Supercritical crystallization of pharmaceuticals: The gas antisolvent process

Among the near- or supercritical gas assisted particle formation technologies that are feasible to match the increasing demand for micron or submicron size particles with controlled size and size distribution, antisolvent techniques are considered particularly promising. These techniques allow microparticles with controlled particle size distribution and product quality to be produced under mild and inert conditions for the pharmaceutical and specialty chemical industry. The GAS process exploits the low solubility of most pharmaceutical compounds in CO2, which is used as an antisolvent for the solute initially solubilized in an organic solvent. Upon addition of high pressure CO2, the solution is expanded, its solvent power is reduced, and precipitation is triggered.The experimental work addressed, as a model system, is the precipitation of phenanthrene and beclomethasone-17,21-dipropionate from different organic solvents using supercritical CO2 as the antisolvent. A systematic investigation of the influence of the key process parameters, the antisolvent addition rate, temperature, initial solute concentration and agitation rate and choice of organic solvent upon particle morphology, size, size distribution and crystallinity was performed. It was found, using scanning electron microscopy (SEM) and laser diffraction, that the mean particle diameter of the product can be reproducibly adjusted in a wide range. Increasing the antisolvent addition rate and the agitation rate, while decreasing the temperature and solute saturation level, led to a decrease in average particle size.The observed experimental behavior for the model system, phenanthrene, upon changes in the operating parameters, i.e., the antisolvent addition rate and saturation level, has been explained using a developed mathematical model for the GAS process accounting for the governing physical phenomena, i.e., the thermodynamics of near-critical solutions, and the particle formation process controlled by primary and secondary nucleation, and crystal growth. The employed model was able to explain the experimental observations physically, which constitutes an important step towards a sound understanding of the precipitation phenomena in the GAS process.This thesis contributes to the development of this novel technology by establishing the process conditions of the GAS process by addressing both theoretical and applicative aspects of this antisolvent technique.