Emulsification of Supersaturated Solutions Amplifies Induction Time Variation in Crystallization

The induction time for the onset of nucleation is known to decrease with increasing solution supersaturation. A large variation in induction time is experimentally observed for various organic crystals, whose origin is often associated with the stochastic nature of the nucleation process. Although several empirical models for induction time and nucleation rate have been developed, they remained highly unreliable, with model predictions differing by orders of magnitude from experimental measurements. A satisfactory explanation for the induction time variation has not been developed yet. We report here that the variations in induction times can be attributed to a previously unrecognized consequence of the phase separation or emulsification of supersaturated solution, in addition to the effect of stochastic nucleation. A large-scale Brownian dynamics simulation of antisolvent crystallization of histidine in a water–ethanol mixture is performed to demonstrate the mechanism of microphase/emulsion formation in supersaturated solutions and its consequence on induction time variation. Furthermore, we show that the average induction time depends on supersaturation, and the supersaturation-dependent diffusion of histidine molecules governs the stochastic nature of the induction time. Moreover, at varying supersaturations, the likelihood of forming stable and metastable polymorphs of histidine was estimated. This approach provides valuable insights into the crystallization behavior of histidine, and predicted induction time reasonably matches the experimentally observed induction time.