文摘
Carbon dioxide has been extensively used as a green solvent medium for the crystallization of active pharmaceutical ingredients (APIs) by replacing harmful organic solvents. This work explores the mechanisms underlying a novel recrystallization method鈥攃ocrystallization with supercritical solvent (CSS)鈥攚hich enables APIs cocrystallization by suspending powders in pure CO2. Six well-known APIs that form cocrystals with saccharin (SAC) were processed by CSS, namely, theophylline (TPL), indomethacin (IND), carbamazepine (CBZ), caffeine (CAF), sulfamethazine (SFZ), and acetylsalicylic acid (ASA). Pure cocrystals were obtained for TPL, IND, and CBZ (with SAC) after 2 h of CSS processing. Convection was revealed to be a determining parameter for successful cocrystallization with high-yield levels. TPL鈥揝AC was selected as a model system to study the cocrystallization kinetics in the gas, supercritical, and liquid phases under different conditions of pressure (8鈥?0 MPa), temperature (30 to 70 掳C), and convection regimes. The solubility of each substance in CO2 was measured at the selected working conditions. TPL鈥揝AC showed a cocrystallization rate of 2.9% min鈥?, two times higher than that of IND鈥揝AC, due to the higher solubility of TPL in CO2. The cocrystallization kinetics was also improved by increasing the CO2 density, showing that cocrystallization was limited by the dissolution of cocrystal formers. Overall, the CSS process has a potential for scale-up as a novel, simple, solvent-free batch process whenever the cocrystal phase is formed in the CO2 media.