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 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 hydrol...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 1994-11, Vol.83 (11), p.1543-1547
Main Authors: Yang, Tian Jian, Long Pu, Quan, Yang, Shen K.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chromatography, High Pressure Liquid
Hydrogen-Ion Concentration
Hydrolysis
Kinetics
Magnetic Resonance Spectroscopy
Male
Medical sciences
Mice
Neuropharmacology
Pentobarbital - pharmacology
Pentylenetetrazole - antagonists & inhibitors
Pentylenetetrazole - pharmacology
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Sleep - drug effects
Spectrophotometry, Infrared
Spectrophotometry, Ultraviolet
Stomach - chemistry
Temazepam - chemistry
Temazepam - pharmacology
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Summary: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 ≈ pKa(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.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.2600831105