2026 Volume 74 Issue 9 Pages 693-698
In this study, the degradation behavior and reaction mechanisms of triazolobenzodiazepines (TBZDs)—alprazolam (ALZ), triazolam, and etizolam—in artificial gastric juice were investigated. Degradation kinetics were evaluated by monitoring time-dependent changes in TBZD standard solutions after the addition of artificial gastric juice at various temperatures using LC with photodiode array detection. Arrhenius analysis provided kinetic parameters for each compound. All TBZDs underwent rapid degradation under acidic conditions, and the reaction was reversible, yielding a single major product that was characterized as the final degradation product. Structural elucidation of the ALZ degradation product by spectroscopic and mass spectrometric analyses identified it as (2-[3-(aminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-5-chlorophenyl)(phenyl)methanone. To gain mechanistic insight, quantum chemical calculations were performed, including geometry optimization, electrostatic potential analysis, and frontier molecular orbital analysis. These analyses indicated that protonation enhances the electrophilicity of the azomethine carbon, facilitating nucleophilic attack by water. These findings demonstrate that electronic structure analysis based on quantum chemical calculations provides valuable mechanistic insight into the hydrolysis of TBZDs under acidic conditions and may contribute to the rational assessment of chemical stability in future drug development.
