Dissolution rate improvement of valsartan by low temperature recrystallization in compressed CO 2: Prevention of excessive agglomeration

Abstract

In this study, the recrystallization of valsartan by ASES (Aerosol Solvent Extraction System), a supercritical micronization process, using compressed CO 2 was carried out to improve the bioavailability of valsartan through preparation of micro sized particles without excessive agglomeration. Fine valsartan particles from an ethyl acetate (EA) solution were precipitated using compressed CO 2 as an antisolvent at low temperature. The EA was considered a proper organic solvent to prevent agglomeration of the prepared valsartan associating to the solubility parameters of the solvents. Ultra fine valsartan particles with a mean diameter of 0.1 μm were obtained without excessive agglomeration at the subcritical CO 2 of 70 bar and 5 °C. When the supercritical CO 2 was at 100 bar and 40 °C, valsartan was precipitated to fine particles that tended to agglomerated due to the melting point depression produced by CO 2. During the agglomeration process, particles were sintered by the Ostwald ripening mechanism, which resulted in an increase in particle size. Agglomeration of the particles was shown to be prevented at low temperature, where re-melting of the precipitated valsartan particles is minimized. Hence, processed valsartan with compressed CO 2 at a low temperature improved its dissolution rate due to the small size of the particles attributing to low level of particle agglomeration.