Cooling Crystallization of Indomethacin: Effect of Supersaturation, Temperature, and Seeding on Polymorphism and Crystal Size Distribution

In this work, the effect of crystallization parameters, i.e., supersaturation, seeding, and temperature, on the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug, indomethacin (IMC), was investigated. First, several crystallization solvents (ethanol, methanol, ethyl acetate, acetone, acetonitrile, and dichloromethane) were screened through the measurement of IMC solubility at different temperatures. This was followed by the investigation of IMC nucleation through measurement of induction times in selected solvents at two supersaturations. Finally, seeded cooling crystallization of IMC in ethanol was performed with different process parameters to investigate the influence on the polymorphism and crystal size distribution. Remarkably long induction times were observed for IMC in ethanol and ethyl acetate solutions, while a shorter induction time was observed in acetone. Cooling crystallization of IMC from ethanol confirmed that supersaturation, operating temperature, and seeding do affect the polymorphism as well as crystal size distribution of IMC. Fine needle-shaped crystals of metastable alpha-IMC were obtained at 5 degrees C with high supersaturation even in the presence of gamma-IMC seeds, while rhombic platelike crystals of thermodynamically stable gamma-IMC were obtained in the remaining experiments. The seed loading only marginally influenced the crystal growth rate and median particle diameter. Particle size analysis of the crystals obtained showed a bimodal distribution in all experiments, and a larger median particle diameter was observed at 15 degrees C with high supersaturation.