Formation of Itraconazole–Succinic Acid Cocrystals by Gas Antisolvent Cocrystallization

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 CO(2) 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 CO(2), which decreased the solvating power of tetrahydrofuran and caused crystallization of itraconazole-succinic acid cocrystals. The cocrystals prepared by GAS cocrystallization were compared to those produced using a traditional liquid antisolvent, n-heptane, for crystallinity, chemical structure, thermal behavior, size and surface morphology, potential clinical relevance, and stability. Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy 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 CO(2) antisolvent cocrystallization. The dissolution profile of itraconazole was significantly enhanced through GAS cocrystallization with succinic acid, achieving over 90% dissolution in less than 2 h. 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 CO(2) to replace traditional liquid antisolvents in cocrystal preparation, thus making cocrystal production more environmentally benign and scale-up more feasible.

Physicochemical Characterization and <i>In Vitro</i> Dissolution Test of Quercetin-Succinic Acid Co-crystals Prepared Using Solvent Evaporation

“…This is in agreement with research that stated that the particle size of S lay between 50 to several hundred µm. 18 Moreover, the photograph of S showed a different crystal habit compared with those of Q. On the other hand, the photomicrograph of Co-QS demonstrated smaller and more homogeneous particles as compared with those of its raw materials.…”

Characterization and Quality Control of Pharmaceutical Cocrystals

“…Specifically, carbon dioxide gas addition effectively induces itraconazolesuccinic acid cocrystal formation and precipitation from aqueous solution (e.g., gas antisolvent (GAS) method). 93) 2) Spray-and Freeze-Drying Techniques Cocrystals, such as CBZ-nicotinamide, can also be formed by spray-drying or freeze-drying API-coformer solutions. 94) These processes feature faster solute solidification compared to crystallization in aqueous solutions, which may promote cocrystal production by reducing the phase separation and precipitation of low-solubility components.…”

Screening and characterization of cocrystal formation between carbamazepine and succinic acid

“…These improvements can be achieved both by developing new final formulations by appropriate selection of excipients and by obtaining crystalline solids composed of an active substance and a conformer, or of two active substances [6,7].…”