Efficiently obtaining atomic-scale thermodynamic parameters characterizing crystallization from solution is key to developing the modeling strategies needed in the quest for digital design strategies for industrial crystallization processes. Based on the thermodynamics of crystal nucleation in confined solutions, we develop a simulation framework to efficiently estimate the solubility and surface tension of organic crystals in solution from a few unbiased molecular dynamics simulations at a reference temperature. We then show that such a result can be extended with minimal computational overhead to capture the solubility curve. This enables an efficient and self-consistent estimate of the solubility and limit of solution stability associated with crystal nucleation in molecular systems from equilibrium molecular dynamics without the need for sophisticated free energy calculations. We apply our analysis to investigate the relative thermodynamic stability and aqueous solubility of the α and β polymorphs of l-glutamic acid. Our analysis enables an efficient appraisal of emergent ensemble properties associated with the thermodynamics of nucleation from solutions against experimental data, demonstrating that while the absolute solubility is still far from being quantitatively captured by an off-the-shelf point charge transferable force field, the relative polymorphic stability and solubility obtained from finite temperature simulation are consistent with the experimentally available information on glutamic acid. We foresee the ability to efficiently obtain solubility information from a limited number of computational experiments as a critical component of high-throughput polymorph screenings.

中文翻译：

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有限尺寸分子动力学模拟中 l-谷氨酸多晶型物的溶液热力学


从溶液中有效地获得表征结晶的原子级热力学参数，是开发工业结晶过程数字设计策略所需的建模策略的关键。基于约束溶液中晶体成核的热力学，我们开发了一个模拟框架，以在参考温度下通过一些无偏分子动力学模拟有效地估计有机晶体在溶液中的溶解度和表面张力。然后，我们表明，这样的结果可以用最小的计算开销来扩展，以捕获溶解度曲线。这使得能够根据平衡分子动力学对分子系统中与晶体成核相关的溶解度和溶液稳定性极限进行有效且自洽的估计，而无需复杂的自由能计算。我们应用我们的分析来研究 l-谷氨酸的 α 和 β 多晶型物的相对热力学稳定性和水溶性。我们的分析能够根据实验数据有效地评估与溶液成核热力学相关的新兴集成性质，表明虽然绝对溶解度仍远未被现成的点电荷转移力场定量捕获，但从有限温度模拟中获得的相对多晶型稳定性和溶解度与谷氨酸的实验可用信息一致。我们预见到从有限数量的计算实验中有效获取溶解度信息的能力，作为高通量多晶型筛选的关键组成部分。