Identification of critical process variables affecting particle size following precipitation using a supercritical fluid.

The critical processing parameters affecting average particle size, particle size distribution, yield, and level of residual carrier solvent using the supercritical anti-solvent method (SAS) were identified. Carbon dioxide was used as the supercritical fluid. Methylprednisolone acetate was used as the model solute in tetrahydrofuran. Parameters examined included pressure of the supercritical fluid, agitation rate, feed solution flow rate, impeller diameter, and nozzle design. Pressure was identified as the most important process parameter affecting average particle size, either through the effect of pressure on dispersion of the feed solution into the precipitation vessel or through the effect of pressure on solubility of drug in the CO2/organic solvent mixture. Agitation rate, impeller diameter, feed solution flow rate, and nozzle design had significant effects on particle size, which suggests that dispersion of the feed solution is important. Crimped HPLC tubing was the most effective method of introducing feed solution into the precipitation vessel, largely because it resulted in the least amount of clogging during the precipitation. Yields of 82% or greater were consistently produced and were not affected by the processing variables. Similarly, the level of residual solvent was independent of the processing variables and was present at 0.0002% wt/wt THF or less.

Identification of physical-chemical variables affecting particle size following precipitation using a supercritical fluid.

The physical-chemical processing variables affecting particle size following precipitation using the supercritical antisolvent (SAS) method were investigated by varying both the composition of the feed solvent and the structure of the solute, using a series of steroids. The key factor influencing particle size in these studies appears to be the solubility of the drug in the organic solvent/supercritical fluid mixture, where relatively high solubility causes a lower degree of supersaturation in the precipitation vessel, resulting in a relatively large particle size. Higher operating pressures result in larger particle sizes, probably through the effect of pressure on solubility. Physical properties of the carrier solvent, such as vapor pressure and dielectric constant, were not effective predictors of relative particle size of the precipitated powder, nor was solubility of the model drug in the carrier solvent. In limited studies of the physical state of the precipitated solid, higher apparent crystallinity was observed for powders with larger particle size. A precipitate of a different crystal form was observed when starting with hydrocortisone hemisuccinate monohydrate and may represent the loss of water of hydration. An amorphous solid was precipitated when starting with yttrium acetate dihydrate. Broad guidelines for effective particle size reduction using this technique are presented.