Improved transdermal permeability of ibuprofen by ionic liquid technology: Correlation between counterion structure and the physicochemical and biological properties

Abstract

The aim of this study was to explore the feasibility of transdermal delivery of ibuprofen using ionic liquid technology. Ibuprofen, a non-steroidal anti-inflammatory drug, was transformed into nine ionic liquids using aromatic, tetraalkylammonium and tetraalkylphosphonium cationic counterions. Both the free drug and synthesized ionic liquids were fully characterized by X-ray Powder Diffractometry (XRPD) analysis, thermal analysis, Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Nuclear Magnetic Resonance Spectrometer analysis (NMR), and the aqueous solubility at 25 °C as well as the octanol-water partition coefficients (LogP) were measured. To evaluate transdermal potential, in vitro skin permeation testing was carried out via Skin Parallel Artificial Membrane Permeability Assays (Skin PAMPA). In addition, the potential skin toxicity of ionic liquids was evaluated by determining their cytotoxicity against HaCaT cells. All the synthesized ibuprofen ionic liquids showed improved skin permeability comparing with the conventional sodium salt. Specifically, ionic liquids with didecyldimethylammonium and tetrahexylammonium counterions were significantly more permeable through artificial skin membrane than the free form of ibuprofen. Conductivity test and 2D NMR nuclear Overhauser effect (NOE) techniques corroborated that ionic liquids with stronger intermolecular intermolecular interaction and higher degree of ion association in aqueous environment crossed the artificial skin membrane more rapidly and efficiently. Taken together, ionic liquids technology could be a versatile platform to turn the physicochemical and biological properties of ionizable drugs and facilitate their transdermal delivery.