Potentiometric titration of phenothiazine compounds in chloroform and its use in pharmaceutical analysis

The potentiometric titration of some phenothiazine drugs in chloroform is described. A standard solution of bromine in chloroform was used as titrant and the end-points were detected with a small platinum indicator electrode, and an Ag/AgCl electrode in 0.01M Et(4)NCl in chloroform as reference. A fast redox reaction occurs during the titrations and the phenothiazine ring is oxidized to the phenothiazonium free radical (P(+)). The low dielectric constant of the medium favours the formation of (P(+)Br(-)) ion-pairs or (P(+)Br(-)(3)) ion-pairs on further addition of bromine, which has no influence on the position of the first end-point. The method was used for the determination of promethazine, chlorpromazine, trifluoperazine and thioridazine in pharmaceutical preparations after extraction into chloroform. The relative standard deviation for the determination of 5 mg of all these phenothazines was about 1%.     

Extractive spectrophotometric determination of some phenothiazine derivatives in pharmaceutical preparations

A simple, accurate, rapid and sensitive spectrophotometric method has been developed for the assay of six phenothiazine derivatives in bulk drug and their pharmaceutical preparations. The method is based on ion-pair complex reaction of phenothiazines with bromocresol green in aqueous acidic buffer. The chromogen, being extractable with chloroform, could be measured quantitatively at 420 nm. All variables were studied in order to optimize the reaction conditions. The proposed method has been successfully applied to the analysis of the bulk drugs and their dosage forms, tablets and injections. No interference was observed from common pharmaceutical adjuvants. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.     

Potentiometric study of reaction between periodate and iodide as their tetrabutylammonium salts in chloroform. Application to the determination of iodide and potentiometric detection of end points in acid-base titrations in chloroform

A potentiometric method for the titration of tetrabutylammonium iodide (TBAI) in chloroform using tetrabutylammonium periodate (TBAPI) as a strong and suitable oxidizing reagent is described. The potentiometric conditions were optimized and the equilibrium constants of the reactions occurring during the titration were determined. The method was used for the determination of iodide both in chloroform and aqueous solutions after extraction into chloroform as ion-association with tetraphenylarsonium. The reaction between TBAPI and TBAI was also used as acid indicator for the potentiometric detection of end points of acid-base titrations in chloroform.     

Fluorimetric determination of phenothiazine derivatives by photooxidation in a flow-injection system

Flow-injection analysis (FIA) was combined with photochemically induced fluorescence (PF) detection for the determination of four phenothiazine derivatives, including unsubstituted phenothiazine, thionine, Azure A and Methylene Blue. The working analytical parameters (flow-rate, injected volume, photoreactor length) were optimized. Linear calibration graphs were obtained over about two orders of magnitude, with relative standard deviation within the range 1-2.3%. Limits of detection were between 13 and 35 ng/ml, according to the compound. The FIA-PF method was applied to the determination of phenothiazines in urine samples. Mean recoveries ranged from 94 to 117%.     

Colorimetric determination of some sulphonamides with phenothiazine

Two simple and sensitive calorimetric procedures for determination of some sulphonamides with phenothiazine (thiodiphenylamine) are presented. One is based on reaction in aqueous alcohol solution in presence of hypochlorite, with direct measurement at 515 nm. The other is based on reaction in presence of copper(II) acetate at 70 degrees , extraction with chloroform and measurement at 515 nm. The method is applied to the determination of sulphonamides in pure and tablet form, with a coefficient of variation less than 2%.     

Utility of diphenylamine and N-bromosuccinimide for colorimetric determination of certain phenothiazine drugs

A sensitive colorimetric method for the quantitative estimation of 11 phenothiazine drugs was developed. The method was based on the interaction of phenothiazine compounds with diphenylamine in presence of N-bromosuccinimide and sulfuric acid. Most of studied phenothiazines yielded bluish green products with two absorption maxima, one in the range of 392-396 nm with higher molar absorptivity and the other in the range of 770-780 nm with lower molar absorptivity. Phenothiazine base, mepazine HCl and pericyazine yielded blue products with only one maximum at 655, 775 and 778 nm, respectively. The color was stable for at least 1 h. The reproducibility and recovery of the method were excellent. The method was applied successfully to the determination of some commercially available phenothiazines in different dosage forms. Results were comparable to those obtained by official and reported methods.     

Determination of the drug content of pharmaceuticals containing phenothiazine compounds by triangle programmed flow titration

Summary A flow-through triangle programmed coulometric titration technique is worked out for the determination of phenothiazine compounds. The oxidation reaction of phenothiazines with hypobromite ion served as titration reaction. A biamperometric detector cell has been used for following the titration process. The titration technique has been used for the determination of the drug content (average and individual) of chlorpromazine, promethazine, diethazine and trifluoperazine in pharmaceutical preparations. The relative standard deviation was in the range of 2.0 to 3.5%.

