Regulation of Template Ionization and Template–Monomer Interactions for Enhanced Molecular Imprinting and Selective Detection of Promethazine

A molecularly imprinted polymer (MIP)-based quartz crystal microbalance (QCM) sensor was developed for the selective detection of promethazine (PMZ) through deliberate regulation of template–monomer interactions during the molecular imprinting process. Various functional monomer systems were systematically evaluated to optimize intermolecular recognition, among which the combination of 4-vinylpyridine (4-VP) and 2-acrylamido-2-methylpropanesulfonic acid (AAMPS) exhibited the strongest interaction toward PMZ. Furthermore, protonation of PMZ using hydrochloric acid significantly enhanced electrostatic complexation between the template and functional monomers, leading to improved pre-polymerization organization, more effective imprinting-site formation and high selectivity towards target analytes. The resulting MIP-QCM sensor exhibited a linear response toward PMZ over the concentration range of 50–2000 ppb with a correlation coefficient (R2) of 0.99148 and a detection limit of 27.4 ppb. The sensor demonstrated favorable selectivity against structurally related compounds, strong anti-interference performance under highly competitive matrix conditions, and excellent regeneration stability, retaining 97.9% of its original response after ten regeneration cycles. Recovery studies in spiked tap water and carbonated beverage samples yielded recoveries ranging from 94.7% to 112.6%. These results demonstrate that regulating template ionization and template–monomer interactions is an effective strategy for improving imprinting-site quality and molecular recognition performance. The proposed approach provides new insight into the rational design of highly selective MIPs for basic pharmaceutical compounds and offers a promising platform for environmental, pharmaceutical and forensic monitoring applications.