Electroanalytical study of the hydrolysis of the thienodiazepine clotiazepam

Abstract

The hydrolysis reaction in an alkaline medium of the thiendodiazepine Clotiazepam has been studied by differential pulse polarography at various pH values at 25, 37, and 5OOC. In an alkaline medium, Clotiazepam exhibits two well-defined polarographic peaks, attributed to the azomethine group of the parent compound and the carboxylic group of the hydrolysis product, with a potential difference of 0.160 V, practically constant in the pH range studied. Kinetic studies of the reversible hydrolysis process based on the current changes with time of the first polarographic peak indicate that the process is a pseudo-first-order reaction with a rate constant dependent on hydroxide ion concentration. Arrhenius parameters were also calculated. A voltammetric study of the hydrolysis product has been carried out, and determination methods have been developed by differential pulse voltammetry and differential pulse polarography. which dlffers from benzodiazepines only in having a thiophene nucleus bound to the diazepinic moiety instead of a benzene nucleus. It is used as a minor tranquilizer 12, 31.Clotiazepam experiences hydrolysis in alkaline media. This fact is an important dlfference with respect to most 1 ,Cbenzodiazepine derivatives, which undergo hydrolysis in acidic media [ 41 or a process catalyzed by acid and bases, as in the case of benzodiazepinooxazoles [5].It is worthwhile to mention the importance of amide group substituents of the diazepinic ring in the behavior of the thienodiazepines because Clotiazepam, with a methyl substituent, undergoes hydrolysis in alkaline media and at room temperature, whereas the derivativewithout substituents in the amide group, does not undergo such a hydrolysis process.Cyclic voltammetry and differential pulse polarography have been the most widely used electroanalytical techniques for kinetic studies, but reports concerning kinetic studies of 1,4-benzodiazepine derivatives are scarce [7-lo].In this work, a kinetic study of the hydrolysis process of the compound was carried out by differential pulse ' To whom correspondence should be addressed.polarography, following the current changes with time. To develop determination methods for the compound, an electroanalytical study of the hydrolysis product was made. Apparatus and ReagentsPrinceton Applied Research Corporation (PAR) Model 174 polarographic analyzer, a PAR Model 303A SMDE cell and a Houston Omnigraphic X-Y recorder were used to carry out the kinetic study and the voltammetric measurements of the hydrolysis product.A threeelectrode thermostated cell of 15 mL capacity, containing a dropping mercury electrode (DME: capillary tube of inside diameter 0.015 mm) as the working electrode, a saturated Ag/AgCl/KCl as the reference electrode, and a platinum wire as auxiliary electrode was employed. A Metrohm glassy carbon electrode served as working electrode in the voltammetric measurements.Polarography was performed in the differential polarographic mode. A pulse of 25 mV was applied using a drop time of 0.5 second, and the...