Solubility-dependent complexation of active pharmaceutical ingredients with trimethyl-β-cyclodextrin under supercritical fluid condition

The effect of the solubility of active pharmaceutical ingredients (APIs) in supercritical carbon dioxide (SC-CO₂) on their complexation behavior with trimethyl-β-cyclodextrin (TM-β-CD) has been investigated. Flurbiprofen or naproxen, the solubility of which is lower than that of ibuprofen, was mixed with TM-β-CD and the complexation phenomena on SC-CO₂ processing was evaluated using powder X-ray diffraction, differential scanning calorimetry and IR measurement. Drug complexation depended both on SC-CO₂ treatment time and on drug solubility in CO₂. The inclusion complex formation of flurbiprofen with TM-β-CD proceeded slowly compared with the case of ibuprofen. The slower complexation behavior was also observed when naproxen was used as the guest molecule. These results indicate that dissolution of drug molecules in SC-CO₂ is a rate-determining step for the inclusion complex formation with TM-β-CD and that complexation proceeds after dissolving the both components in SC-CO₂.