In the recent years, polymorphism, a phenomenon in which the molecules of a compound pack in different arrangements in their solid-state, has drawn much attention in the pharmaceutical industries. The polymorphs differ in their physicochemical properties such as melting point, density and solubility, thereby affecting the dissolution rate and bioavailability of the active ingredients in the final dosage forms. They also have an impact on the downstream processing and formulation of the solid products. Above all, polymorphism in pharmaceuticals has transcended from a scientific subject to a regulatory issue due to its implications on product patent legislation [1]. Of the many factors influencing the nucleation of crystal polymorphs, recent studies on solution crystallization have focused on the effects of pH, supersaturation, temperature and impurities [2-5]. These factors (could be process parameters or variables) impact the structural outcome of the crystallization process through a delicate interplay of kinetics and thermodynamics controlling crystal nucleation. We have made interesting observations in our studies on the effect of structurally related impurities (α-amino acids) on the crystallization of glycine. Glycine, the simplest of the α-amino acids, is a trimorphic system with α, β and γ crystal forms. α-glycine is the kinetically favored form and is obtained from solution crystallization at the isoelectric pH conditions. γ-glycine is the stable form at ambient conditions and is obtained from acidic or basic solutions. The unstable β-form is obtained from ethanol/ water solution and has a tendency to undergo a solution mediated transformation to α-form. In the presence of ‘certain' amino acid impurities, we observed the nucleation of γ-glycine instead of the α-form usually obtained from pure solution. These impurities (or additives) dissociated in glycine solution forming charged molecular species and decreased the solution pH. The impact of the speciation of impurities was also reflected on the stereoselective habit modification in α-glycine crystals [6]. We are currently investigating the mechanism for the polymorphic modification by systematically studying the effect of impurities on the solubility, supersaturation and the intermolecular interactions at the nucleation stage. The results from this study could enable a better understanding of the nucleation behavior in polymorphic systems and also provide guidelines for isolating the desired crystal phase consistently in pharmaceutical crystallization.

References [1] Bernstein, J. in “Polymorphism in Molecular Crystals”, Oxford Science Publications, 2002, pp. 240-255. [2] Towler et al., “Impact of Molecular Speciation on Crystal Nucleation in Polymorphic Systems: The Conundrum of γ Glycine and Molecular ‘Self Poisoning'”, J. Am. Chem. Soc., 126, 13347 – 13353 (2004). [3] Jones et al., “Crystallization of a salt of a Weak Organic Acid and Base: Solubility Relations, Supersturation Control and Polymorphic Behavior”, J. Phys. Chem. B, 109, 5273-5278 (2005). [4] Mukuta et al., “Influence of Impurities on the Solution-Mediated Phase Transformation of an Active pharmaceutical Ingredient”, Cryst. Growth. Des., 5 (4), 1429-1436 (2005). [5] Yu et al., “Control of Crystal Polymorphism by Tuning the Structure of Auxiliary Molecules as Nucleation Inhibitors. The β-polymorph of Glycine Grown in Aqueous Solutions”, Cryst. Growth. Des., 5(6), 2190-2196 (2005). [6] Poornachary et al., “Molecular Speciation Controlling Stereoselectivity of Additives: Impact on the Habit Modification in α-Glycine Crystals”, submitted to Cryst. Growth. Des., April 2006.