The behavior of 1,4-benzodiazepine drugs in acidic media. V. Kinetics of hydrolysis of flutazolam and haloxazolam in aqueous solution.

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Abstract
The hydrolysis of flutazolam and haloxazolam was investigated kinetically. The cleavage reaction of the diazepinone nucleus of flutazolam was reversible, and the ring-cleaved form was in equilibrium with the ring-closed form in aqueous solution. On the other hand, the cleavage reaction of haloxazolam was irreversible. It was concluded that the 2-hydroxyethyl substituent attached to the amide nitrogen atom of flutazolam is responsible for the reversible character of the hydrolytic cleavage of the diazepamine nucleus. The hydrolysis mechanism was elucidated on the basis of the pH-rate profile. To compare the effects of substituents on the hydrolysis, the rate constants of oxazolam and cloxazolam in acidic solution were also determined.