Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole.

In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.

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 Cmax, σmax 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 σmax 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.