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 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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