Dissolution rate improvement of valsartan by low temperature recrystallization in compressed CO2: Prevention of excessive agglomeration

In this study, the recrystallization of valsartan by ASES (Aerosol Solvent Extraction System), a supercritical micronization process, using compressed CO2 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 CO2 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 CO2 of 70 bar and 5 °C. When the supercritical CO2 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 CO2. 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 CO2 at a low temperature improved its dissolution rate due to the small size of the particles attributing to low level of particle agglomeration.

The micron valsartan particles with mean diameter of 0.1 μm were obtained without excessive agglomeration by low temperature recrystallization using ASES in the compressed CO2 at 70 bar and 5 °C. In condition of the supercritical CO2 at 100 bar and 40 °C as relatively high temperature, valsartan was precipitated to fine particles which tend to join together by agglomeration process due to melting point depression by means of CO2.Hence, processed valsartan at compressed CO2 of low temperature improved its dissolution rate due to small particle size and reduction of excessive agglomeration.Figure optionsDownload as PowerPoint slideHighlights
► Melting point depression of drug in CO2 is responsible for particle agglomeration.
► We performed low temperature recrystallization of drug using CO2 as an antisolvent.
► Low T recrystallization yields to micron particles of valsartan without agglomeration
► Low temperature recrystallization can reduce Ostwald ripening process during ASES.
► The recrystallized particles show fast dissolution in water without adding excipients