Concomitant polymorphs routinely observed in fine chemical industry could impact product purity and consistency; however, both molecular mechanism and process kinetics of concomitant crystallization remain elusive. Herein, we developed a population balance model to understand process kinetics of concomitantly dipolymorphic crystallization using DL-methionine as a model compound. Kinetic parameters were estimated from induction time measurements and unseeded crystallization experiments. Experimental and simulation results demonstrate that the stable β form has a comparable nucleation rate with α form thanks to their close nucleation barrier leading to the concurrent nucleation. Several solution chemistry techniques were utilized to examine the speciation of solute molecules, together revealing the solutes' self-association and the formation of micelle-like aggregates driven by hydrophobic interactions, not hydrogen bonds. These aggregates show dynamic nature against conventional thoughts of classical nucleation kinetics. Finally, the molecular mechanism of concomitant crystallization was uncovered and the implications for polymorph selection and control were discussed.

中文翻译：

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伴随多晶型物的结晶机理和动力学模型研究


精细化工行业中经常观察到的伴随多晶型物可能会影响产品的纯度和一致性；然而，伴随结晶的分子机制和过程动力学仍然难以捉摸。在此，我们开发了一个群体平衡模型，以了解使用 DL-蛋氨酸作为模型化合物伴随二多晶型结晶的过程动力学。根据诱导时间测量和无晶种结晶实验估计动力学参数。实验和模拟结果表明，稳定的β形式具有与α形式相当的成核率，这要归功于它们紧密的成核势垒导致同时成核。利用几种溶液化学技术来检查溶质分子的形态，共同揭示溶质的自缔合以及由疏水相互作用而非氢键驱动的胶束状聚集体的形成。这些聚集体表现出动态性质，与经典成核动力学的传统思想相反。最后，揭示了伴随结晶的分子机制，并讨论了对多晶型选择和控制的影响。