Electrochemical, Chemical and Enzymatic Oxidations of Phenothiazines

Abstract

The oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H 2 O 2 . Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects.

Electroanalytical Determination of Promethazine Hydrochloride in Pharmaceutical Formulations on Highly Boron‐Doped Diamond Electrodes Using Square‐Wave Adsorptive Voltammetry

“…According to previous studies of PH and other compounds of the same chemical group (phenothiazines), the oxidation process occurs by the removal of one electron from the nitrogen atom, leading to the formation of a relatively stable cation radical whose oxidation results in promethazine sulfoxide [10,11,41]. Figure 1 illustrates cyclic voltammetric responses obtained for PH oxidation on HBDD electrode in BR buffer, pH 4.0, at a scan rate of 100 mV s À1 , indicating the first and tenth cycles of potential scans.…”

Electroanalytical Performance of (SiPy+Cl−/CuTsPc)5 LbL Film for Detecting Promethazine Hydrochloride

“…There are several electrode surfaces used as working electrodes in the quantification of PMZ, such as glassy carbon [12,15,16], graphite powder [13], gold [17] and highly boron-doped diamond electrodes [18]. However, no study has been reported on the application of modified electrodes with LbL films for PMZ determination.…”

Electrochemical and Hyphenated Electrochemical Detectors in Liquid Chromatography and Flow Injection Systems for Drug Compound Analysis

“…Porous graphite-based cells and flow through thin-layer cells with a large working area/cell volume ratio are suitable online in LC and FIA setups coupled with mass spectrometric detection of electrochemically generated products. The latter are formed by electrons' removal (in the case of an oxidation) from the investigated analyte (i.e., a faradaic process) at the working electrode-solution interface giving rise to, e.g., sulfoxidation, N-dealkylation, and/or aromatic ring hydroxylation [58,59]. Production of hydrogen peroxide at the counter electrode can also generate interesting and metabolic relevant oxygenated species as recently demonstrated for lidocaine [60].…”