。

更新日期：2017-09-20

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