Polyethylene glycol derivatization of the non-active ion in active pharmaceutical ingredient ionic liquids enhances transdermal delivery

Abstract

We report the synthesis of four salts composed of the salicylate anion ([Sal]⁻) paired with tributylammonium ([HN₄₄₄]⁺), choline ([Cho]⁺), 1-methylpyrrolidinium ([HMPyrr]⁺), and triethylene glycol monomethyl ether tributylammonium ([mPEG₃N₄₄₄]⁺) cations. Three of the synthesized salts (room temperature liquids [mPEG₃N₄₄₄][Sal] and [Cho][Sal], and a supercooled liquid [HN₄₄₄][Sal]) belong to the category of ionic liquids (ILs), and one salt (solid [HMPyrr][Sal]) was a crystalline solid. ILs in their neat form were studied for membrane transport through a silicon membrane, and exhibited higher transport compared to a control experiment with sodium salicylate dissolved in mPEG₃OH as solvent, but lower membrane transport compared to salicylic acid dissolved in mPEG₃OH. The ‘PEGylated’ IL, [mPEG₃N₄₄₄][Sal], crossed the membrane with an ca. ∼2.5-fold faster rate than that of any of the non-PEGylated ILs. This work demonstrates not only that API–ILs can eliminate the use of a solvent vehicle during application and notably transport through a membrane as opposed to a higher melting crystalline salt, but also that the membrane transport can be further enhanced by PEGylation of the counter ions.