Synthesis and transdermal delivery of dual functional phenothiazine ionic liquids

Abstract

Many pharmaceuticals presently available on the market have disadvantages associated with the solid state (i.e., multiple crystalline states, decreased bioavailability/aqueous solubility, etc.). Prior research has proven that conversion of active pharmaceutical ingredients (APIs) in the solid state to a liquid form (i.e., ionic liquid or IL) is highly advantageous, in that the drug has increased solubility in water or simulated body fluids, improved bioavailability/dissolution, and increased delivery through a skin-mimicking membrane. These liquid state APIs (API-ILs) can also be dual functional, where both drugs forming the IL retain their functionality as well as have synergistic effects.

Phenothiazine drugs (PHZ) are good candidates for liquid conversion as they 1.) have disadvantages associated with the solid form, and 2.) have no analgesic effect. Conversion to a liquid form and combination with an NSAID can rectify both of these issues. Here, we synthesized API-ILs of various combinations, with PHZs acting as cations and NSAIDs as anions. Each new API-IL was then purified and analyzed with NMR and IR spectroscopic methods. A select cation and anion were then tested against their respective API-IL combinations via transdermal delivery experiments in order to determine if conversion to a liquid form improved upon the drugs’ delivery through a skin-mimicking membrane.