Photochemical decomposition of 1,4-benzodiazepines

Abstract

By labelling chlordiazepoxide and diazepam with t4C it was possible to follow quantitatively the photochemical decomposition of these compounds. It was found for chlordiazepoxide that the wavelength of light does not determine the character, but only the concentrations of the products formed.On irradiation of chlordiazepoxide, dissolved in methanol or methanol-water (pH=7.4), an oxaziridine is formed, which is subsequently converted into a quinoxaline and a benzoxadiazocine derivative. However, by irradiation in the presence of glutathione, the rate of decomposition is increased and the scheme is completely changed. Instead of the quinoxaline and the benzoxadiazocine derivative, the reduced form ofchlordiazepoxide and a conjugate are formed. It was established that the oxaziridine, the first photoproduct of chlordiazepoxide, reacts spontaneously with glutathione at room temperature without light.On irradiation of diazepam, dissolved in methanolwater (pH=7.4), with light of 300 nm a benzophenone derivative is the only decomposition product, while with light of 254 nm also a quinazoline derivative is formed as a minor product. With methanol as solvent (2 =254 nm) the concentration of the products formed is strongly influenced, quinazoline derivatives become the main products and the benzophenone derivative a minor product. (Pharm. Weekblad Sci. Ed. 2,(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).

Aqueous Phototransformation of Diazepam and Related Human Metabolites under Simulated Sunlight

“…This compound was identified previously when methanolic solutions of diazepam were exposed to UV radiation. 16 Peak III was identified as 2-amino-5-chlorobenzophenone in a similar manner; by comparison with the retention times and mass spectra (MS 1−3 ) of an authentic standard of 2amino-5-chlorobenzophenone (SI Figure 5S). Solutions of pure I and III in water were also irradiated herein and the rate constants and half-lives determined (ref 25; Table 1).…”

“…15 The major removal mechanisms for diazepam in water were identified as sorption to sedimenting particles, dilution, advection, and importantly, rapid photodegradation in the superficial layers. 11 However, the only available data for photolysis were derived from a study of diazepam in methanol irradiated with 254 nm (UV) wavelength radiation of unspecified intensity 16 and a reference to one of our own unpublished preliminary experiments (cited by Straub). 11 A review 17 conducted in 2003 summarizing the existing literature concerning the photochemical behavior of many pharmaceuticals concluded that with some exceptions, the environmental photochemistry of the vast majority of pharmaceuticals had not been studied adequately.…”

Pitfalls in forensic toxicology

“…nitrazepam. 31 For a study of the stability of six drugs and one metabolite in blood, see Giorgi and Meeker. 32 Temperature Several studies have addressed the effect of temperature on stability.…”

Photochemistry of drugs: An overview and practical problems

“…The alkylenethioxanthines flupenthixol (89), clopenthixol(90), thiotixene (9 1) and chlorprothixene (92) are used as E j z isomeric mixtures. The E L ratio changes upon irradiation (>300 nm, see Among phenothiazines, chlorpromazine (94) has been extensively investigated (see Scheme 30).…”