Synthesis of a Tacrine–Cinnamic Acid Hybrid and Its Chitosan Nanoparticle Formulation for Sustained Release

Abstract

Tacrine remains a potent acetylcholinesterase inhibitor (AChEI), motivating tacrine-based hybrids and controlled-release formulations for Alzheimer’s disease. Here, a tacrine–cinnamic acid hybrid (compound 2) was synthesized and structurally confirmed by HRMS, 1H-NMR, and 13C-NMR. In vitro AChE inhibition was assessed by Ellman’s assay, where compound 2 showed an IC50 of 0.735 ± 0.041 μM compared with tacrine (0.00153 ± 0.00015 μM). To develop a delivery system, compound 2 was incorporated into chitosan nanoparticles (CSNPs) via ionic gelation to afford a compound 2-CSNPs nanocomposite. FTIR and XRD were used to evaluate functional groups and solid-state changes, and TGA was applied to compare thermal behavior of compound 2, CSNPs, and the nanocomposite. DLS indicated a submicron population with a main intensity peak around 568 nm, while zeta potential measurements showed a negative surface charge (-17 mV). SEM micrographs revealed irregular micrometer-scale agglomerates with a rough, heterogeneous surface and needle/rod-like features. In vitro release at pH 7.4 displayed biphasic behavior, reaching approximately 50% by 400 min and about 80% by 1400 min, indicating sustained release under physiological conditions.