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Bestimmung des Wirkstoffgehaltes von Phenothiazin-haltigen Pharmazeutica mit Hilfe einer Dreieck-programmierten Durchflu\-Titration

     

Selective construction of indeno[1,2-b]phenothiazine and indeno[2,1-c]phenothiazine via tandem annulation reaction

AcOH promoted annulation reaction of 2-arylideneindane-1,3-diones with methyl 2-(benzo[b][1,4]thiazin-3-ylidene)acetate in refluxing ethanol afforded pentacyclic tetrahydroindeno [1,2-b]phenothiazine in satisfactory yields and with high diastereoselectivity according to the unexpected tandem annulation process. When the above reaction was carried out in refluxing acetic acid, isomeric dihydroindeno [1,2-b]phenothiazines and dihydroindeno [2,1-c]phenothiazines were obtained in comparable yields according to alternate tandem annulation process.     

Determination of some antipsychotropic and anticholinergic phenothiazine drugs by vanadium (V) titration

Three simple, rapid and accurate titrimetric procedures using ammonium metavanadate have been developed for the determination of six phenothiazine drags in pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in acid medium to colourless sulphoxides via orange or purple coloured intermediates. In the first method, phenothiazines are titrated directly in H₂SO₄-H₃PO₄ medium to a colourless end-point. In the second procedure, a known excess of oxidant is added and after a specified time, the residual oxidant is determined using standard ammonium ferrous sulphate titration. The third method employs electrometric end-point detection. The optimum reaction conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drags has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.     

Titrimetric micro determination of some phenothiazine neuroleptics with potassium hexacyanoferrate(III)

Three simple, rapid and accurate titrimetric procedures using potassium hexacyanoferrate(III) have been developed for the micro determination of five phenothiazine drugs in pure form and in dosage forms. The procedures are based on the oxidation of phenothiazines in an acid medium to colourless sulphoxides via orange or purple coloured products. In the first procedure, phenothiazines are titrated directly in H(2)SO(4)-H(3)PO(4) medium to a colourless end point. In the second method, a known excess of the oxidant is added and after a specified time, the residual oxidant is determined iodometrically. The third method employs electrometric end-point detection. The optimum reactions conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drugs has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.     

Extractive spectrophotometric determinations of some phenothiazine derivatives in pharmaceutical preparations

Two sensitive methods for the determination of phenothiazine derivatives based on the formation of coloured salts of these drugs formed with Brilliant Blue or Orange-II in the presence of 0.1 M HCl are described. The ion pair salts formed are quantitatively extracted into chloroform and the dried chloroform solutions analyzed using spectrophotometry.     

Post-column oxidative derivatization for the liquid chromatographic determination of phenothiazines

A first post-column chemical derivatization method for the liquid chromatographic determination of phenothiazines is presented. Peroxyacetic acid is introduced as a derivatizing agent for phenothiazines, yielding the colored radical cations or fluorescent sulfoxides, depending on reaction conditions. Both reaction products were successfully employed for the detection of the phenothiazines after their liquid chromatographic separation. The fluorescence spectroscopic detection of the sulfoxides proved to be the more robust and sensitive method. Limits of detection ranged from 4 nM for triflupromazine and trimeprazine to 300 nM for phenothiazine for the fluorescence spectroscopic detection of the sulfoxide and from 0.3 μM for phenothiazine and triflupromazine to 2 μM for trifluperazine for the UV–Vis spectroscopic detection of the radical cation. The calibration functions for the fluorimetric sulfoxide determination ranged from two to more than three decades, starting at the limit of quantification.     

Thin-layer chromatographic identification of phenothiazine derivative drugs

Data are presented on the thin-layer chromatographic identification of 20 phenothiazine bases official in the U.S.P. XX. On the basis of four chemically different solvent systems and the color developed with a spray reagent, all phenothiazines could be distinguished from each other. For greater precision, relative RF values (ratios of the RF of each phenothiazine to the RF of chlorpromazine) have been used. The relative efficiencies of various brands of commercially prepared thin-layer plates were evaluated for these solvent systems.     

Pulse radiolysis and cyclic voltammetry studies of redox properties of phenothiazine radicals

One-electron transfer equilibria between seven phenothiazines were characterized by pulse radiolysis, producing radical-cations via oxidation by Br₂^·− or (SCN)₂^·− radicals. The reduction potentials of the phenothiazine radicals were determined by cyclic voltammetry. As an independent check, the redox equilibrium between one phenothiazine and the redox indicator ABTS was investigated. The data establish phenothiazines as useful indicators for radical redox properties. However, there are potential problems of aggregation, additional reactions with Br⁻/Br₂^·− and reactivity of the radicals towards buffers or other nucleophiles.     

