Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach.
Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach.
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使用互补的机械合成和计算结构预测方法有效筛选三元分子离子共晶。
DOI：
10.1002/chem.201904672
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Shunnar AF
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文献类型：
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作者：
Shunnar AF
活性药物成分（API）的分子离子共晶（ICC）的发现拓宽了优化API的物理化学性质同时促进多种治疗剂的递送的机会。然而，ICC经常在结晶屏幕中偶然观察到，并且对决定其结晶的因素知之甚少。我们在这里证明，机械化学球磨是一种多功能的技术，可重复的三元分子ICCs的合成在不到30分钟的研磨或没有溶剂。 计算晶体结构预测（CSP）的计算已经进行了三元分子ICCs的第一次和观察到的所有ICCs的晶体结构被正确地预测。周期性色散校正的DFT计算表明，相对于二元盐和酸的物理混合物的结晶，所有ICC都是化学稳定的（平均稳定化能=−2 kJ mol−1）。 结果表明，组合的机械合成和CSP方法可用于靶向合成具有功能性质的高阶分子ICC。
The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol−1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties.