Experimental study of the effect of process parameters in the recrystallization of an organic compound using compressed carbon dioxide as antisolvent

A difficult-to-comminute organic pharmaceutical substance was precipitated successfully through a carbon dioxide gas antisolvent (GAS) recrystallizati on process. Several experimental runs were performed, changing key process parameters such as the rate of addition of carbon dioxide and temperature, which was varied between 5 and 50 degrees C. Mean particle size of the prec ipitated product could be reproducibly adjusted between 0.2 and 10 mu m. Pa rticle size distribution was unimodal and rather narrow for very fast or ve ry slow antisolvent addition rates but was bimodal for intermediate rates. The product was obtained in amorphous, partially agglomerated spheres if pr ecipitated from ethanol, whereas pure crystals were formed from acetone or acetonitrile under otherwise identical operating conditions. These experime ntal results, particularly the key role of the carbon dioxide addition rate , are discussed and explained in the light of conventional crystallization theory as well as of the theoretical understanding of the GAS recrystalliza tion process. In fact, it is shown how three kinetic phenomena, namely nucl eation, particle growth, and supersaturation buildup, compete. The rate of the last one is determined by the carbon dioxide addition rate, which can t hus be exploited to tune the average particle size and the particle size di stribution of the final product.