In this research work, nucleation and growth phenomena of organic crystals from solution were investigated experimentally, with an objective to produce a dispersion of submicron particles. Specifically, the effects of solute concentration and polymeric additives on the precipitation kinetics of naproxen (organic model compound) were studied. The ultimate goal isto gain fundamental understanding of the combination of process variables that will consistently produce submicron crystals during an antisolvent precipitation process.
Naproxen solution and antisolvent (deionized water with trace amounts of polymeric additives dissolved) were rapidly and homogenously premixed in a Y-micromixer using two syringe pumps. The degree of supersaturation was varied by changing the solute concentration in ethanol. The outlet stream from the Y-mixer was directly fed into a glass vial and the solution turbidity monitored online using the Avantium Crystalline system. The rate of desupersaturation during precipitation process was determined by offline measurement of solute concentration usingUV-Vis spectroscopy. Initial results show that in the presence of HPMC K86 polymer additive, induction period for nucleation of naproxen crystals increased significantly as compared to the pure system. On the otherhand, in the presence of PVP K10 polymer additive, the induction time apparently decreased. In line with this trend, the rate of desupersaturation in the presence of HPMC decreased significantly as compared to the pure system. These kinetic data correlate well with the effectiveness of the polymeric additives in controlling particle size of naproxen crystals in the submicron range. From the experimentally determined induction periods for crystal nucleation as a function of supersaturation, the nucleation mechanism (viz.,primary homogeneous and heterogeneous) controlling the precipitation process was determined.
Future work will focus on unraveling the mechanisms underpinning the effects of polymer additives on stabilization of colloidal crystal dispersion using both experimental techniques and molecular modeling.