Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?
Unraveling Complexity in the Solid Form Screening of a Pharmaceutical Salt: Why so Many Forms? Why so Few?
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DOI：
10.1021/acs.cgd.7b00842
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发表时间：
2017-10-04
影响因子：
3.8
通讯作者：
Reutzel-Edens SM
中科院分区：
文献类型：
--
作者：
Braun DE;Lingireddy SR;Beidelschies MD;Guo R;Müller P;Price SL;Reutzel-Edens SM
5-HT2a拮抗剂3-（4-（苯并[d]异恶唑-3-基）哌嗪-1-基）-2,2-二甲基丙酸盐酸盐（B5HCl）的固体形态难以确定。许多晶体材料是通过固体形态筛选产生的，但很少有形式容易生长出高质量的晶体，从而提供清晰的图像或对固体形态景观的理解。仔细控制结晶条件、一系列实验方法、溶剂化物结构的计算建模和晶体结构预测都需要看到盐在其晶体形式中的潜在排列。B5HCl固体形态景观的结构多样性在无水多晶（形式I和II）、二水和一类醇溶剂化物的层结构中表现得很明显。与纯溶剂和二水溶剂相比，醇溶剂化物提供了独特的填料，在B5HCl和溶剂之间形成了具有保守氢键的层，并形成了芳环的堆叠。醇类烃部分在两层之间有效堆积的能力解释了一些溶剂化物晶体难以生长和其他溶剂化物无法完全结晶的原因。通过实验与计算相结合，在分子水平上理顺了B5HCl的结晶问题、形态稳定性和脱溶途径。通过实验与计算相结合，从分子水平上对3-（4-（苯并[d]异恶唑-3-基）哌嗪-1-基）-2,2-二甲基丙酸盐酸盐（B5HCl）的结晶问题、形态稳定性和脱溶途径进行了合理化。
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. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) have been rationalized at a molecular level.
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影响因子：
4.9
作者：
Braun DE;Koztecki LH;McMahon JA;Price SL;Reutzel-Edens SM
通讯作者：
Reutzel-Edens SM
DOI：
10.1039/c1cc10762c
发表时间：
2011-05-21
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Braun DE;Karamertzanis PG;Price SL
通讯作者：
Price SL
影响因子：
2
作者：
Antoniadis, Constantinos D.;D'Oria, Emiliana;Jones, Alan G.
通讯作者：
Jones, Alan G.
影响因子：
16.6
作者：
Bond, Andrew D.;Boese, Roland;Desiraju, Gautam R.
通讯作者：
Desiraju, Gautam R.
影响因子：
3.8
作者：
Borodi, Gheorghe;Pop, Mihaela M.;Filip, Xenia
通讯作者：
Filip, Xenia