The aims of this study were to identify how the solvent selection affects particle formation and to examine the effect of the initial drug solution concentration on mean particle size and particle size distribution in the supercritical antisolvent (SAS) process. Amorphous atorvastatin calcium was precipitated from seven different solvents using the SAS process. Particles with mean particle size ranging between 62.6 and 1493.7 nm were obtained by varying organic solvent type and solution concentration. By changing the solvent, we observed large variations in particle size and particle size distribution, accompanied by different particle morphologies. Particles obtained from acetone and tetrahydrofuran (THF) were compact and spherical fine particles, whereas those from N-methylpyrrolidone (NMP) and dimethylsulfoxide (DMSO) were agglomerated, with rough surfaces and relatively larger particle sizes. Interestingly, the mean particle size of atorvastatin calcium increased with an increase in the boiling point of the organic solvent used. Thus, for atorvastatin particle formation via the SAS process, particle size was determined mainly by evaporation of the organic solvent into the antisolvent phase. In addition, the mean particle size was increased with increasing drug solution concentration. In this study, from the aspects of particle size and solvent toxicity, acetone was the better organic solvent for controlling nanoparticle formation of atorvastatin calcium.Key words atorvastatin; nanoparticle; supercritical antisolvent; amorphous A new approach in particle engineering developed to obtain micro/nanoparticles with peculiar characteristics is represented by the supercritical fluid technology.1) Among the several types of supercritical fluid processes, supercritical antisolvent (SAS) process have some advantages such as easy handling of difficult-to-comminute materials, use of a nontoxic medium, and a mild operating temperature may provide ideal conditions for the processing of pharmaceutical compounds. Moreover, fast diffusion of supercritical antisolvent into the liquid solvent produces the supersaturation of the solute and its precipitation in micronized particles down to particle diameters, and control of the particle size distribution is also possible.2,3) Many researchers have been studied that the morphology, crystallinity, particle size and particle size distribution can be controlled through the changing of various process conditions such as temperature, pressure, solvent, drug solution concentration, solution to antisolvent flow rate ratio, and the rate of mass transfer in SAS process. [4][5][6][7][8][9] Previously, we investigated the effect of SAS process parameters such as the pressure, temperature, and feed rate ratio of CO 2 /drug solution on the particle formation of atorvastatin calcium using methanol as a solvent.10) In addition, we reported the usefulness of the amorphous nanoparticles as a method of enhancing the supersaturation, dissolution, and absorption properties of atorvastatin.11) However...
