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

• Published in: International journal of pharmaceutics 2021-04, Vol.599, p.120441-120441, Article 120441
• Main Authors: Vasilev, Nikita A., Surov, Artem O., Voronin, Alexander P., Drozd, Ksenia V., Perlovich, German L.
• Format: Article
• Language: English
• Subjects: Cocrystal; Dissolution rate; Itraconazole; Polymorphism; Supersaturation; Thermodynamic analysis
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120441

New pharmaceutical cocrystals of itraconazole (ITR) with 4-aminobenzoic acid (4AmBA) and 4-hydroxybenzamide (4OHBZA) were obtained. Cocrystals were found to exhibit higher solubility, Cmax, RAUC, dissolution rate and supersaturation compared to the parent ITR. Binary phase diagrams, FTIR spectra, hot stage microscopy and DSC investigations were performed for the obtained forms, with special attention paid to the [ITR+4OHBZA] (1:2) polymorphic forms. [Display omitted] •New solid forms of extremely insoluble antifungal drug itraconazole(ITR) were found.•For a cocrystal with 4-hydroxybenzamide, two enantiomorphic forms were discovered.•Formation thermodynamics of new ITR cocrystals was studied in details.•Cocrystals are found to exhibit higher solubility, Cmax, RAUC, and dissolution rate.•Cocrystals demonstrate significantly better pharmacokinetics compared to pure ITR. 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 Cmax, σma