Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods
Overcoming the difficulties of predicting conformational polymorph energetics in molecular crystals via correlated wavefunction methods
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DOI：
10.1039/c9sc05689k
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发表时间：
2020-02-28
期刊：
影响因子：
8.4
通讯作者：
Beran, Gregory J. O.
中科院分区：
文献类型：
--
作者：
Greenwell, Chandler;McKinley, Jessica L.;Beran, Gregory J. O.
分子晶体结构预测越来越多地被应用于研究更大，更灵活的药物分子的固体形态景观。尽管在晶体结构预测方面取得了许多成功，但货车德瓦尔斯包含密度泛函理论（DFT）方法在预测许多表现出构象多态性的系统的多晶型稳定性方面表现出严重的失败，其中分子内构象的变化导致不同的分子间晶体堆积。在这里，o-乙酰氨基苯甲酰胺，ROY，和草酰二酰肼的构象多晶型物的稳定性进行了详细检查。DFT泛函，以前已经非常成功的晶体结构预测表现不佳，在所有三个系统中，主要是由于穷人的分子内构象能，但也由于在草酰二酰肼的分子间描述。在所有这三种情况下，基于片段的分散校正的二阶Moller-Plesset微扰理论（MP 2D）治疗的晶体克服了这些困难，并预测构象多晶型物的稳定性与实验吻合良好。这些结果突出了需要超越当前一代DFT泛函的方法，使晶体多晶型稳定性预测真正可靠。
Molecular crystal structure prediction is increasingly being applied to study the solid form landscapes of larger, more flexible pharmaceutical molecules. Despite many successes in crystal structure prediction, van der Waals-inclusive density functional theory (DFT) methods exhibit serious failures predicting the polymorph stabilities for a number of systems exhibiting conformational polymorphism, where changes in intramolecular conformation lead to different intermolecular crystal packings. Here, the stabilities of the conformational polymorphs of o-acetamidobenzamide, ROY, and oxalyl dihydrazide are examined in detail. DFT functionals that have previously been very successful in crystal structure prediction perform poorly in all three systems, due primarily to the poor intramolecular conformational energies, but also due to the intermolecular description in oxalyl dihydrazide. In all three cases, a fragment-based dispersion-corrected second-order Moller-Plesset perturbation theory (MP2D) treatment of the crystals overcomes these difficulties and predicts conformational polymorph stabilities in good agreement with experiment. These results highlight the need for methods which go beyond current-generation DFT functionals to make crystal polymorph stability predictions truly reliable.