Simultaneous Control of Crystal Habit and Particle Size of Ecabet Sodium Hydrate with Rapid Cooling Crystallization and Temperature Cycling

A practical strategy for the simultaneous control of particle size and shape of active pharmaceutical ingredients has been investigated using ecabet sodium (Na-ECA) hydrate, which tends to generate large plate-like crystals, as a model compound. In conventional batch-cooling crystallization, particle size and relative thickness decreased with increasing cooling rates. However, the particle size was still too large following fast cooling at a rate of 40 degrees C/h. In rapid cooling crystallization with water, achieved by mixing hot Na-ECA solution with cold water, the particle size and relative thickness became 1/3.8 and 1/3, respectively, compared to that under batch-cooling crystallization at a rate of 40 degrees C/h. It was also revealed that both the particle size and relative thickness increased with temperature cycling; however, the morphology of the obtained particles was still plate-like. In rapid cooling crystallization in aqueous NaCl, the particle size was reduced further to 1/4.7, and the relative thickness of the particle increased sixfold over that obtained in water. Moreover, the shape of the particle evolved effectively by temperature cycling. Consequently, granular and smaller particles could be obtained successfully. The mechanism of shape evolution was also discussed with respect to contact angles. Based on the qualitative analysis results obtained using Young's equation, we propose that shape evolution is induced by surface free energy, which drives the progression towards equilibrium shape during repeated partial dissolution and crystal growth.