Bachtiger Fabienne, Rahimee Aliff, Li Lunna, Salvalaglio Matteo
Thomas Young Centre and Department of Chemical Engineering, University College London, London WC1E 7JE, U.K.
Ind Eng Chem Res. 2025 Jan 7;64(2):1309-1318. doi: 10.1021/acs.iecr.4c02558. eCollection 2025 Jan 15.
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.
从溶液中高效获取表征结晶过程的原子尺度热力学参数，是开发工业结晶过程数字设计策略所需建模方法的关键。基于受限溶液中晶体成核的热力学原理，我们开发了一个模拟框架，通过在参考温度下进行少量无偏分子动力学模拟，来高效估算有机晶体在溶液中的溶解度和表面张力。然后我们表明，这样的结果可以以最小的计算开销进行扩展，以捕捉溶解度曲线。这使得我们能够从平衡分子动力学出发，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高效且自洽的估算，而无需进行复杂的自由能计算。我们应用我们的分析方法来研究L-谷氨酸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，对与溶液中成核热力学相关的新兴系综性质进行高效评估，这表明虽然现成的可转移点电荷力场仍远不能定量捕捉绝对溶解度，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现有实验信息是一致的。我们预见，能够从有限数量的计算实验中高效获取溶解度信息，将成为高通量多晶型筛选的关键组成部分。
