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.

中文翻译：

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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。

活性药物成分 (API) 的分子离子共晶 (ICC) 的发现拓宽了优化 API 理化性质的机会，同时促进多种治疗剂的输送。然而，ICC 经常在结晶筛选中偶然观察到，而决定其结晶的因素却知之甚少。我们在此证明，机械化学球磨是一种通用技术，可在使用或不使用溶剂的情况下，在不到 30 分钟的研磨时间内可重复合成三元分子 ICC。首次对三元分子ICC进行了计算晶体结构预测（CSP）计算，并正确预测了所观察到的所有ICC的晶体结构。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 都是热力学稳定的（平均稳定能=-2 kJ mol-1 ）。结果表明，机械合成和 CSP 相结合的方法可用于合成具有功能特性的高阶分子 ICC。