Polyethylene glycol derivatization of the non-active ion in active pharmaceutical ingredient ionic liquids enhances transdermal deliveryElectronic supplementary information (ESI) available. CCDC 1519695. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6nj03709g

We report the synthesis of four salts composed of the salicylate anion ([Sal] − ) paired with tributylammonium ([HN 444 ] + ), choline ([Cho] + ), 1-methylpyrrolidinium ([HMPyrr] + ), and triethylene glycol monomethyl ether tributylammonium ([mPEG 3 N 444 ] + ) cations. Three of the synthesized salts (room temperature liquids [mPEG 3 N 444 ][Sal] and [Cho][Sal], and a supercooled liquid [HN 444 ][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 mPEG 3 OH as solvent, but lower membrane transport compared to salicylic acid dissolved in mPEG 3 OH. The 'PEGylated' IL, [mPEG 3 N 444 ][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. Introducing PEGylated moieties into the counterion structure of API-ILs can significantly enhance the transport through a membrane without a solvent.