Size control of azilsartan by drowning-out crystallization with phase transformation

摘要

To complement the insufficient bioavailability of azilsartan, particle size reduction of azilsartan by drowning-out was attempted. By injecting an azilsartan/ethanol solution into the antisolvent of water, two phases of azilsartan, amorphous and crystalline type A, were found along with phase transformation. The crystal size was strongly affected by the operating parameters such as the volume ratio of antisolvent/azilsartan solution, crystallization temperature, and additives. The crystal size decreased upon increasing the antisolvent/azilsartan solution volume ratio and lowering the temperature. Furthermore, addition of carboxylic acids to the antisolvent of water produced nano-meter sized crystals. In particular, 200 nm particles were obtained with acetic acid. An enhancement in the dissolution rate was found for size-reduced azilsartan crystals, especially when the crystals' sizes were in the nanometer range.