Electrochemical Oxidation of Phenothiazine

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Analytical Letters, 41: 789–805, 2008 Copyright # Taylor & Francis Group, LLC ISSN 0003-2719 print/1532-236X online DOI: 10.1080/00032710801935038


Electrochemical Oxidation of Phenothiazine Derivatives at Glassy Carbon Electrodes and Their Differential Pulse and Squarewave Voltammetric Determination in Pharmaceuticals Katarzyna Mielech-Łukasiewicz, Helena PuzanowskaTarasiewicz, and Aneta Panuszko Institute of Chemistry, University of Białystok, Białystok, Poland

Abstract: Three 2,10-disubstituted phenothiazines—chlorpromazine hydrochloride (CPM), thioridazine hydrochloride (TR) and propericiazine (PRC)—were electrochemically studied in various buffer systems at different pH values, using a glassy carbon electrode. The substances were electrochemically oxidized at potential range 0.55– 0.75 V. The oxidation was reversible and exhibited diffusion-controlled process. The mechanism of the oxidation process is discussed. According to the linear relation between peak current and concentration, differential pulse voltammetry (DPV) and square wave voltammetry (SWV) methods for quantitative determination of chlorpromazine and propericiazine in 0.1 M HClO4, and thioridazine in pH 2 phosphate buffer, was applied. Both the repeatability and reproducibility of the methods were also determined for all studied substances. The developed procedures were successfully applied to the determination of chlorpromazine and thioridazine in pharmaceutical dosage forms. Keywords: Phenothiazine derivatives, determination in pharmaceuticals, voltammetry, electrooxidation

Received 19 November 2007; accepted 19 December 2007 Address correspondence to Katarzyna Mielech-Łukasiewicz, Institute of Chemistry, University of Białystok, Hurtowa, Białystok, Poland. E-mail: [email protected] uwb.edu.pl 789


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INTRODUCTION Phenothiazines derivatives represent a major class of therapeutic agents for treating various mental and personality disorders. These substances are used as neuroleptics in the treatment of schizophrenia and other psychotic illnesses; they are also used as sedatives, antihistaminics, antiemetics, and anaesthetics (Gupta 1988). Phenothiazines derivatives are characterized by tricyclic rings with sulfur and nitrogen atoms at positions 5 and 10. Chlorpromazine hydrochloride, thioridazine hydrochloride, and propericiazine are three such compounds and belong to the big phenothiazine group. Their chemical structures are shown Fig. 1. Phenothiazine derivatives easily become chemically, electrochemically, and photochemically oxidized. The first step in the oxidation of these substances occurs at the sulphur atom, while the second wave can be attributed to the transformation of the radical cation into a dication (Mirel at al. 2000; Starczewska et al. 1996). The importance of these drugs prompted the development of many methods for their determination. The official methods (British Pharmacopoeia 2001; The United States Pharmacopeia 2004) for the assay of phenothiazines include nonaqueous titrimetry for pure drugs, and UV spectrophotometry. Other procedures for the determination of these substances in pharmaceuticals and biological fluids involve, for example, gas or high-performance liquid chromatography with detection by various detectors (Papp et al. 1990), spectrofluorimetry (Mohamed 1995), chemiluminometry (Fatma et al. 1998; Kojło et al. 2000) and spectrophotometry (Basavaiah et al. 2000; PuzanowskaTarasiewicz and Karpin´ska 2003). Reviews of methods for the determination of phenothiazine derivatives have also been published (El-Maali 2004; Hefnawy 2002; Puzanowska-Tarasiewicz and Karpin´ska 1992; PuzanowskaTarasiewicz et al. 2005). Voltammetric methods based on the oxidation behavior of phenothiazines have been recommend for their assay. Electrochemical techniques have been used for the determination of a wide range of drug compounds. The techniques have been excellent for the determination of pharmaceutical compounds in different matrices. The selectivity of voltammetric methods is normally

Figure 1.

