A computational study of the mechanism of the selective crystallization of α- and β-glycine from water and methanol-water mixture.

Understanding the control of polymorphism in organic crystals is of paramount importance to the pharmaceutical, chemical, and food industries. In this work, we investigated two mechanisms described in the literature about the selective crystallization of α- and β-glycine from water and from mixtures of water and methanol using molecular simulations. The link hypothesis (J. Phys. Chem. B 2008, 112, 7794; Cryst. Growth Des. 2006, 6, 1788; J. Inclusion Phenom. Mol. Recognit. Chem. 1990, 8, 395; J. Am. Chem. Soc. 1986, 108, 5871.), which tries to relate the structure of the polymorph obtained from crystallization to the structure of the prenucleation aggregates in the solutions, says the abundance of glycine cyclic dimers in aqueous solutions leads to the crystallization of α-glycine, the polymorph using cyclic dimers as the packing units. This hypothesis was studied first. We revisited the self-assembly of glycine molecules in solution using molecular dynamics to address the debate (Phys. Rev. Lett. 2007, 99, 115702; J. Phys. Chem. B 2008, 112, 7280; J. Am. Chem. Soc. 2008, 130, 13973.) about which is the dominating species in the glycine aqueous solutions and whether there is a link between the solution chemistry and the polymorphic outcome of crystallization. The structures of the glycine clusters were characterized using a structural parameter called cyclic dimer fraction. The glycine clusters in methanol-water mixtures have higher cyclic dimer compositions than those in the pure aqueous solutions. Moreover, the glycine open-chain dimer is more stable than the cyclic dimer regardless of the presence of methanol. All these suggest that the link hypothesis does not work for the polymorphic system of glycine, and the selective crystallization of α- and β-glycine from water and methanol-water mixture, respectively, is not due to the abundance of glycine aggregates in the solution phase with a similar structure to the crystallizing solid form. The hypothesis of the methanol inhibition on the growth of α-glycine {010} and {010} faces, proposed by Weissbuch (Angew. Chem., Int. Ed. 2005, 44, 3226.), was also studied. The interfaces between the {010} and {010} faces of both crystal forms (α and β) and both solvents (water and methanol-water 3:7 mixture) were studied using molecular simulation. No strong binding of methanol onto the {010} and {010} faces of both crystal forms was observed, and the addition of methanol dilutes the crystal-solvent interactions on all faces. Therefore, the selective crystallization of β and α-glycine with and without methanol does not follow either of the two mechanisms in the literature.