Polymorph screening: Influence of solvents on the rate of solvent-mediatedpolymorphic transformation

Solvent-mediated polymorphic transformation is an efficient technique to ob tain the most stable polymorph. The rate of solvent-mediated polymorphic tr ansformation of sulfamerazine at 24 degreesC in various solvents and solven t mixtures is controlled by the nucleation rate of the more stable Form II. The transformation rate is generally higher in the solvent giving a higher solubility and is low in the solvent giving a low solubility (8 mmol/L). I n these solvents, because of a high interfacial energy, the metastable zone may be wider than the solubility difference between two polymorphs, such t hat the critical free energy barrier for nucleation cannot be overcome. In addition to the solubility, the strength of the solvent-solute interactions is also important in determining the transformation rate. For sulfamerazin e, the transformation rate is lower in the solvent with a stronger hydrogen bond acceptor propensity. Because solubility is higher in the solvent with stronger hydrogen bond acceptor propensity, the balance of solubility and strength of hydrogen bonding interactions between the solute and solvent mo lecules determines the polymorphic transformation rate. Degree of agitation and temperature also change the polymorphic transformation rate by influen cing the crystallization kinetics of the more stable polymorph. (C) 2001 Wi ley-Liss, Inc. and the American Pharmaceutical Association.