Crystallization of Azilsartan with Acidification of Azilsartan Disodium Salt

A reactive crystallization process induced by acidification of azilsartan disodium salt was proposed to produce sub-micron-sized crystals. In the present work, azilsartan crystals were obtained by mixing two aqueous solutions of azilsartan disodium salt (ADS solution) and acetic acid (AA solution). When ADS solution was injected into AA solution, the crystalline azilsartan (type I), the thermodynamically stable form, could be obtained by the phase transformation of amorphous intermediates of azilsartan initially precipitated. Azilsartan crystals transformed from amorphous phase were found to be much smaller than those obtained directly with no transformation by addition of AA solution into ADS solution. The spectra of ATR-FTIR and particle counts from the focused beam reflectance measurement (FBRM) were utilized to investigate the effect of temperature on the transformation process. Final crystal size of azilsartan was found to be influenced by the relative scale of dissolution time for amorphous intermediates. Furthermore, the recovery of azilsartan crystals was found to be strongly affected by the final pH of mixed suspension. Finally, azilsartan crystals with size of about 500 nm and the recovery of higher than 90% were successfully produced from the proposed process with pH 5 mixed suspension at 20 °C.