Nucleation and Crystal Growth of Polymorphs Relevant to Screening

摘要

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