Nucleation and Crystal Growth of Polymorphs Relevant to Screening

摘要

Discovering the various polymorphs of a compound is an essential step inrnpreformulation. Usually, the most stable polymorph is preferred in the marketed product.rnSolvent-mediated polymorphic transformation is an efficient technique for polymorphrnscreening and for obtaining the most stable polymorph. However, solvents and impuritiesrnprofoundly influence the rate of polymorphic transformation. This talk describes therninfluence of solvents and impurities on the rate of solution-mediated polymorphicrntransformation (ⅠtoⅡ) of sulfamerazine (SMZ), and explores the underlying mechanismrnand molecular interactions. The nucleation rate of the more stable polymorph,Ⅱ,rndetermines the transformation rate at 24oC in various solvents or solvent mixtures. Therntransformation rate is negligible in solvents giving low solubility (< 8 mmol/L) andrnincreases and then decreases with increasing solubility. Transformation is slowed inrnsolvents with strong hydrogen bond acceptor propensities. The balance of solubility andrnstrength of hydrogen bonding between solute and solvent determines the transformationrnrate. Also, the structurally related additives, N4-acetylsulfamerazine (NSMZ),rnsulfadiazine (SD) or sulfamethazine (SM), in acetonitrile at 24oC slow down the rate ofrnsolution-mediated transformation (Ⅰ toⅡ ). The rank order of inhibitory effects on thernrates of nucleation and crystal growth (NSMZ SD>SM) parallels the rank order ofrnbinding energy of the impurity molecules to the surface of the SMZ crystal.