Enhancing the solubility of carbamazepine using ionic liquids: An experiment and theoretical calculation

Abstract

This work investigates the solubility and dissolution mechanism of the insoluble drug, carbamazepine (CBZ), classified as class II drug in the Biopharmaceutical Classification System, in environmentally friendly solvent ionic liquids (ILs). The COSMO-RS model is used to identify suitable ILs for solubilizing CBZ. Experimental data of six ILs confirms the accuracy of the model, validating its usefulness for IL selection. The solubility of CBZ is influenced by both the anionic structure and temperature. Cytotoxicity tests on HUVEC and GES-1 cells show that all ILs are safe for CBZ dissolution. Based on solubility and toxicity data, [EMIM][Ac] is determined to be the optimal IL.The dissolution mechanism of CBZ in ILs is explored using the σ-profile calculated from the COSMO-RS model and quantum chemical (QC) analysis. ILs with anions that have effective hydrogen bond (HB) acceptability ([Ac]-) are found to be the most efficient solvents for CBZ solvation. ILs with longer alkyl chains in the imidazole cations exhibit reduced polarity, increasing their affinity with CBZ. Therefore, [EMIM][Ac] is the superior IL choice due to its moderate polarity in [EMIM]+ and ideal cationic characteristics with long alkyl chains, along with the strong HB acceptability of [Ac]- anions. The findings have significant implications for choosing appropriate solvents, namely ionic liquids, for CBZ, as well as for selecting solvents with comparable structures for other medicines.