Kinetics and mechanism of the equilibrium reaction of triazolam in aqueous solution

Abstract

The equilibrium kinetics of triazolam in aqueous solution was investigated in the pH range of 1-11 at body temperature. The quantitative study indicated that it forms equilibrium mixtures consisting of ring-opened and closed forms with the composition being dependent on pH. The equilibrium constants of the two species in the pH range studied were determined by GLC method. The apparent first-order rate constants were estimated from the decreasing or increasing absorbance of the mixture in solutions. The forward-reaction rate constant (kf) showed a bell-shaped kf-pH profile with a rate maximum at pH 4.59, which indicates not only that the carbinolamine intermediate forms during the equilibrium reaction, but that the rate-determining step of the reaction differs for the acidic and basic sides of the rate maximum. The reverse-reaction rate constant decreased with increasing pH and could not be estimated in the pH region greater than 5.65. Theoretical curves for both forward and reverse reactions satisfactorily fit the observed data. The pKa values of triazolam and its opened-form amine were estimated to be 1.52 and 6.50, respectively.