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.



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 CO2 causes 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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