The impact of ionic liquid formation on the activity, solubility and pharmacokinetics of rifampicin

Abstract Rifampicin (RIF) is a key first-line antitubercular agent. However, its clinical utility is hindered by poor solubility and suboptimal oral absorption. When paired with oppositely charged citric acid (CA) at 1:5 molar ratio, the interaction yields an active pharmaceutical ingredient ionic liquid (API-IL); RIF-CA IL. This transformation resulted in a new liquid form that modulated RIF’s physicochemical properties. This study explores the pharmaceutical and biological properties of a RIF-CA IL, 1:5. The conditions of the solvent-evaporation method were found to be critical for its stability and antimicrobial activity. Spectroscopic analyses confirmed IL formation and significant intermolecular interactions. RIF-CA IL exhibited improved wettability and hydrophilicity, resulting in a 20-fold increase in RIF saturation solubility. The IL had comparable cytotoxicity and cellular uptake to RIF in A549 lung cells. A Novel greenness-assisted HPLC method was developed to precisely and selectively determine rifampicin levels in serum. An in-vivo pharmacokinetic study in rabbits demonstrated a more than 2.2-fold increase in oral bioavailability compared to native RIF. Notably, these enhancements were not observed with a physical mixture of RIF and CA at the same molar ratio. These results suggest RIF-CA IL is a promising alternative to conventional RIF form with comparable bioactivity, yet superior bioavailability.