Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? 2. Crystal Structure Prediction
Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? 2. Crystal Structure Prediction
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DOI：
10.1021/ct8004326
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发表时间：
2009-05-01
影响因子：
5.5
通讯作者：
Price, Sarah L.
中科院分区：
文献类型：
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作者：
Karamertzanis, Panagiotis G.;Kazantsev, Andrei V.;Price, Sarah L.
我们报告了一个多级晶格能量最小化方法产生稳定的包装安排的共晶含有灵活的分子。在第一近似中，分子间的静电相互作用与原子电荷建模和分子变形能内插在一组预先计算的量子力学值。在随后的阶段中，通过首先使用解析旋转，然后使用从孤立分子电荷密度计算的构象依赖的多极矩，以及“即时”量子力学计算来计算分子内变形能，来提高精度。这种多级方法提高了搜索的效率，并建立了分子依赖的错误，由于原子电荷表示的电荷密度和忽略的构象依赖的原子多极矩。用该方法研究了4-氨基苯甲酸与2，2 '-联吡啶和4-硝基苯乙酸共晶以及单组分晶体的晶格能谱。所有单组分，实验确定的晶体结构的搜索范围内发现，或非常接近，全球最小值。与2，2 '-联吡啶的实验共晶也被预测是最稳定的堆积排列之一。相反，与4-硝基苯乙酸的共晶的晶格能景观包含几个低能量的结构，比实验观察到的形式更稳定，并具有不同的氢键基序。总体而言，该方法可以提供有价值的晶体能量景观多组分有机固体，从而有助于了解共晶形成。
We report a multistage lattice energy minimization methodology for generating stable packing arrangements of cocrystals containing flexible molecules. In the first approximation, the intermolecular electrostatic interactions are modeled with atomic charges and the molecular deformation energy is interpolated over a set of precomputed quantum mechanical values. At subsequent stages, the accuracy is improved by first using analytically rotated and then conformation-dependent multipole moments, computed from the isolated-molecule charge density, and "on-the-fly" quantum mechanical calculations to compute the intramolecular deformation energy. This multistage approach increases the efficiency of the search and establishes the molecule-dependent error due to the atomic charge representation of the charge density and the neglect of the conformational dependence of atomic multipole moments. The methodology is used to study the lattice energy landscapes of the cocrystals of 4-aminobenzoic acid with 2,2'-bipyridine and 4-nitrophenyl acetic acid, as well as the single-component crystals. All single-component, experimentally determined crystal structures within the scope of the search were found at, or very close to, the global minimum. The experimental cocrystal with 2,2'-bipyridine is also predicted to be among the most stable packing arrangements. On the contrary, the lattice energy landscape of the cocrystal with 4-nitrophenyl acetic acid contains several low energy structures that are more stable than the experimentally observed form and have different hydrogen bonding motifs. Overall, the methodology can provide worthwhile crystal energy landscapes for multicomponent organic solids and thereby contribute to understanding cocrystal formation.