Selective Crystallization of Racemic Polymorph via Native Enantiomer Inhibition: DL-Methionine

Crystallization of chiral compounds is dictated by chiral recognition and molecular self-assembly in solution. However, their interplay remains elusive. The reason for the considerably reduced polymorphism in chiral molecules than that of nonchiral molecules remains unclear. Herein, we use a combination of experimental and computational techniques to show that excessive enantiomer functioning, as a native crystallization inhibitor, selectively suppresses the crystallization of racemic polymorphs, affording preferential crystallization of the metastable alpha polymorph of DL-methionine. Bulk crystallization assays show concomitant crystallization of the alpha and beta polymorphs of racemic DL-methionine in the solution with no enantiomeric excess. However, when the solution contains excessive D-/L-methionine enantiomer, only the metastable alpha form can be crystallized. Crystal growth experiments, fluoresce confocal microscopy, and atomic force microscope surface topology measurements reveal the growth inhibition of both polymorphs with preferential suppression of the beta form by excess native enantiomer. Binding energy calculations and molecular dynamic simulations further demonstrate the preferential adsorption of excessive enantiomers on the (0 0 2) facet of the beta form over the alpha form. Overall, our results uncover a unique chiral self-positioning mechanism where the excess enantiomer solutes serve as a native growth inhibitor to disrupt the kinetics of racemic polymorphic crystallization, affording selective crystallization of only one polymorph of DL-methionine. Our results highlight the important effect of excess enantiomer in a solution on the polymorph occurrence of chiral molecules.