Crystal Energy Landscape of Nifedipine by Experiment and Computer Prediction
Crystal Energy Landscape of Nifedipine by Experiment and Computer Prediction
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通过实验和计算机预测硝苯地平的晶体能量景观
DOI：
10.1021/acs.cgd.1c01317
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发表时间：
2022
影响因子：
3.8
通讯作者：
Yu, Lian
中科院分区：
文献类型：
--
作者：
Gui, Yue;Jin, Yingdi;Ruan, Shigang;Sun, Guangxu;López-Mejías, Vilmalí;Yu, Lian
目前已知的硝苯地平（NIF）的六种多晶型是在过去50年中发现的，最近的一种（δ）于2020年发现，来自一种不寻常的途径。这种多晶型物在热力学稳定性方面排名第二，但回避了所有以前的工作者，直到其熔体被外来物质非洛地平的晶体接种，其中分子具有与当时已知的所有其他NIF多晶型物不同的构象。鉴于实验室中的这一不寻常的发现，我们研究了晶体结构预测（CSP）是否可以在“常规”搜索中找到这种和其他多晶型。我们表明，我们的CSP发现了目前已知的低能结构（秩1，3，4和43）的NIF的所有有序多晶型物，包括最近通过伪播种（秩4）揭示的一个。NIF是一种灵活的分子，了解它的许多构象中哪一种为晶体提供了最佳的构建块是很有意义的。对这个问题的实验研究受到生存的限制;也就是说，信息存在于观察到的结构上，而不存在于那些难以观察或尚未发现的结构上。在这方面，我们的“计算机实验”获得了所有的可能性。我们发现，thesynperiplanar（sp）构象相对于苯基扭转产生较低的能量晶体比反periplanar（ap）构象，与最稳定的跳跃晶体是4 kJ/mol的能量高于最稳定的pstructure。实验上，pconformer占主导地位的茶氨酸溶液，是唯一的构象观察晶体。对于酯扭转，顺式/反式构象异构体产生的能量最低的晶体，其次是顺式/顺式构象异构体和反式/反式构象异构体。实验上，六种已知的多晶型物中有五种含有顺式/反式构象异构体，一种含有顺式/顺式构象异构体，没有一种含有反式/反式构象异构体。总的来说，CSP是非常成功的预测NIF的多晶型物，尽管其复杂的构象空间，并提供了一个定量评估的相对成本采用不同的构象作为单位的晶体建设。
The six polymorphs of nifedipine (NIF) known at present have been discovered over the past 50 years, and the most recent one (δ), discovered in 2020, came from an unusual route. This polymorph is ranked second in thermodynamic stability but evaded all previous workers until its melt was seeded with the crystal of a foreign substance, felodipine, in which the molecule has a different conformation from all other NIF polymorphs known at that time. Given this unusual discovery in the lab, we investigated whether crystal structure prediction (CSP) can find this and other polymorphs in a “routine” search. We show that our CSP finds all ordered polymorphs of NIF known at present as low-energy structures (Ranks 1, 3, 4, and 43), including the most recent one unveiled by pseudoseeding (Rank 4). NIF being a flexible molecule, it is of interest to learn which of its many conformers provides the best building block for crystals. An experimental investigation of this question is limited bysurvival; that is, information exists on the structures that are observed but not on those that are difficult to observe or not yet discovered. In this regard, our “computer experiments” access the full range of possibilities. We find that thesynperiplanar(sp) conformer with respect to phenyl torsion produces lower-energy crystals than theantiperiplanar(ap) conformer, with the most stableapcrystal being 4 kJ/mol higher in energy than the most stablespstructure. Experimentally, thespconformer dominates theapin solution and is the only conformer observed in crystals. With respect to the ester torsions, thecis/transconformer produces the lowest-energy crystals, followed by thecis/cisconformer and by thetrans/transconformer. Experimentally, five of the six known polymorphs contain thecis/transconformer, one contains thecis/cisconformer, and none contain thetrans/transconformer. Overall, the CSP is remarkably successful in predicting the polymorphs of NIF in spite of its complex conformational space and provides a quantitative assessment of the relative costs of employing different conformers as units of crystal building.