Structures of studied phenothiazine derivatives.

Voltammetric Determination in Pharmaceuticals


excellent because the analyte can be identified by its peak potential. Several voltammetric methods use bare electrodes (Biryol and Dermis 1988; Dermis and Biryol 1989; Huang et al. 2004; Jarbawi 1986; Ni et al. 2001; Ozkan et al. 1996) or modified electrodes (Ferancova et al. 2000; Ferancova et al. 2001; Vanickova et al. 2000; Wang et al. 1996; Zeng and Huang 2004; Zeng et al. 2003) have been reported for the determination of phenothiazine derivatives. The aim of this study is to establish the experimental conditions needed to investigate the determinations of chlorpromazine, thioridazine, and propericiazine in tablets using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and square-wave voltammetry (SWV) SWV method was applied for the first time for the determination of studied phenothiazine derivatives.

EXPERIMENTAL Apparatus and Reagents Voltammetric measurements were performed using a m-Autolab electrochemical analyzer (Eco Chemie, The Netherlands). A three-electrode system consisted of a glassy carbon disc electrode as working electrode (F ¼ 3 mm BAS), saturated calomel electrode as reference electrode, and a Pt wire as auxiliary electrode. Before measurements, the glassy carbon electrode was polished manually with an aqueous slurry of 0.05 mm alumina powder on a smooth polishing cloth. For analytical application, the following parameters were employed: DPV conditions—pulse amplitude 50 mV, pulse width 50 ms, interval time 0.2 s; SWV conditions—pulse amplitude 25 mV, frequency 15 Hz, step potential 4 mV; CV conditions—initial and final potential were variable, depending on the pH value and the cut of the electrolyte. Scan rate measurements in the range 5– 500 mV/s were carried out. A Hewlett-Packard Model 845217 diode-array spectrophotometer was used for recording cation radical absorption spectra of studied phenothiazine derivative (CPM). All measurements were carried out at ambient temperature of the laboratory (20 + 28C). The pH was measured using a pH meter inoLab Level 1 (WTW, Austria) and a SenTix 41 electrode (WTW). Phenothiazine derivatives (chlorpromazine hydrochloride, thioridazine hydrochloride, propericiazine) were obtained from Sigma. Promazinw and Thioridazinw tablets containing 25 mg chlorpromazine hydrochloride and thioridazine hydrochloride, respectively, were obtained from a local pharmacy. The stock solution of CPM (1 . 1022 M) was prepared in water; stock solutions of TR and PRC (1 . 1022 M) were prepared in water –ethanol


K. Mielech-Łukasiewicz et al.

solution (1:1 v/v). Standard solutions were prepared by dilution of the stock solution with Millipore water to give solutions containing CPM, TR, and PRC. Other chemicals, all of analytical reagent grade (Merck, Germany) were used. The 0.1 M HClO4, 0.5 M KHSO4/K2SO4, 0.04 M BrittonRobinson buffer (pH 1.8), 0.1 M phosphate buffer (pH 2.0), 0.2 M acetate buffer (pH 3.6), 0.1 M KCl, and 0.1 M NaClO4 were used as supporting electrolytes. All solutions were de-aerated with argon for 10 min and were kept in an argon atmosphere during voltammetric experiments.

Analysis of Pharmaceutical Formulations Ten tablets of Promazinw or Thioridazinw (each tablet contained 25 mg chlorpromazine hydrochloride or thioridazine hydrochloride, respectively) were accurately weighed and finely powdered by pestle in a mortar. A weighed portion of this powder equivalent to 25 mg of the drug was transferred into a small conical flask and about 50 ml of Millipore water was added. The flask contents were stirred for 10 min, filtered into a 100 ml volumetric flask, and completed to volume with Millipore water. Appropriate solutions were prepared by taking suitable aliquots of the clear supernatant liquor and diluting with the selected supporting electrolyte in order to obtain a final solution. The amount of CPM (or TR) was calculated using the linear regression equation obtained from the calibration curve of pure CPM (or TR).

