Synthesis, purification, and micronization of pharmaceuticals using the gas antisolvent technique

The synthesis, purification, and micronization of the nonsteroidal antiinflammatory [Cu2-(indomethacin)(4)L-2] [Cu-Indo]; indomethacin = 1-4-(chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, L = N,N-dimethylformamide (DMF)] has been investigated using DMF as the solvent and CO2 as the antisolvent. The phase behavior of the binary system DMF + CO2 and the ternary system DMF + CO2 + Cu-Indo at 25, 30, and 40 degreesC and pressures up to 7.6 MPa was examined. The phase behavior of the ternary system DMF + CO2 containing copper(II) acetate monohydrate (Cu-Acetate), indomethacin, or acetic acid and the quaternary system DMF + CO2 containing Cu-Indo and either Cu-Acetate, indomethacin, or acetic acid at 25 degreesC and pressures up to 5.8 MPa was also examined to determine optimum synthesis conditions. The effect of variables such as reactant concentration, CO2 wash volume, and rate of expansion on the purity and characteristics of the Cu-Indo produced in the synthesis was investigated. The recrystallization of Cu-Indo from DMF was investigated and the effect of the rate of expansion on the size of the particles produced was determined at 25 degreesC. It was found that Cu-Indo solubility in a DMF expanded solution decreased with increasing pressure and decreasing temperature. The solubility of Cu-Acetate in a DMF expanded solution was slightly increased as the pressure increased to 2.7 MPa and decreased rapidly at higher pressures. Upon addition of CO2 to DMF + indomethacin saturated solutions, a second liquid phase formed in the system and precipitation only occurred at pressures above 5.5 MPa. Acetic acid was found to remain soluble in the DMF expanded solution at the range of pressures and temperatures examined. The addition of a second solute to the DMF + CO2 + Cu-Indo solutions was found to significantly influence the phase behavior of the system. The solubility of Cu-Indo increased in the presence of acetic acid and Cu-Acetate and decreased in the presence of indomethacin. The product, Cu-Indo, with greater than 95% purity was produced in a single step at 25 degreesC. The presence of a slight excess of either reactant did not alter the purity of the Cu-Indo produced. The rate of expansion substantially varied the size and morphology of the particles produced. Rapid expansion resulted in bipyramidal crystalline particles that were less than 10 mum in size. Slow expansion resulted in rhombic crystals with an average size of between 20 and 10 mum.