Understanding nucleation processes in the crystallization of polymorphs

This thesis describes the effect of process variables on the crystallization of polymorphs of carbamazepine and indomethacin, using two commonly used crystallization techniques, namely, addition of anti-solvent and cooling.; The effect of binary solvent composition on solubility of solute was analyzed using combined Redlich-Kister nearly ideal binary solution model. Solvatochromic analysis was performed to identify solvent parameters that are important in determining the solubility of the solute. A systematic approach was developed to identify the binary solvent for anti-solvent crystallization. Based on the solubility behavior with increase in concentration of anti-solvent, two types of solubility curves were identified. The crystallization behavior of solute from a binary solvent depended on the type of solubility curve.; The effect of temperature on solubility was modeled using approaches developed by van't Hoff, Hildebrand, and Grant. The applicability of dispersive Raman spectroscopy to monitor cooling crystallization, in situ was demonstrated. The metastable zone width increased with cooling rate and also depended on the hydrogen bond forming propensity of the solvent. Broad metastable zone widths were observed in solvents capable of disrupting the hydrogen bonding between solute molecules, while narrow metastable zone widths were observed in solvents that did not disrupt the hydrogen bonding between solute molecules. The influence of process variables on the polymorphic form that crystallized was also dependent on the crystallization technique, whether cooling or anti-solvent addition.; Molecular aggregation in undersaturated and supersaturated solutions of indomethacin in acetonitrile and ethanol was investigated using various spectroscopic techniques. Acetonitrile was found to interact weakly with indomethacin and the low viscosity of acetonitrile solutions remained unaffected with increase in solute concentration. These results explain the observed narrow metastable zone width during crystallization from acetonitrile. The viscosity of the ethanol solutions increased continuously with increase in solute concentration due to formation of strong intermolecular hydrogen bonds between indomethacin and ethanol. These results explain the crystallization behavior of indomethacin from ethanol solutions.