Three-Step Mechanism of Antisolvent Crystallization

Abstract

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.

The Effect of Chain Length and Conformation on the Nucleation of Glycine Homopeptides during the Crystallization Process

“…Apart from the classical nucleation theory, other nonclassical nucleation models have been developed over the last two decades. ,− For the glycine homopeptides, the liquid–liquid phase separation was also observed for hexaglycine before the nucleation, which can be seen in Figure d,e. The solution became blurry first, and there were some gel-like particles that will not settle for a long time, similar to the liquid–liquid separation process observed in the literatures. , …”

Emulsification of Supersaturated Solutions Amplifies Induction Time Variation in Crystallization

“…The classification into either of the thermodynamic states of the histidine molecule (fully solvated or partially desolvated) was based on the number of solvent (water) molecules in the solvation shell of histidine and the pairwise distance between solute molecules. The solvation shell thickness of histidine was found to be 0.63 nm . The transition state and the activation barrier required to achieve the transition state are calculated using the semiclassical double-well approach (Figure S2).…”

“…The BD simulation scheme was used to simulate the motion of histidine molecules with a higher box volume and a greater number of molecules in the simulation box as per the desired concentration. The number of molecules in the BD simulations is scaled based on previously reported values . A higher box volume allows dividing the simulation box into smaller bins to effectively analyze the local concentration experienced by each histidine molecule.…”

“…Experimental induction times and critical nuclei sizes were obtained from the literature. , In the literature, the critical nuclei sizes are reported as the thickness (in nm) of growth units based on the unit cell of histidine . These thickness values are used to calculate the volume of growth unit at each supersaturation, which in turn denotes the number of histidine molecules required to form the critical nucleus.…”

“…The solvation shell thickness of histidine was found to be 0.63 nm. 37 The transition state and the activation barrier required to achieve the transition state are calculated using the semiclassical double-well approach (Figure S2). The transition state is the step before the integration of molecules into the crystal surface.…”