(527a) Formation of Itraconazole-Malic Acid Cocrystals In a CO2-Expanded Liquid

Itraconazole, an antifungal drug, has poor aqueous solubility.  To improve the dissolution rate, cocrystals of itraconazole with l-malic acid were prepared in tetrahydrofuran using supercritical carbon dioxide as an antisolvent. In this novel process, the drug (itraconazole) and cocrystal former (l-malic acid) are dissolved in a liquid solvent (tetrahydrofuran). Cocrystals of the two components are precipitated by pressurization with CO₂. The liquid solvent is then removed and the cocrystals dried with excess supercritical CO₂. These cocrystals were compared to cocrystals produced by using n-heptane, a traditional liquid antisolvent. The cocrystals produced by each method were characterized for crystallinity by X-ray diffraction (XRD), thermal behavior by differential scanning calorimetry (DSC), composition by high pressure liquid chromatography (HPLC), and size and surface morphology by scanning electron microscopy (SEM). Dissolution studies were also conducted for the cocrystals.

The XRD results indicate that cocrystals of itraconazole with l-malic acid can be produced using either supercritical CO₂ or a traditional liquid solvent, such as n-heptane. Both XRD and DSC confirm the presence of an itraconazole-malic acid cocrystal and verify the absence of either of the pure components. HPLC confirmed that the composition of the cocrystals matched that previously reported in the literature. Although the cocrystals produced by CXLCF were slightly larger than those precipitated with n-heptane, their microporous structure allowed for improved dissolution. Through use of XRD, DSC, HPLC, SEM, and dissolution studies, it is shown that the proposed cocrystallization is a viable method for producing pharmaceutical cocrystals of poorly water-soluble drugs to improved dissolution and reduce organic solvent content.