Modulation of Donepezil Release Through Hydrophobic Ion- Pairing with Oleic Acid in Liquid Crystalline Nanodispersions for Transdermal Delivery.

Precursor liquid crystals based on unsaturated monoglycerides, with or without oleic acid (OA), exhibited anisotropy characteristic of an inverse hexagonal phase. Donepezil-loaded liquid crystalline nanodispersions (LCNs) were produced by sonication and exhibited encapsulation efficiencies of 91.3-97.9%, with the OA-containing formulation (LCN-2) displaying a smaller particle size (183.0 ± 1.5 nm), lower polydispersity (0.183 ± 0.006), and improved colloidal stability over 90 days. NMR (1H NMR, 1D NOESY/ROESY and DOSY), molecular docking, and molecular dynamics simulations consistently demonstrated hydrophobic ion-pair formation between donepezil and oleic acid. These molecular interactions reduced drug mobility within the lipid domains, resulting in anomalous release behavior (n = 0.79), more sustained in vitro release, and an approximately 45% higher steady-state skin flux than the control donepezil solution. Overall, hydrophobic ion-pair formation with oleic acid represents an effective strategy to modulate drug release and enhance the transdermal performance of liquid crystalline nanodispersions for donepezil delivery.