Enhanced solubility of carbamazepine using cholinium-based ionic liquid: From COSMO-RS screening to molecular dynamics simulation

Abstract

In this study, the objective was to identify a suitable cholinium-based ionic liquid (IL) for carbamazepine (CBZ), a Biopharmaceutics Classification System (BCS) Class II drug. The solubility and dissolution mechanism of CBZ in various ILs were systematically investigated. Potential ILs were screened using the logarithm of the infinite-dilution activity coefficient (lnγ^∞) derived from the Conductor-like Screening Model for Real Solvents (COSMO-RS) model. Through the integration of experimental results and COSMO-RS model predictions, CBZ was found to exhibit the highest solubility (70.37 mg/mL) in cholinium bis(trifluoromethylsulfonyl)imide ([Ch][Tf₂N]) at 25 °C, a 600-fold increase over its solubility in water. Moreover, cell assays confirmed the low-toxic nature of [Ch][Tf₂N]. Quantum chemical calculations and molecular dynamics simulations revealed that hydrogen bonds formed by electrostatic interactions between [Ch][Tf₂N] and CBZ, together with the significant free volume provided by [Ch][Tf₂N], synergistically enhance CBZ dissolution by stabilizing drug-solvent interactions and facilitating molecular mobility. Cholinium-based ILs, characterized by low toxicity and remarkable dissolution efficiency, can serve as cosolvents in novel formulations for poorly soluble drugs, demonstrating substantial development potential. This study offers valuable insights into enhancing the dissolution of BCS Class II poorly soluble drugs with similar structural features.