Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening.
Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening.
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DOI：
10.1038/ncomms8793
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发表时间：
2015-07-22
影响因子：
16.6
通讯作者：
Grassmann O
中科院分区：
文献类型：
--
作者：
Neumann MA;van de Streek J;Fabbiani FP;Hidber P;Grassmann O
有机分子，如药物、农用化学品和颜料，经常形成几种具有不同物理化学性质的晶体多晶态。长期以来，寻找多态一直是一种纯粹的试验游戏。在这里，我们利用硅晶型筛选结合合理规划的结晶实验来研究药物化合物Dalcetrapib的多态性，Dalcetrapib具有10个扭转自由度，是迄今为止计算研究的最灵活的分子之一。在计算的晶格能量图的底部发现了实验晶体多晶，并且确定了两个预测结构作为缺失的、热力学上更稳定的多晶的候选结构。压力相关的稳定性计算表明，高压是使这些多晶体存在的一种手段。随后，其中一个确实可以在0.02至0.50 GPa的压力范围内结晶，并且在环境压力下被发现是亚稳态的，有效地避免了在Dalcetrapib开发后期出现更稳定的多晶型的风险。晶体多态可以导致物质的物理化学性质有很大的不同，这在制药工业中有着严重的影响。在这里，作者使用硅多晶筛选来准确预测在固定结晶环境下产生的结构。
Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib. Crystal polymorphism can lead to substances with vastly differing physicochemical properties, which has serious implications in the pharmaceutical industry. Here, the authors use in silico polymorph screening to accurately predict the resulting structures under set crystallisation environments.