Novel cocrystals of itraconazole: Insights from phase diagrams, formation thermodynamics and solubility

In this work, the cocrystallization approach was applied to itraconazole (ITR), a very slightly soluble triazole antifungal drug, which led to the formation of two new solid forms of ITR with 4-aminobenzoic acid (4AmBA) and 4-hydroxybenzamide (4OHBZA). A thermodynamic analysis of the solid-liquid binary phase diagrams for the (ITR + 4AmBA) and (ITR + 4OHBZA) systems provided conclusive evidence of the cocrystal stoichiometry: 1:1 for the cocrystal with 4-aminobenzoic acid, and 1:2 for the cocrystal with 4-hydroxybenzamide. Powder X-Ray diffraction analysis confirmed the formation of two different polymorphic forms of the [ITR + 4OHBZA] (1:2) cocrystal obtained either through solution or melt crystallization. Cocrystal formation and polymorphic transition processes were investigated in detail by the DSC and HSM methods. The thermodynamic functions of cocrystal formation were estimated from the solubility of the cocrystals and the corresponding solubility of the pure compounds at different temperatures. The combination of ITR and 4OHBZA was found to be more favorable than the reaction between ITR and 4AmBA in terms of both Gibbs energy and enthalpy. The pH-solubility behavior of the cocrystals was investigated at different pH values using eutectic concentrations of the components and the cocrystal solubility advantage was estimated. It was found that the cocrystallization of itraconazole with 4OHBZA and 4AmBA can potentially increase the drug solubility at pH1.2 and 37. C by 225 and 64 times, respectively. The cocrystal dissolution behavior in biorelevant media was analyzed in terms of C-max, sigma(max) parameters (the maximum ITR concentration and supersaturation), and AUC (the concentration area under the curve during the dissolution - supersaturation - precipitation process). The cocrystals had similar sigma(max) values during the dissolution and sustained supersaturation for up to 6 h, which gave them an advantage in the AUC values (13-37 times higher) over the drug. The differences in the dissolution profiles of the cocrystals were rationalized in terms of their dissolution rate values.

Automated summary

In this study, the cocrystallization of itraconazole with 4-aminobenzoic acid and 4-hydroxybenzamide led to the formation of two new solid forms, with detailed analysis on their stoichiometry, polymorphic forms, and dissolution behavior. The cocrystallization with 4OHBZA was found to significantly increase the drug solubility and exhibited higher AUC values compared to the drug.