Second-derivative spectrofluorometric determination of sulphoxide impurity in phenothiazine drug substances and formulation

A direct second-derivative spectrofluorimetric procedure for determining sulphoxide impurity in phenothiazines and their formulations has been developed. The method, which has been applied to the analysis of chlorpromazine hydrochloride and prochlorperazine mesylate, as examples of typical phenothiazine substances, and to their formulations, is based on the measurement of the amplitude taken from the minimum at ca. 270 nm to the longer wavelength maximum in the second-derivative excitation spectrum of the sulphoxide in pH 8 buffer solution. The method is rapid, accurate and precise, and can be used to measure the concentration of sulphoxide in phenothiazines and their formulations at concentrations down to 0.1% m/m of that of the parent phenothiazine.     

Spectrophotometric determinations of some phenothiazine drugs

A rapid and sensitive spectrophotometric method has been developed for the quantitative determination of some phenothiazine derivatives as the pure substances and in different dosage forms. The method is based on the formation of red coloured products with 1% iodic acid in sulphuric or phosphoric acid medium. The reaction involves oxidation of the phenothiazine nucleus into a semiquinonoid radical. The optimum reaction conditions and other analytical parameters are evaluated. The influence of the substrates commonly employed as excipients with phenothiazine drugs has been studied. Statistical comparison of the results with those of an official method shows excellent agreement and indicates no significant difference in precision.     

Photochemically generated stable cation radical of phenothiazine aggregates in mildly acid buffered solutions

This work characterizes, for the first time, the photochemical behavior of the antipsychotic drugs thioridazine (TR), trifluoperazine (TFP), and fluphenazine (FP) influenced by the aggregation state of the molecules. Samples of monomeric and aggregated forms of phenothiazines were submitted to 20 min of irradiation at 254 nm for intervals of 1, 5, 10, 15, 20, or 25 days. In high phenothiazine concentrations, the irradiation led to the appearance of absorbance bands in the visible region peaking at 633 nm for TR and 509 nm for FP and TFP. In the dark, at room temperature and at 4 degrees C, these bands disappeared, after approximately 15 and approximately 60 min, respectively, but reappeared after a new irradiation session. These visible bands were assigned to stable cation radicals that were characterized by direct EPR measurements and by flash photolysis. Photogenerated stable cation radicals in the phenothiazine aggregates at room temperature are formed probably due to the stacking of the thiazine phenyl moieties. For the monomeric forms of phenothiazines, the spectral changes observed during the irradiation suggested the formation of sulfoxide and hydroxylated derivates. Oxidized derivates were detected by mass spectrometry of the aggregated forms of phenothiazines (>100 microM) only in the samples irradiated for more than 20 days. In contrast, monomeric phenothiazines were totally converted to the oxidized forms after 20 min of irradiation. Surface tension measurements of phenothiazines revealed that, in concentrations above 100 microM, the drugs formed aggregates. In the case of TR, small-angle X-ray scattering measurements indicated that this compound forms large lamellar-like aggregates in aqueous solutions.     

Determination of dissociation constants of sparingly soluble phenothiazine derivatives by second-derivative spectrophotometry

The dissociation constants (pK_a) for sparingly soluble phenothiazines (promazine, chlorpromazine, trifluoropromazine) in water were measured by second-derivative spectrophotometry. The intense background signals in the absorption spectra due to the turbidity caused by the precipitation of insoluble free base of the phenothiazine derivatives were eliminated in the second-derivative spectra, and the solubilities of the phenothiazine derivatives could be easily determined from the peak-to-trough lengths (D values) of the second-derivative signals. The pK_a values were calculated from the pH dependence of the D values. The pK_a values obtained agreed well with reported values and the standard deviations for 6–10 determinations were ? 0.02. The solubilities of the free bases of the phenothiazines were also determined.     

Tungstophosphoric acid as a new reagent for the spectrophotometric determination of phenothiazines

A simple and rapid spectrophotometric method for the determination of phenothiazines based on the formation of a colored compound between tungstophosphoric acid and phenothiazines is described. The proposed method is successfully employed for the determination of phenothiazine drugs in various pharmaceutical products.     

A study on one-electron oxidation of phenothiazine derivatives BV piperidine oxoammonium ion in SDS micelle

N-Substituted phenothiazines were oxidized by 2,2,6,6-tetramethy-4-acetyloxypiperidine oxoammonium hexachloroantimonate (TAPO) to the corresponding radical cations in sodium dodecyl sulfate (SDS) micellar solution. The radical cations of phenothiazine derivatives were generated and stabilized by the anionic micelle in queous solution. An electron transfer mechanism has been proposed.