Crystallization from supercritical fluids; application to pharmaceutical and biochemical compounds

Crystallization from supercritical fluids was studied as a nontoxic, noncontaminating alternative to conventional techniques for purification and size manipulation of pharmaceutical solids. To proceed with crystallization solubilities of several pharmaceutical compounds in supercritical carbon dioxide were experimentally determined and modeled using solid-vapor phase equilibria. The compounds studied included benzoic acid, salicylic acid, aspirin, griseofulvin, and digoxin among others. A high pressure crystallizer was constructed and operated in batch and continuous modes. Supersaturation was generated by various schemes, such as optimal pressure reduction and salting-out. It was determined that, depending on the crystallization scheme, particles can be produced at submicron as well as large sizes. Particle nucleation and growth rates from saturated supercritical solutions were estimated and the product size distributions were simulated using the population balance theory. Observations were made regarding habit and morphology of particles nucleated and grown at supercritical conditions.