Recovery Experiments To study accuracy and precision, and to check the interference from excipients used in dosage forms of the proposed procedures, recovery experiments were carried out using the standard addition method. In order to exclude interferences by excipients, known amounts of pure drug were added to different preanalyzed formulations of studied phenothiazine derivatives, and the mixtures were analyzed by the proposed methods.

RESULTS AND DISCUSSION Electrochemical Behavior of Phenothiazine Derivatives The cyclic voltammetric behavior of phenothiazine derivatives (chlorpromazine) at glassy carbon electrode in phosphate buffer (pH 2) is shown in Fig. 2. The electrochemical behavior of the phenothiazine derivatives at this electrode over the pH range 1– 7 yielded a reversible oxidation process in the potential window of 0.3– 0.78 V (Fig. 2, curve 3). This process was not completely reversible because the difference between the potentials was

Voltammetric Determination in Pharmaceuticals


Figure 2. Cyclic voltammograms of 1.75 . 1024 M chlorpromazine in phosphate buffer at pH 2, V ¼ 50 mV/s: (1) blank; (2) in the range of potentials 20.521.3 V; (3) window potentials 0.3 –0.78 V, glassy carbon electrode.

about 78 mV, higher than the expected value of 59/n mV for a theoretical reversible process. However, a stable value of peak potential in the range 5– 500 mV/s (Fig. 3) and a linear relationship between peak current and the square root of the scan rate (Fig. 4A) show that the process is reversible. Scan rate studies were also carried out to assess whether the process on glassy carbon electrode was under diffusion or adsorption control. A linear dependence of the peak intensity upon the square root of the scan rate was found, demonstrating diffusional behavior. A plot of logarithm of peak current versus logarithm of scan rate (Fig. 4B) gave a straight line with a slope of 0.525, which is very close to the theoretical value of 0.5 that is expressed for an ideal reaction for a diffusion-controlled electrode process (Galus 1994). In some supporting electrolytes we also observed the second irreversible oxidation process (Fig. 2, curve 2). The first step in the electrochemical oxidation of these substances occurs at the sulphur atom, while the second wave can be attributed to the transformation of the radical cation into a dication. The mechanism of oxidation of phenothiazine derivatives proposed by Mirel (2000), is shown in Fig. 5. In this work we studied the first reversible-step electrochemical oxidation of some phenothiazine derivatives—chlorpromazine, thioridazine, and propericiazine. The oxidation of these substances takes place at a relatively low


K. Mielech-Łukasiewicz et al.

Figure 3. Cyclic voltammograms of 3 . 1024 M thioridazine in phosphate buffer at pH 2, scan rate: (1) 5; (2) 10; (3) 25; (4) 50; (5) 75; (6) 100; (7) 200; (8) 400; (9) 500 [mV/s].

Figure 4. (A) A plot of peak current versus the square root of the scan rate; (B) A plot of logarithm of peak current versus logarithm of scan rate; Thioridazine concentration 3 . 1024 M.

Voltammetric Determination in Pharmaceuticals


Figure 5. Electrochemical oxidation of 2, 10-disubstituted phenothiazines: (A) cation radical; (B) dication diradical; (C) sulfoxide, (D) sulfone [3].

