DEHALOGENATION REACTIONS IN THE FAST-ATOM-BOMBARDMENT MASS-SPECTROMETRY OF PHENOTHIAZINE-RELATED DRUGS

Dehalogenation reactions of selected phenothiazine antipsychotic and tricyclic antidepressant drugs were studied during fast atom bombardment (FAB) mass spectral analysis. All of these halogenated compounds demonstrated the presence of ions corresponding to the loss of a halogen and its replacement by a hydrogen atom. The structure of the dechlorinated ion for chlorpromazine and the source of the hydrogen atoms replacing the chlorine were studied using perdeuterio-glycerol, accurate mass measurement and comparison of the spectrum with its authentic dechlorinated analog. In addition tandem mass spectrometric studies illustrated identical daughter ion spectra for the dechlorinated ion arising during FAB mass spectrometry of chlorpromazine and the analogous ion present in its unhalogenated analog promazine. The dechlorination process once started by exposure to the atom beam during static FAB mass spectrometry demonstrates an accumulation of dechlorinated ion with time. During continuous flow FAB where the sample is refurbished with time the extent of dechlorination remains relatively constant. The extent of dehalogenation was greater for chlorinated compounds as compared to fluorinated derivatives. The percentage exchange of chlorinated compounds ranged from 7.2% to 32.6% while the percentage exchange for triflupromazine was 3.3%. The recognition that such ions can arise during FAB mass spectrometry avoids the possible misinterpretation of such ions as being due to sample contamination or due to in vivo metabolic dehalogenation during metabolism studies.