Modulating crystal polymorphism via membrane-regulated supersaturation: an experimental and molecular dynamics simulation study.

HYPOTHESIS: Crystal properties are essential in determining the functionality of final products in pharmaceutical and food applications. This study hypothesizes that membrane-assisted antisolvent crystallization (MAAC) can regulate supersaturation profiles to influence polymorph selection and crystal growth kinetics in glycine crystallization. By using polyvinylidene fluoride (PVDF) membranes to control ethanol diffusion, it is expected that MAAC can promote the formation of specific polymorphs, particularly α-glycine, through modulation of molecular self-assembly pathways.

EXPERIMENTS: To test this hypothesis, MAAC was implemented with PVDF membranes to generate stable supersaturation conditions during glycine crystallization. The membrane served as a mass transfer barrier, enabling controlled ethanol diffusion and allowing for detailed analysis of crystal size and polymorphic distribution. Experimental crystallization outcomes were complemented by molecular dynamics (MD) simulations of glycine-water-ethanol systems at three supersaturation levels (S = 0.74, 1.35, and 2.39). These simulations were used to investigate the formation of molecular aggregates and hydrogen bonding patterns, and to quantify nucleation induction times under varying supersaturation conditions.

FINDINGS: MAAC enabled the formation of α-glycine with a narrow chord length distribution and a mean size of 86 μm. MD simulations revealed that cyclic glycine dimers, precursors to α-glycine, formed at lower supersaturation, while disordered aggregates associated with β-glycine dominated at higher supersaturation. Ethanol was shown to modulate hydrogen bonding and self-assembly, influencing polymorphic outcomes. Induction times decreased significantly with increasing supersaturation, from 1.9 ns to less than 100 ps, highlighting the kinetic control enabled by membrane-regulated crystallization.