90. Ober,
Courtney A.; Gupta, Ram B., Formation of Itraconazole-Succinic
Acid Cocrystals by Gas Antisolvent
Cocrystallization, AAPS PharmSciTech
(2012), 13(4), 1396-1406.
Abstract
Cocrystals of itraconazole,
an antifungal drug with poor bioavailability, and succinic acid, a
water-soluble dicarboxylic acid, were formed by gas antisolvent (GAS) cocrystallization
using pressurized CO2 to improve itraconazole
dissolution. In this study, itraconazole and succinic
acid were simultaneously dissolved in a liquid solvent, tetrahydrofuran,
at ambient conditions. The solution was then pressurized with CO2, which
decreased the solvating power of tetrahydrofuran and
caused precipitation of itraconazole-succinic acid cocrystals. The cocrystals
prepared by GAS cocrystallization were compared to
those produced using a traditional liquid antisolvent,
n-heptane, for size and surface morphology, crystallinity,
thermal behavior, chemical structure, clinical relevance, and stability.
Scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy
analyses showed that itraconazole-succinic acid cocrystals with physical and chemical properties similar to
cocrystals produced using a traditional liquid antisolvent technique can be prepared by CO2 antisolvent cocrystallization.
The dissolution profile of itraconazole was
significantly enhanced through GAS cocrystallization
with succinic acid, achieving over 90% dissolution in less than 2 hours. The cocrystals appeared stable against thermal stress for up to
4 weeks under accelerated stability conditions, showing only moderate decreases
in their degree of crystallinity but no change in
their crystalline structure. This study shows the utility of an itraconazole-succinic acid cocrystal
for improving itraconazole bioavailability while also
demonstrating the potential for CO2 to replace traditional liquid antisolvents in cocrystal
preparation, thus making cocrystal production more
environmentally benign and scale-up more feasible.
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