Formation of itraconazole/L-malic acid cocrystals by gas antisolvent cocrystallization

Cocrystals of itraconazole, an antifungal drug with poor aqueous solubility, and l-malic acid were prepared in tetrahydrofuran (THF) using CO2 as an antisolvent. Using the gas antisolvent (GAS) crystallization technique, the drug (itraconazole) and former (l-malic acid) were dissolved in a liquid solvent (THF) and cocrystals of the two components precipitated by pressurization with CO2. The THF was then removed and the cocrystals dried by flushing with excess supercritical CO2. The itraconazole/l-malic acid cocrystals prepared by GAS cocrystallization were compared to those produced using a traditional liquid antisolvent, n-heptane, for crystallinity, thermal behavior, size and surface morphology, composition, and dissolution rate. X-ray diffraction and differential scanning calorimetry analyses showed that an itraconazole/l-malic acid cocrystal could be produced using either CO2 as an antisolvent in the GAS technique or a traditional liquid antisolvent, n-heptane, but with some content of uncocrystallized amorphous material also being present. Although the cocrystal powder produced by GAS cocrystallization had slightly larger particles than those precipitated with n-heptane, their microporous structure and amorphous content allowed for improved dissolution. Cocrystallization of itraconazole with l-malic acid using CO2 as an antisolvent is a viable means of increasing itraconazole dissolution while reducing solvent use in favor of environmentally benign CO2. With the GAS technique, recycling of THF is facile as compared to the need for expensive distillation in the case of n-heptane.

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► Itraconazole cocrystals were prepared by gas antisolvent (GAS) cocrystallization.
► Some uncocrystallized amorphous material also precipitated.
► The GAS technique reduced organic solvent use in favor of benign CO2.