Molecular Modelling in Prediction of Oxidative Degradation Mechanism of Ibuprofen

Ibuprofen, a widely used nonsteroidal anti-inflammatory drug (NSAID), is susceptible to oxidative degradation, which can compromise its stability and safety. While experimental studies have explored its degradation pathways, a detailed molecular-level understanding of the oxidative mechanism remains limited. This study employed Density Functional Theory (DFT) to investigate the electronic properties, reactive sites, and bond dissociation energies of ibuprofen, aiming to elucidate its oxidative degradation mechanism. Geometry optimization, HOMO-LUMO analysis, Fukui functions, and bond dissociation energy calculations were performed using the B3LYP-D3/6-31G** level of theory. Results revealed a small HOMO-LUMO gap (0.27715 kcal/mol), indicating high reactivity, and identified the carboxylic acid group and O14–C12–C11 bond as primary sites for oxidative attack. The proposed degradation mechanism aligns with experimental observations, providing insights into the formation of stable degradation products. These findings offer a theoretical foundation for designing more stable ibuprofen formulations, potentially enhancing drug efficacy and safety. The study underscores the utility of DFT in predicting pharmaceutical degradation pathways and informs future strategies to mitigate oxidative instability.