Kinetic and mechanistic studies on the hydrolysis and photodegradation of diazepam and alprazolam

Abstract

The corresponding o-aminobenzophenones are usually reported as the main degradation products in the hydrolysis of 1,4-benzodiazepinones. Nevertheless, in previous studies of diazepam (DZ) in acidic aqueous medium we isolated and characterized seven unexpected degradation products. Kinetic measurements under several reaction conditions shed some light on the mechanisms of the complex reactions that are taking place, and photochemical studies give hints on the mechanisms of chlorination and annelation processes. Alprazolam (AL) seems to exhibit an unusually high stability against hydrolysis under several conditions; nevertheless, the structure is sensitive to photolytic cleavage. The photodegradation of AL was studied in aqueous and methanolic solutions. Characterization of the isolated products by 1 H and 13 C NMR and mass spectrometry revealed that electron transfer, oxidation and rearrangement reactions take place. The influence of several variables such as pH, solvent composition and light irradiation were examined and mechanisms for the formation of three photoproducts are proposed. A specific method for the determination of AL in the presence of photoproducts was developed, which allowed kinetic determinations of the photostability of AL. The photosensitivity observed in some patients treated with AL seems to be due to one of the characterized photoproducts.

Persistence of alprazolam in river water according to forced and non‐forced degradation assays: adsorption to sediment and long‐term degradation products

“…Alprazolam is a relatively stable benzodiazepine in comparison with other pharmaceutical drugs, and human metabolites, of the same family according to the results of some forced assays reported on several aqueous matrixes. Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the wileyonlinelibrary.com/journal/dta photodegradation assays carried out in this work. In the same way, although the different assays are not totally comparable, it can be stated that the acidic or alkaline hydrolysis of lorazepam, oxazepam, diazepam and bromazepam is easier than for alprazolam [12,[20][21][22][23][24][25] ; conversely, midazolam and clonazepam seem to be more resistant to hydrolysis than alprazolam.…”

“…Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the photodegradation assays carried out in this work. Thus, the half-life of alprazolam in solution was notably higher than those of diazepam, oxazepam, nordiazepam, temazepam, and mainly midazolam and lorazepam, when they were irradiated with simulated sunlight, [16][17][18][19] which is coherent with the stability observed for alprazolam in the photodegradation assays carried out in this work.…”

Degradation of benzodiazepines using water falling film dielectric barrier discharge reactor

“…It has been shown that during benzodiazepine oxidation a cleavage in nitrogen-carbon double bond occurs most commonly. 34 Besides that, the alprazolam carbon C4 (Fig. 1) 35 is more susceptible to oxidation than the diazepam carbon C3 (Fig.…”

“…However, either of these ways results in the same end products of hydrolysis. 34 In the case of alprazolam, the hydrolysis, even under several different conditions, was not a major degradation source. 35 The aromatic diazo ring of alprazolam probably protects it from hydrolysis, ensuring its better stability in both acidic and alkaline environment.…”

“…Some authors describe the degradation of this kind of compounds using a photodegradation method, such as UV irradiation, 34 light-stress exposure testing with a medium-pressure metal halide lamp and mirrors 35 or photolysis under conditions simulating the natural sunlight. 36 This kind of degradation could produce some oxidative species.…”