HYDROLYSIS OF TEMAZEPAM IN SIMULATED GASTRIC FLUID AND ITS PHARMACOLOGICAL CONSEQUENCE

Temazepam (TMZ), a hypnotic and anxiolytic drug, underwent hydrolysis in simulated gastric fluid (SGF; pH 1.2). The hydrolysis reaction of T MZ in acetonitrile:SGF (1:19, v/v) at 37 degrees C was an apparent fir st-order reaction, with a half-life of 5.47 +/- 0.17 h (i.e., similar to 12% of the remaining TMZ was hydrolyzed per hour). The predominant hydrolysis product l-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, w ere characterized by ultraviolet-visible absorption mass, infrared, an d proton nuclear magnetic resonance spectra analyses. The kinetics of the hydrolysis reaction were studied as a function of acid concentrati on, temperature, and ionic strength and in deuterated solvent. Results indicated that the predominant hydrolysis reaction at pH approximate to pK(a) (1.46) was caused by protonation at N4, followed by a nucleop hilic attack by water at C5 of the C5-N4 iminium ion and a subsequent ring-opening reaction. Pharmacological activity tests in mice indicate d that the predominant hydrolysis product of TMZ was inactive. The res ults suggest that a fraction of an orally taken TMZ may be inactivated by hydrolysis in the highly acidic gastric fluid.