Design of active pharmaceutical ingredient-ionic liquids for enhanced delivery to skin.

Active pharmaceutical ingredient ionic liquids (API-ILs) can enhance skin delivery by tuning physicochemical properties based on ion-pair structure. We developed a four-step workflow to screen non-steroidal anti-inflammatory drug (NSAID)-based ion pairs formed by salt metathesis by (i) verifying IL formation using nuclear magnetic resonance spectroscopy, thermogravimetric analysis and differential scanning calorimetry; (ii) quantifying API-IL physicochemical properties relevant to skin transport, including drug concentration, molecular weight, aqueous solubility, and distribution coefficient; (iii) measuring API-IL skin permeation through pig skin ex vivo; and (iv) formulating API-ILs to reduce viscosity to further increase skin delivery. Of the screened ion pairs, 51% formed API-ILs, with ibuprofen and loxoprofen anions and benzethonium and triethylamine cations most associated with liquid formation. Relative to parent sodium salts, API-ILs exhibited higher drug concentration, higher molecular weight, generally lower aqueous solubility, and generally higher octanol-water distribution coefficient values. Balancing trade-offs between higher drug concentration (which increased skin delivery), higher molecular weight (which decreased skin delivery) and other factors, three of the API-ILs outperformed their parent salts, with more-than three-fold increased transdermal flux and 4-15 times greater intradermal delivery after viscosity reduction with ethanol. This integrated workflow identified API-ILs with improved skin delivery by tuning ion-pair properties, offering a path to rational API-IL design for topical and transdermal therapy.