Sequential Biofunctionalization of a Choline-Based Monomeric Ionic Liquid and Polymerized Ionic Liquid: A Route to Dual Anionic Drug Polymer Conjugates of Piperacillin-Tazobactam

The choline-based monomeric ionic liquid (MIL), that is, [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA), was modified by ion exchange to introduce a pharmaceutical anion (aspartic acid (APT), diclofenac (DIC), cholic acid (CHA), ibuprofen (IBU), nalidixic acid (NAL), naproxen (NAP), piperacillin (PIP), tazobactam (TAZ), and valproic acid (VPA)). The TMAMA MILs with satisfactory exchange efficiency containing DIC, IBU, TAZ, or VPA anions were polymerized by "grafting from" multifunctional macroinitiators. The reactions yielded successful synthesis of PIP-anion-based ionic graft polymer conjugates with a tunable ionic fraction, with drug contents reaching 74-92%. These single-drug delivery systems (DDSs) were developed into co-delivery systems by conjugating ionic TAZ into PIP-polymer carriers, achieving drug contents of 48-68% for PIP and 31-41% for TAZ. Under physiological dialysis conditions, the conjugates demonstrated similar release efficiencies (51-84% for PIP and 66-81% for TAZ). Surface analysis by water contact angle (WCA) indicated increased hydrophilicity in dual systems (36-52°) compared to the single systems (48-59°). In aqueous solutions, the conjugates formed nanosized self-assemblies with diameters of 180-330 nm. Biomodification of TMAMA-based MILs with pharmaceutical anions faces limitations; nevertheless, the successful incorporation of selected substances, such as PIP, enables the formation of ionic conjugates. The hybrid sequential ion exchange strategy provides a versatile platform for controlled co-delivery of PIP and TAZ.