Flow-injection chemiluminometric determination of some thioxanthene derivatives in pharmaceutical formulations and biological fluids using the [Ru(dipy)3(2+)]-Ce(IV) system.

A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids.

Comprehensive high-performance liquid chromatographic methodology for the determination of thiothixene in bulk drug, finished product, and dissolution testing samples.

An HPLC methodology is described which enables the quantitation of thiothixene (N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthe ne-2- sulfonamide) in bulk drug, finished product, and dissolution samples using a single analytical column (SiAl: a mixture of silica and alumina). The Z (cis) and the less pharmacologically active E (trans) isomers of thiothixene, as well as synthetic precursors and degradants, are well resolved within a short chromatographic run. A minor modification of the mobile phase allows direct injection and quantitation of low-concentration samples in a simulated gastric fluid (SGF) dissolution medium. The method is capable of supplanting the three separate procedures currently included in the thiothixene monograph of the U.S. Pharmacopeia XXI.

Colorimetric determination of thioxanthenes with tetracyanoethylene.

A simple and rapid colorimetric method for the quantitative determination of the thioxanthene derivatives, chlorprothixene, tiotixene and metixene has been performed either in their pure form or in tablets. The procedure is based upon the formation of charge transfer complexes with the pi-acceptor tetracyanoethylene. The spectra of the complex show maxima at 415, 410 and 390 nm with a high apparent molar absorptivity which facilitates the determination of 5-100 micrograms X ml-1 of the studied compounds. The mean recoveries are 100.1 +/- 1.4%, 99.8 +/- 0.8% and 100.2 +/- 1.1% for chlorprothixene, tiotixene and metixene, respectively. This procedure is applied to determine these drugs in certain formulations and the results compare favourably to compendial methods.

Serum effects confound the neuroleptic radioreceptor assay.

The neuroleptic radioreceptor assay (NRRA) is used widely to monitor total neuroleptic-like activity (NLA) in patients taking one or more antipsychotic drugs. The original report of Creese and Snyder (1) stated that serum alone caused a small effect on binding which was negligible compared to normal daily variations in the assay. Conversely, in studies with striata from rat or cow brain, we found that sera from healthy, drug free volunteers, when used at 50 microL/1 mL assay volume, caused marked inhibition of binding. Although any sample of serum causes reproducible inhibition with a given preparation of bovine or rat striatal membranes, the effects of various serum samples may differ markedly when several striatal membrane preparations are compared. Moreover, samples taken from people at different times may also vary, although less than the interindividual differences. Despite this variance, the slopes of log-logit plots were equal to 1 either in the presence or absence of serum. Because of the differences in the interaction of individual sera with different membrane preparations, it is difficult to compensate accurately for this serum effect by simply including control serum in the standard curve. Thus, the use of the NRRA as a quantitative tool in the clinical pharmacology of neuroleptics may be limited by this non-specific effect of serum, and this finding may offer one explanation for some of the inconsistencies found in comparing the NRRA with direct analytical methods.

High-pressure liquid chromatographic determination of thiothixene in pharmaceutical formulations.

A method was developed for the quantitative determination of thiothixene in pharmaceutical formulations by high-pressure liquid chromatography after dissolution of the sample in methanol.