Four structurally related phenothiazines available in South Africa in a variety of dosage forms and as fine chemicals were investigated to ascertain whether their structural differences in terms of the 2-chloro-/ trifluoromethyl-substituents on the phenothiazine nucleus and the methyl-/ ß-hydroxethyl groups on the piperazine ring accouning for the differences in pharmacological activity can be correlated with their photostability².The four propyl piperazine-substituted derivatives are ranked in the following decreasing order of neuroleptic activity: fluphenazine> trifluoperazine> perphenazine > rochlorperazine. In order to assess their photostability an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection and quantitation and ruggedness. Preliminary solution photostudies under controlled light conditions (UV, sunlight, fluorescent light) indicated that the rate of degradation followed first-order kinetics with perphenazine the most susceptible to.photodegradation under all light conditions studied. In vitro and in vivo metabolism yielding the 5-sulphoxide and its reported presence on decomposition of the phenothiazines25 led to the development of a synthetic procedure suitable for the sutphoxides of all four derivatives based on the method proposed by Owens et al. in order to provide standards for comparison in the photostudies⁷. Since ICH regulations require that impurities> 0.1 % are examined and identified⁷⁴ and semi-preparative isolation of photoproducts proved unsuccessful, LC-MS having been well documented for structural.elucidation⁷⁵ ⁷⁵ ⁷⁶ ⁷⁷ was used to characterize solution (UV, sunlight, fluorescent light) and preliminary solid (UV) photostudies. The chloroderivatives underwent dechlorination and sulphoxidation with subsequent photosubstitution in the case of prochlorperazine to yield the 2-hydroxy derivative and sulphoxidation of the dechloro-derivative of perphenazine. The sulphoxides of both trifluoperazine and fluphenazine were formed with further oxidation to the respective sulphones occurring. Preliminary solid state (UV) photostudies showed fluphenazine to be the least stable with 30.71 % degradation as opposed to 7.57% for prochlorperazine, 4.28% for perphenazine and 7.10% for trifluoperazine witn sulphoxidation observed to be. the major degradation pathway. Since in vitro metabolism of perazine derivatives is reported to occur via N-oxidation, N-demethylation, sulphoxidation and aromatic hydroxylation¹⁸ it does appear that there is some correlation between metabolic and photoproducts. However the fact that solution (UV) photostudies indicates trifluoperazine to be the most and perphenazine the least stable does not concur with the proposed order of pharmacological activity.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:rhodes/vital:3756 |
| Date | January 1997 |
| Creators | Drummond, Patricia Mary |
| Publisher | Rhodes University, Faculty of Pharmacy, Pharmacy |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis, Masters, MSc |
| Format | 179 p., pdf |
| Rights | Drummond, Patricia Mary |
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