Karamertzanis Panagiotis G, Day Graeme M, Welch Gareth W A, Kendrick John, Leusen Frank J J, Neumann Marcus A, Price Sarah L
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom.
J Chem Phys. 2008 Jun 28;128(24):244708. doi: 10.1063/1.2937446.
The predicted stability differences of the conformational polymorphs of oxalyl dihydrazide and ortho-acetamidobenzamide are unrealistically large when the modeling of intermolecular energies is solely based on the isolated-molecule charge density, neglecting charge density polarization. Ab initio calculated crystal electron densities showed qualitative differences depending on the spatial arrangement of molecules in the lattice with the greatest variations observed for polymorphs that differ in the extent of inter- and intramolecular hydrogen bonding. We show that accounting for induction dramatically alters the calculated stability order of the polymorphs and reduces their predicted stability differences to be in better agreement with experiment. Given the challenges in modeling conformational polymorphs with marked differences in hydrogen bonding geometries, we performed an extensive periodic density functional study with a range of exchange-correlation functionals using both atomic and plane wave basis sets. Although such electronic structure methods model the electrostatic and polarization contributions well, the underestimation of dispersion interactions by current exchange-correlation functionals limits their applicability. The use of an empirical dispersion-corrected density functional method consistently reduces the structural deviations between the experimental and energy minimized crystal structures and achieves plausible stability differences. Thus, we have established which types of models may give worthwhile relative energies for crystal structures and other condensed phases of flexible molecules with intra- and intermolecular hydrogen bonding capabilities, advancing the possibility of simulation studies on polymorphic pharmaceuticals.
当仅基于孤立分子电荷密度对分子间能量进行建模而忽略电荷密度极化时，草酰二肼和邻乙酰氨基苯甲酰胺构象多晶型物的预测稳定性差异大得不符合实际。从头算计算得到的晶体电子密度显示出定性差异，这取决于晶格中分子的空间排列，对于分子间和分子内氢键程度不同的多晶型物，观察到的变化最大。我们表明，考虑诱导作用会显著改变多晶型物计算得到的稳定性顺序，并减小其预测的稳定性差异，使其与实验结果更吻合。鉴于对氢键几何结构存在显著差异的构象多晶型物进行建模存在挑战，我们使用原子基组和平面波基组，对一系列交换相关泛函进行了广泛的周期性密度泛函研究。尽管此类电子结构方法能很好地模拟静电和极化贡献，但当前交换相关泛函对色散相互作用的低估限制了它们的适用性。使用经验色散校正密度泛函方法能持续减小实验晶体结构与能量最小化晶体结构之间的结构偏差，并实现合理的稳定性差异。因此，我们确定了哪些类型的模型可为具有分子内和分子间氢键能力的柔性分子的晶体结构及其他凝聚相提供有价值的相对能量，提高了对多晶型药物进行模拟研究的可能性。
