Synthesis of crystalline materials involves the two most important methods: antisolvent and cooling crystallization. Despite the extensive use of the antisolvent method in the crystallization of various organic and inorganic crystals, the governing mechanism of the antisolvent in activating this process is not fully understood. Thermodynamically, the antisolvent is known to increase the chemical potential, and thereby supersaturation, of solute in the solution leading to crystal nucleation and growth. It is well-known that, before the solute molecules can self-assemble to form crystals, they must leave their solvation shell. Here, we show a previously unrecognized three-step mechanism of antisolvent-driven desolvation, where the antisolvent first enters the solvation shell due to attractive interactions with solute, followed by its reorganization and then expulsion of an antisolvent−solvent pair from the solvation shell due to repulsive forces. To confirm this mechanism, molecular simulations of histidine (solute) in water (solvent) at various concentrations of ethanol (antisolvent) and supersaturation are performed. The simulations reveal competitive binding of ethanol to hydrated histidine followed by its dewetting to allow significant solute−solute interactions for crystal growth. This threestep mechanism is then used to obtain an activation barrier for desolvation of histidine followed by prediction of crystal growth rates using a computationally inexpensive semiclassical approach. Growth rates obtained from the activation barrier reproduce the experimental growth rates reasonably, thereby validating the governing three-step mechanism for antisolvent crystallization.
Illustrated is a two-step nucleation process, where solute molecules in the solution are first partially desolvated to form locally dense liquid clusters followed by selective desolvation to yield crystalline solids.
The chemical pathway for synthesizing covalent organic frameworks (COFs) involves a complex medley of reaction sequences over a rippling energy landscape that cannot be adequately described using existing theories. Even...
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.