92. Ober, Courtney A.; Montgomery, Stephen E.; Gupta, Ram B., Formation of itraconazole/L-malic acid cocrystals by gas antisolvent cocrystallization, Powder Technology 2013, 236, 122-131.

Abstract

Cocrystals of itraconazole, an antifungal drug with poor aqueous solubility, and L-malic acid are prepared using the gas antisolvent (GAS) cocrystallization technique. The drug (itraconazole) and former (L-malic acid) are first dissolved in a liquid solvent (THF), and then pressurization with CO₂causes the two components to precipitate in a cocrystal form. The THF is then removed and the cocrystals dried by flushing with excess supercritical CO₂. The itraconazole/L-malic acid cocrystals prepared by GAS cocrystallization are 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 itraconazole/L-malic acid cocrystals can 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 has slightly larger particles than those precipitated with n-heptane, their microporous structure and amorphous content allows 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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