Evaluation of Solubility, Physicochemical Properties, and Cytotoxicity of Naproxen-Based Ionic Liquids

[Image: see text] To solve the problems associated with poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen-based ionic liquids (ILs) containing naproxen as an active pharmaceutical ingredient (API) anion were prepared with benzalkonium (tetradecyldimethylbenzyl ammonium), choline, and 1-octyl-3-methylimidazole as the cation. The structures and thermal properties were analyzed. Through the conductivity method, the solubility at 25 and 37 °C and the critical micelle concentration (CMC) at 25 °C were determined in water and ethanol. The octanol–water partition coefficients (K(ow)) at 25 °C were measured with the shake-flask method. The cytotoxicity was evaluated with the MTT method. The results showed that the conversion of naproxen into the API-ILs increased the API’s solubility in water by more than 850 times compared with the original API, and the thermostability was satisfactory with a lower glass transition temperature (t(g)). Moreover, the variation trends of solubility, hydrophilicity, and K(ow) were consistent with the different structures of naproxen-based ILs, except for benzalkonium naproxen. The CMC (10(–5)–10(–6) M) in water and ethanol demonstrated that the naproxen-based ILs were surface activite ILs. The IC(50) values exhibited the low cytotoxicity of the naproxen-based ILs, which was better than 100 μM. The results provide essential information and a research basis for future topical and transdermal administration and oral administration of naproxen-based ILs.