The Role of Intermolecular Interactions between Donepezil and Methacrylic Acid in the Synthesis of Crosslinked Polymer Microgels for Drug Delivery

Cross-linked polymer microgels were synthesized via precipitation polymerization, and the influence of intermolecular interactions between methacrylic acid (monomer) and donepezil (anticholinergic drug) on microgel properties were investigated. Ion pair formation, confirmed by proton nuclear magnetic resonance spectroscopy (¹H NMR) and nuclear Overhauser effect (NOE) studies, enabled molecular imprinting using donepezil as a template. The microgels were characterized for their adsorption capacity, swelling behavior, mucin binding, and drug release kinetics. Imaging by atomic force microscopy (AFM) and field emission gun scanning electron microscopy (FEG-SEM) revealed dry particles ca. 120-200 nm in size, which swelled to ca. 1 µm in aqueous media. Swelling increased with pH and ionic strength, and the microgels exhibited high adsorption capacity (ca. 200 mg g-1). Donepezil adsorption followed the Sips model, indicating heterogeneous binding sites. Molecular imprinting in oil-based formulations modulated drug release via Higuchi kinetics, attributed to enhanced interactions within the hydrophobic vehicle. These findings demonstrate the potential of drug-polymer interactions in designing tunable drug delivery systems for clinically relevant doses. Donepezil base and drug-free microgels exhibited lower cytotoxicity than microgels with adsorbed donepezil in human lung fibroblast (MRC-5) cells, possibly due to the swelling and agglomeration of these polymer particles. Additional studies, including histological analysis of mucosal tissues at potential application sites, should be conducted in animal models to confirm whether microgels exhibit increased cytotoxicity.