(238h) Biphasic Nature of Supersaturated Solutions Increases Induction Time Variation in Crystallization

Induction time is governed by the molecular self-assembly that occurs during crystallization. Self-assembly's inherent stochastic nature causes fluctuations in induction time under identical operating conditions, making it difficult to control the crystallization process. Traditionally, induction time is understood in the framework of classical nucleation theory, which assumes that crystal-like ordering begins during the self-assembly of molecules. In this instance, the dynamics of induction time are comprehended through the empirical correlation of experimental data. This approach shows large deviations between theoretically calculated and experimentally observed induction time. More recently, two-step nucleation has been observed where molecules form a non-crystalline dense phase leading to crystalline nuclei formation. In two-step nucleation, the induction time is governed by the lifespan of dense clusters, and the relationship between operating conditions and induction time is not yet elucidated. The limited understanding of fluctuations in induction time is more pronounced in the case of non-covalent crystallization, as precise control over the process of crystallization is necessary to prevent polymorphism. In this article, we simulate the large-scale antisolvent crystallization of histidine molecules over a prolonged timescale using Brownian dynamics (BD) simulations. Local fluctuations in the supersaturation lead to the formation of two distinct dense phases in the simulation box, as demonstrated by the results. In addition, we demonstrate that the average induction time is dependent on supersaturation and that the diffusion of histidine molecules determines the stochastic character of the induction time. This method predicts an induction time that corresponds reasonably well with the experimentally observed induction time.