potential. The values of the potentials are strongly influenced by the type of substituent at position 2 of the phenothiazine skeleton (Zimova et al. 1986; Zimova-Sulcova et al. 1985), as shown in Fig. 6. The values of the potentials increase as follows: -SCH3 , -OCH3  -SO2N(R)2 , -Cl , -CF3 , -CN. Figure 7 shows of cyclic curve of studied phenothiazines in the first step of reversible oxidation to the free radical. To confirm that the anodic current was related to the formation of cation radical in phenothiazine derivatives, a controlled potential electrolysis of chlorpromazine solution was carried out at þ0.64 V and a red solution was obtained. Comparing the absorption spectrum of this solution with that of solution prepared from a chemically synthesized radical perchlorate salt (Gupta 1988), they are in good agreement. Absorption spectra of chlorpromazine solution electrolyzed shown in Fig. 8. The first step of reversible oxidation of studied phenothiazine derivatives to the free radical will be discussed. According to previous work (Cheng et al. 1978) the cation radicals of phenothiazine derivatives are more stable in acidic solution. The stability of the cation radicals in various media can be observed easily from cyclic voltammograms. The voltammetric behavior of chlorpromazine, thioridazine, and propericiazine has been investigated in different supporting electrolytes such as HClO4, KCl, NaClO4, Britton-Robinson, phosphate, and acetate buffer. Peak currents, the ratios of anodic peak current to cathodic peak current, peak potentials, and the differences

Figure 6.

Generally structure of 2, 10-disubsitituted phenothiazine.


K. Mielech-Łukasiewicz et al.

Figure 7. Cyclic voltammograms of 1.75 . 1024 M thioridazine, chlorpromazine, and propericiazine in 0.1 M KCl; V ¼ 50 mV/s.

between anodic peak potential and cathodic peak potential, are listed in Table 1. The results (Table 1) show that the cation radical is more stable in acidic solution than in neutral solution. Based on this, the best solution proved to be 0.1 M HClO4 or phosphate buffer of pH 2. In these solutions, the ratio of Ipa/ Ipc gave a value of about 1.2. This value is close to the theoretical value of 1.0,

Figure 8.

Absorption spectra of chlorpromazine solution electrolyzed at þ0.64 V.




Solution or buffer solution


Epa [V]

Epc [V]

DEp [mV]


Epa [V]

Epc [V]

DEp [mV]


Epa [V]

Epc [V]

DEp [mV]


0.1 M HClO4 0.5 M KHSO4/K2SO4 B-R buffer Phosphate buffer Acetate buffer 0.1 M NaClO4 0.1 M KCl

1.0 1.3 1.8 2.0 3.6 7.0 7.0

0.63 0.63 0.657 0.645 0.64 0.65 0.64

0.56 0.55 0.593 0.583 0.558 0.586 0.57

70 80 64 62 82 64 70

1.22 1.20 1.39 1.469 1.468 1.87 1.56

— 0.558 0.58 0.59 0.591 — 0.57

— 0.49 0.495 0.512 0.513 — 0.496

— 68 85 78 78 — 74

— 1.30 1.40 1.16 1.24 — 1.21

0.746 0.724 0.75 0.76 0.78 — 0.74

0.677 0.65 0.67 0.687 0.70 — 0.665

69 74 80 73 80 — 75

1.338 1.386 1.48 1.33 1.55 — 1.52

Voltammetric Determination in Pharmaceuticals

Table 1. Cyclic voltammetric peak potentials value of anodic (Epa) and cathodic (Epc) wave, the difference between Epa and Epc (DEp), and ratio of Ipa/Ipc (where Ipa and Ipc are anodic and cathodic peak current respectively) of 4 . 1024 M chlorpromazine, thioridazine, and propericiazine in various supporting electrolytes at a glassy carbon electrode

— represents sediment.



K. Mielech-Łukasiewicz et al.

which is expressed for a theoretically reversible process (Galus 1994). In order solutions the ratio of anodic peak current to cathodic peak current deviated greatly from unity. Therefore, the optimum condition for voltammetric determination of studied phenothiazine derivatives were 0.1 HClO4 and phosphate buffer of pH 2 which were chosen for all further measurements as the best supporting electrolytes. Moreover, peak potentials of studied compounds hardly shift with pH increasing from 1 to 7, which means that electrochemical oxidation of phenothiazine derivatives is just a single electron transfer process and no proton transfer occurs (Figure 5, the first step).

