(108a) Antimicrobial Agent Crystal Formation with CO2 Under Supercritical CO2

Poor water-solubility of active pharmaceutical ingredients is a bottleneck in the pharmaceutical formulation developments. The solubility and dissolution rate in human body should be key factors for the absorption of the active pharmaceutical ingredients. Cocrystal formation of the active pharmaceutical ingredients with coformer molecule could be the technique for solving the problems on the solubility and dissolution rate in human body. There are some techniques for the formation of cocrystal for the active pharmaceutical ingredients. However, the conventional techniques for the cocrystal formation requires the toxic organic solvent and the solvent evaporation process for removing the solvent. Supercritical CO₂ is expected to be a solvent for the cocrystal formation of the active pharmaceutical ingredients because of its high dissolubility, high diffusivity and non-toxicity for human body. The cocrystal formation process using supercritical CO₂ allows to make a simple solvent removing by only depressurization because CO₂ is a gas state at the atmospheric pressure. Supercritical CO₂ has been applied for the pharmaceutical process on the extraction of the active pharmaceutical ingredients, drug particle formation and drug loading into the supporting matrix by using supercritical antisolvent (SAS), rapid expansion of supercritical solution (RESS) and supercritical solution impregnation (SSI). This work focused on a new crystal formation of antimicrobial drugs in supercritical CO₂. Antimicrobial drugs, norfloxacin and enoxacin were treated under supercritical CO₂ at various temperatures and pressures. The crystal structure of the antimicrobial drugs after the supercritical CO₂ treatments was characterized by differential scanning calorimetry (DSC), power X-ray diffraction, FT-IR, thermogravimetric analysis (TGA) and solubility in water.

The results of the powder X-ray diffraction show the formation of a new crystal structure of norfloxacin by the treatment in supercritical CO₂ at 313 K and 20 MPa. This new crystal structure of norfloxacin could be resulted from the interaction with CO₂ under high-pressure conditions. The characterization by DSC and TGA propose that CO₂ could be incorporated into the crystal structure of norfloxacin. We also investigated the effect of the process temperatures and pressures on the norfloxacin crystals coupled with CO₂ under the supercritical CO₂. Higher temperatures and pressures of supercritical CO₂ lead to the increases of the norfloxacin crystal formation with CO₂. Enoxacin was also treated in supercritical CO₂ with cosolvent for the crystal formation with CO₂. The supercritical CO₂ treatment achieve the formation of the new-type crystal of enoxacin. The effect of temperature in supercritical CO₂ on the crystal formation of enoxacin with CO₂ was investigated. The higher temperature conditions result in the large amount of the formation of the enoxacin crystal coupled with CO₂. Cosolvents, such as ethanol, 1-propanol, 1-butanol and acetone promote the formation of the enoxacin crystal coupled with CO₂ in supercritical CO₂. The ethanol amount loaded into supercritical CO₂ increases the ration of the formation of enoxacin crystal with CO₂. The results of DSC and TGA suggest the incorporation of CO₂ into the enoxacin crystal by the treatment in supercritical CO₂ as well as those of norfloxacin.

In this work, antimicrobial drugs, norfloxacin and enoxacin can form the new-type crystal structure coupled with CO₂ by the treatment in supercritical CO₂. The results in this work provide the important and useful knowledge for the design of pharmaceutical processing using supercritical CO₂ toward the improvement of its dissolution properties in human body.