Role of ionic liquids in ibuprofen-based eutectic systems: Aqueous solubility, permeability, human cytotoxicity, hemolytic activity and anti-inflammatory activity

• Published in: Journal of molecular liquids Vol. 404; p. 124966
• Main Authors: Bastos, Joana C., Manuela Gaspar, Maria, Pereiro, Ana B., Araújo, João M.M.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.06.2024
• Subjects: Anti-inflammatory activity; Bioavailability; Cytotoxicity; Eutectic Systems; Hemocompatibility; Hydrogen bonding; Ibuprofen; Ionic liquids; Ionicity; Polarity; Eutectic Systems; Hemocompatibility; Ibuprofen; Ionic liquids; Ionicity; Polarity; Cytotoxicity; Anti-inflammatory activity; Bioavailability; Hydrogen bonding
• ISSN: 0167-7322; 1873-3166
• DOI: 10.1016/j.molliq.2024.124966

[Display omitted] •Twelve pharmaceutically active eutectics based on ibuprofen conjugated with imidazolium-based ILs or cholinium salt at different molar ratio were prepared.•An upgrade of the aqueous solubility (water and biological simulated fluids) for the ibuprofen-based eutectics relatively to ibuprofen was verified.•The assessment of ionicity was attained, confirming the formation of ion-pairs or clusters, that increase the potential of these liquids to be more membrane diffusive.•The biocompatibility of the ibuprofen-based eutectics was evaluated through a hemolytic activity assay and in vitro cytotoxicity assays with two human cell lines, without impairing their hemolytic and cytotoxic response.•The anti-inflammatory activity was evaluated by the inhibition of BSA denaturation and inhibition of cyclooxygenases enzymes, showing that the ibuprofen eutectic formulations maintain the anti-inflammatory response of ibuprofen with the opportunity to improve the selectivity towards COX-2, allowing the development of safer NSAIDs. Eutectic systems, as well as ionic liquids (ILs), offer a potential solution to the challenges associated with low solubility, polymorphism, and limited bioavailability of active pharmaceutical ingredients (APIs). Herein, we prepared twelve pharmaceutically active eutectics based on ibuprofen (Ibu), a widely accessible without prescription non-steroidal anti-inflammatory drug (NSAID), and imidazolium-based ILs ([C2C1Im]Cl, [C2(OH)C1Im]Cl and [C2C1Im][C1CO2]) and cholinium salt ([N1112(OH)]Cl) at different molar ratio (2:1, 1:1, 1:2 and 1:5). All eutectic systems were characterized by DSC and NMR, and their polarity was assessed using the Kamlet-Taft approach to characterize the non-specific (polarity/polarizability) and specific (hydrogen bonding ability) interactions. An upgrade of the aqueous solubility (water and biological simulated fluids) for the Ibu-based eutectics relatively to ibuprofen was verified. Also, the assessment of ionicity (viscosity, conductivity, and density) was attained, confirming the formation of ion-pairs or clusters, that increase the potential of these liquids to be more membrane diffusive. The biocompatibility of the Ibu-based eutectics was evaluated up to 3 mM (well above the ibuprofen maximum plasma concentration) through a hemolytic activity assay and in vitro cytotoxicity as-says with two human cell lines (Caco-2 colon carcinoma cells and HepG2 hepatocellular carcinoma cells), without impairing their hemolytic and cytotoxic response. Additionally, the anti-inflammatory activity was evaluated by the inhibition of bovine serum albumin (BSA) denaturation and inhibition of cyclooxygenases (COX-1 and COX-2) enzymes, showing that the ibuprofen eutectic formulations maintain the anti-inflammatory response of ibuprofen with the opportunity to improve the selectivity towards COX-2, allowing the development of safer NSAIDs.