Hydrolysis of temazepam in simulated gastric fluid and its pharmacological consequence

Article abstract of DOI:10.1002/jps.2600831105

Temazepam (TMZ), a hypnotic and anxiolytic drug, underwent hydrolysis in simulated gastric fluid (SGF; pH 1.2). The hydrolysis reaction of TMZ in acetonitrile:SGF (1:19, v/v) at 37 °C was an apparent first-order reaction, with a half-life of 5.47 ± 0.17 h (i.e., ~12% of the remaining TMZ was hydrolyzed per hour). The predominant hydrolysis product (2'-benzoyl-4'- chloro-N-methyl-2-amino-2-hydroxyacetanilide) and a minor hydrolysis product [2-(methylamino)-5-chlorobenzophenone], derived from acid-catalyzed reaction of TMZ in an aqueous solution, were characterized by ultraviolet-visible absorption mass, infrared, and proton nuclear magnetic resonance spectra analyses. The kinetics of the hydrolysis reaction were studied as a function of acid concentration, temperature, and ionic strength and in deuterated solvent. Results indicated that the predominant hydrolysis reaction at pH ? pK(a) (1.46) was caused by protonation at N4, followed by a nucleophilic attack by water at C5 of the C5-N4 iminium ion and a subsequent ring-opening reaction. Pharmacological activity tests in mice indicated that the predominant hydrolysis product of TMZ was inactive. The results suggest that a fraction of an orally taken TMZ may be inactivated by hydrolysis in the highly acidic gastric fluid.