Molecular insights on the solvent effect of methanol additive in glycine polymorph selection

Abstract

In an effort to improve control and design in organic crystallization, the effect of solvent on polymorph selection has gained tremendous interest in recent years. In this thesis, molecular simulation techniques are used to gain insight into the solvent effect on glycine crystallization in water-methanol mixtures. We report the validation of the Optimized Potential for Liquid Simulations (OPLS) force field and parameters with modified Lennard-Jones parameters for hydrogens attached to a-carbon in glycine zwitterion. Solution and interface simulations in water and 50% v/v water-methanol solutions reveal the mechanism through which methanol additive results in the crystallization of the least stable [Beta]-glycine polymorph. Free energy calculations through the Umbrella Sampling method show an increased stability of the centrosymmetric dimer structure ([alpha]-glycine growth unit) in the presence of the methanol additive. Even though the dimer structure is more stable in water-methanol mixtures, a higher fraction of glycine monomers were observed in water-methanol mixtures. It is revealed through thermodynamic arguments that a drastic decrease in solubility results in a higher fraction of glycine monomers in water-methanol mixtures. It was hypothesized in previous studies that the presence of monomer units docking onto the (010) interface of [alpha]-glycine inhibits further growth due to exposed ammonium groups at the interface. The effect of solvent on crystal growth inhibition is explored by the interface simulations of a-glycine in water-methanol mixtures. When the monomer units are docked onto the interface, water is shown to be more effective than methanol in inhibiting crystal growth of (010) interface of [alpha]-glycine. This study sheds light on the role played by the solvent on glycine polymorph selection in water-methanol solutions.