Investigation of the Underlying Phenomena of Precipitation in Supercritical Antisolvent Processes

Abstract

There is significant industrial interest in the ability to effectively produce organic and polymeric microparticles of controllable size and size distribution for numerous applications including certain pharmaceutical formulations. One method to produce microparticles is the supercritical antisolvent precipitation process. This method is performed by spraying a solution through a nozzle into a supercritical antisolvent, typically carbon dioxide. The solution consists of a solute which is insoluble in the antisolvent and an organic solvent which is soluble in the antisolvent. The organic solvent and the antisolvent mix as the solution is sprayed into the supercritical antisolvent. As the concentration of antisolvent increases the affinity of the solute for the solvent/antisolvent mixture decreases which leads to supersaturation and precipitation of the solute.

Studies were performed to probe the underlying phenomena of the supercritical antisolvent (SAS) precipitation process. To study the relationship between operating conditions, spray characteristics, and the resulting particles, sprays of solutions into supercritical carbon dioxide were characterized by visualizing the sprays at various distances from the nozzle outlet to measure jet break up lengths and droplet diameters using a high magnification visualization setup. A 1 wt% solution of poly(L-lactic) acid in methylene chloride was sprayed into carbon dioxide to study the effect of pressure, temperature, and density. Despite very different spray characteristics, performing the SAS precipitation process on poly(L-lactic) acid produced particles within a similar size range at most conditions. The effect of the affinity of the solute for the solvent on the SAS precipitation process was evaluated by processing polyvinyl pyrrolidone, polymethyl methacrylate, and poly(methyl methacrylate-vinyl pyrrolidone) which have different solubilities in the solvent ethanol. The different polymer solutes had a negligible effect on the spray characteristics, so the diffusion of ethanol and carbon dioxide was similar regardless of the solute used at a particular operating condition. The smallest polymer particles were obtained when operating near the transition from atomization to break up as gaseous plume. By changing the affinity between the polymer solute and the organic solvent, the tendency to form microballoons was altered. Also, a new particle precipitation process which utilizes the tendency for buoyant forces to induce flow in variable density fluids and the relation between supercritical fluid density and saturation concentration of a solute in the fluid was developed. This thermosyphon process was successfully demonstrated when naphthalene dissolved in a cold zone, was transported by the buoyant flow of carbon dioxide, and precipitated in a hot zone.