This LC-MS method applied to solid-state photostability studies was undertaken to establish not only the nature of the degradants but also any commonality between major metabolic pathways of iV-dealkylation, iV-oxidation, sulphoxidation and hydroxylation. The rate of these in vitro transformations is dependent on the concentration of the substrates, and the formation of the sulphoxides has been proved to be a slow reaction in vitro?5

In spite of previous reports,26 sulphoxidation is identified as the principal degradation pathway for irradiated samples of prochlorperazine and trifluoperazine giving rise to the 5-sulphoxide in the presence of each respective parent compound, while the relative intensities indicate the prochlorperazine sulphoxide to be 1.93% and trifluoperazine 0.1%, confirming the instability of the chlorine containing derivatives. For fluphenazine /V-dealkylation, sulphoxidation and dehalogenation are the proposed degradation pathways in Figure 7.

Solid-state perphenazine gave rise to three degradants including the dechloro derivative which upon subsequent fragmentation showed identical product ions to those observed for the N-dealkylated derivative of fluphenazine, suggesting a pattern of dehalogenation and N-dealkylation for the fi-hydroxyethyl derivatives. Similar degradation pathways exist for the chloro derivatives with dehalogenation and subsequent photoreduction and photosubstitution most prominent with sulphoxidation of the parent compounds of secondary importance. Perphenazine is more susceptible to dehalogenation with levels of between 18.90 and 26.85% for the dechloro derivative while prochlorperazine results in significantly lower levels of between 3.89 and 18.54 %.

Sulphoxidation is evident throughout the solution studies at levels greater than 0.1% with the exception of trifluoperazine / perphenazine under fluorescent-diffuse light/sunlight. However, in the case of perphenazine the sulphoxide is formed after dechlorination, a phenomenon not observed for prochlorperazine. While solid-state irradiation of trifluoperazine and prochlorperazine yields only the sulphoxides, fluphenazine, in addition to the sulphoxide (20.23%), loses the trifluoro group from the sulphone and undergoes N-dealkylation as additional pathways.

It can thus be concluded that sulphoxidation appears to be a common route of degradation for these four derivatives on exposure to light while evidence of dehalogenation, sulphonation and dealkylation are amongst the other degradation pathways observed in the photostudies. These results concur with the routes of degradation which have been well documented in previously reported in vitro studies.26 In order of decreasing stability the following is proposed: trifluoperazine, fluphenazine, prochlorperazine and perphenazine.

7 - XH3 ch2— ch2— ch2 — n n — ch2ch2oh (18) N '

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