Solvent Effect on Crystal Polymorphism: Why Addition of Methanol or Ethanol to Aqueous Solutions Induces the Precipitation of the Least Stable β Form of Glycine

Abstract

Crystal polymorphism, which embodies the ability of molecules to form diverse packing arrangements displaying different physical and chemical characteristics, is of paramount importance in fields such as pharmacology, solid-state chemistry, and material science. However, the conditions to induce the precipitation of various (metastable) polymorphs is invariably achieved by “mix and try” methods, which are kinetically driven. Various factors should be considered in trying to understand these complex processes, for example, the formation of structured clusters in solution prior to crystallization, the structure of growing surfaces that delineate emerging nuclei, the interaction between these surfaces and the solvent, as well as solvent–solute and solute– solute interactions. Herein, we attempt to unravel some of these factors to rationalize the preferred crystallization of the b form of glycine (gly) in water–alcohol solutions as opposed to the more stable a or g polymorphs. The thermodynamic stability of the three polymorphs of glycine at room temperature is in the order g>a> b. The a form (space group P21/n), grown from supersaturated aqueous solutions (33.3 g/100 mL water) at 25 8C, has a bipyramidal habit and is composed of centrosymmetric bilayers formed by strong NH···O hydrogen-bonding interactions between cyclic hydrogen-bonded zwitterionic molecular pairs. These bilayers are related along the b axis by glide symmetry through weak CH···O interactions (Figure 1a). Previous studies indicated that a-gly crystallizes primarily in aqueous solutions through hydrogen-bonded cyclic dimer growth units: Diffusion-coefficient measurements of supersaturated aqueous solutions of glycine point to the formation of clusters with an average of 1.8 molecular growth units. Furthermore, atomic force microscopy (AFM) and phase interferometry microscopy measurements established that steps approximately 1 nm in size were formed, which correspond to the thickness of a glycine bilayer. Grazingincidence X-ray diffraction studies on growing a-gly {010}