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) recrystallization 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 precipitated product could be reproducibly adjusted between 0.2 and 10 mu m. Particle size distribution was unimodal and rather narrow for very fast or very slow antisolvent addition rates but was bimodal for intermediate rates. The product was obtained in amorphous, partially agglomerated spheres if precipitated from ethanol, whereas pure crystals were formed from acetone or acetonitrile under otherwise identical operating conditions. These experimental 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 recrystallization process. In fact, it is shown how three kinetic phenomena, namely nucleation, particle growth, and supersaturation buildup, compete. The rate of the last one is determined by the carbon dioxide addition rate, which can thus be exploited to tune the average particle size and the particle size distribution of the final product.