A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs
A Prolific Solvate Former, Galunisertib, under the Pressure of Crystal Structure Prediction, Produces Ten Diverse Polymorphs
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DOI：
10.1021/jacs.9b06634
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发表时间：
2019-09-04
影响因子：
15
通讯作者：
Reutzel-Edens, Susan M.
中科院分区：
文献类型：
--
作者：
Bhardwaj, Rajni M.;McMahon, Jennifer A.;Reutzel-Edens, Susan M.
Galunisertib的固体形式筛选产生了许多溶剂，促使对I形式V进行了广泛的调查，以研究开发受欢迎的一水合物形式可能存在的风险。受晶体结构预测的启发，对纯净多晶型的搜索扩展到了一系列不同寻常的实验，包括在压力下熔融结晶，以解决溶剂形成和分子的热不稳定性。已经发现了10个Galunisertib的多态；然而，预测最稳定的结构尚未得到。我们给出了Galunisertib的所有十个非溶剂型的晶体结构，展示了最先进的表征方法如何与新兴的计算建模技术相结合，以产生看起来更稳定的完整的结构图景。这种多产的溶剂型化合物的特殊构象多态吸引了计算和实验方法的进一步发展，这些方法适用于具有复杂固体形态的较大、灵活的分子。
The solid form screening of galunisertib produced many solvates, prompting an extensive investigation Form I Form V into possible risks to the development of the favored monohydrate form. Inspired by crystal structure prediction, the search for neat polymorphs was expanded to an unusual range of experiments, including melt crystallization under pressure, to work around solvate formation and the thermal instability of the molecule. Ten polymorphs of galunisertib were found; however, the structure predicted to be the most stable has yet to be obtained. We present the crystal structures of all ten unsolvated polymorphs of galunisertib, showing how state-of-the-art characterization methods can be combined with emerging computational modeling techniques to produce a complete structure landscape appearing, more stable polymorphs. The exceptional conformational polymorphism of this prolific solvate former invites further development of methods, computational and experimental, that are applicable to larger, flexible molecules with complex solid form landscapes.