Association of the Ionizable Organic Compound Lamotrigine with Dissolved Humic Acid: Mechanistic Insights and Modeling Optimization

The association of ionizable organic compounds (IOCs) with natural organic matter (NOM) plays a critical role in governing their bioavailability and transport in the environment. However, the complexity of these interactions poses a significant challenge to accurately predict their environmental fate. In this study, we investigated the binding mechanisms of the cationic pharmaceutical lamotrigine (LTG) with soil humic acid under different environmental conditions. While LTG-humic acid binding is primarily driven by electrostatic attraction, the conventional NICA-Donnan model failed to accurately capture its pH dependence, which accounts for the binding of LTG-H⁺ to low-affinity proton sites in humic acid. Incorporating proton cobinding significantly improved model performance across pH, ionic strength, and cation competition scenarios, suggesting that humic acid-bound protons facilitate LTG adsorption. The nonionic interaction between LTG and humic substances was further identified by spectroscopic characterization, revealing hydrogen bonding mechanisms including COOH···N interactions between protonated carboxylic acids and the LTG triazine ring and charge-assisted N⁺-H···COO^- bonding stabilized by electrostatic attraction. Finally, STD-NMR epitope mapping revealed preferential binding at the C-Cl position, indicating a spatially organized, cooperative interaction of hydrogen bonding and electrostatic attraction. These findings integrate molecular-scale insights with model refinement, offering a more robust framework for predicting IOC-NOM interactions in environmental systems.