(744b) Mechanism of the Formation of Enantiotropic Polymorphs in Solution Crystallization

From preclinical development through manufacture of the final drug product, the identification, selection and understanding of drug solid form will have an enormous practical and commercial impact. Crystallization is the critical step in solid form control. Physical and chemical properties denoted by cluster structure, size and shape affect the rate of crystallisation and therefore influence the polymorph selection process. The nucleation kinetics (i.e., induction time), of drug molecules in methanol, ethanol, 2-propanol and water was studied using Raman spectroscopy with multiple probes at 25^oC at varying levels of supersaturation ranging from 1.3 to 2.3. Induction periods varied markedly with respect to relative supersaturation. While at the same relative supersaturation, the induction time in methanol was shortest and increased in order from ethanol, 2-propanol and water. The interfacial tensions, between drug crystal and methanol, ethanol, 2-propanol and water were estimated from their induction times based on nucleation theory and were found to be about 3.6, 4.1, 4.5 and 5.7 mJ/m² respectively. These values were of the same order of magnitude as those obtained from solubility data. The polymorphism of drug substance was studied in these solvents by maintaining a constant supersaturation (»1.6) and varying temperature from 15 to 45^oC. Under these conditions the polymorph remained unchanged. The equation that displays the influence of interfacial tension, supersaturaton and temperature on crystallization kinetics was derived, and was found to be consistent with experimental observations. The mechanism of enantropic polymorphism in the solution crystallization is illustrated. Prediction of polymorphs in pure or mixtures of solvents based on interfacial tension values derived from solubility data is in agreement with the experimental findings.