Design of a Chitosan-Based Ternary Nanocomposite for Sensitive Electrochemical Clozapine Detection

Abstract The accurate determination of clozapine (CLZ), an essential antipsychotic drug, remains challenging due to complex pharmaceutical matrices and the need for high sensitivity. Conventional methods like HPLC and UV-Vis are limited by time-consuming procedures and unsuitability for on-site analysis. To address this, a novel hybrid nanocomposite based on a chitosan Schiff base functionalized with 2-(2-acetamidophenyl)-2-oxoacetic acid (Chs-KA), β-cyclodextrin (β-CD), and zinc oxide nanoparticles (ZnO NPs) was successfully synthesized. Structural characterization confirmed the formation of the Chs-KA Schiff base via imine linkage (FTIR band at ~ 1640 cm⁻¹), while XRD analysis revealed the incorporation of crystalline ZnO with a wurtzite structure and an average crystallite size of 8–20 nm. This composite was employed to fabricate a modified carbon paste electrode (Chs-KA/β-CD/ZnO NPs/CPE) for the sensitive detection CLZ. The sensor demonstrated a proton-coupled electron transfer mechanism (slope of − 47 mV/pH) with adsorption-controlled kinetics (heterogeneous electron transfer rate constant, ks = 2.67 s⁻¹). Under optimized conditions, the electrode exhibited a wide linear response range from 0.5 nM to 7.0 µM, a very low detection limit of 0.13 nM, and high selectivity against common interferents (signal change < 5%). The sensor showed excellent reproducibility (RSD = 2.05%) and retained 95.64% of its initial response after one month. Practical applicability was validated by determining CLZ in commercial tablet formulations, with recovery rates ranging from 97.0% to 102.0%. This work provides a powerful platform for pharmaceutical quality control and establishes a design strategy for advanced biopolymer-based electrochemical sensors. Future work includes application to other psychoactive drugs, biological fluid monitoring, and commercial scalability.