Validation of the Analytical Procedure The determinations of phenothiazine derivatives (chlorpromazine hydrochloride, thioridazine hydrochloride, and propericiazine) were carried out in aqueous media at a glassy carbon electrode using electrochemical techniques. We selected differential pulse voltammetry (DPV) and square-wave voltammetry (SWV) methods. These electroanalytical techniques are effective and rapid with well-established advantages, including good discrimination against background current, and low detection and determination limits (Faulkner and Bard 1998; Heineman and Kissinger 1996). The best conditions for analytical application proved to be 0.1 M HClO4 or phosphate buffer of pH 2. These solutions were selected, both for DPV and SWV techniques, as supporting electrolytes. Pulse amplitude variation in the DPV method indicated that 50 mV results in the most intense peaks, and 50 ms was chosen as the pulse width due to the most symmetrical peak shape. The optimum interval time was found to be 0.2 s. Pulse amplitude variation in the SWV method indicated that 25 mV results in the most intense peaks; 15 Hz was chosen as the frequency, with a step potential of 4 mV due to the sharpest peak shape. According to obtained results, it is possible to apply DPV and SWV techniques to the quantitative analysis of some phenothiazine derivatives. Quantitative evaluation is based on the dependence of the peak current on the phenothiazine derivative concentration. Anodic peak current increased linearly with increasing amounts of CPM, TR, or PRC by DPV and SWV methods (Figs. 9 and 10). Two calibration equations from the standard solutions of studied phenothiazine derivatives, according to procedures previously described, were constructed using DPV and SWV techniques. The calibration plot characteristics are shown in Table 2. The limit of detection (LOD) and limit of quantification (LOQ) were calculated on the peak current using the following equation (Miller and Miller 1988), LOD ¼ 3 s=m

LOQ ¼ 10 s=m

where s, the noise estimate, is the standard deviation of the peak current

Voltammetric Determination in Pharmaceuticals


Figure 9. DPV voltammograms of TR in phosphate buffer at pH 2, pulse amplitude 50 mV; pulse width 50 ms; interval time 0.2 s; concentration range 3.2 . 1026 27.5 . 1024 M.

Figure 10. SWV voltammograms of CPM in 0.1 M HClO4; pulse amplitude 25 mV; frequency 15 Hz; step potential 4 mV; concentration range 2.4 . 1026 24.8 . 1024 M.

800 Table 2. Regression data of the calibration lines for quantitative determinations of thioridazine (TR), chlorpromazine (CPM), and propericiazine (PRC) by DPV and SWV methods DPV

Working electrode potential (V) (vs. SCE) Linearity range (M)













3.2  1026 to 7.5  1024 15 1.6  104 0.070 0.9998 0.9 7.5  1027 2.5  1026 1.25

2.4  1026 to 4.8  1024 15 2.2  104 0.057 0.9995 8.7 6.0  1027 2.0  1026 2.26

3.2  1026 to 1.2  1023 15 1.6  104 0.001 0.9999 8.0 7.0  1027 2.3  1026 2.21

3.2  1026 to 7.5  1024 15 2.05  104 0.136 0.9992 7.5 7.15  1027 2.4  1026 1.50

2.4  1026 to 4.8  1024 15 4.1  104 0.062 0.9992 4.65 3.0  1027 9.8  1026 1.80

3.2  1026 to 1.2  1023 15 2.60  104 0.094 0.9999 2.0 3.6  1027 1.2  1026 1.68



















K. Mielech-Łukasiewicz et al.

Number of data points Slope (mA M21) Intercept (mA) Correlation coefficient (r) R.S.D.% of slope LOD (M) LOQ (M) Repeatability of peak current (R.S.D.%) Repeatability of peak potential (R.S.D.%) Reproducibility of peak current (R.S.D.%) Reproducibility of peak potential (R.S.D.%)


Voltammetric Determination in Pharmaceuticals


(five runs) of the blank, and m is the slope of the calibration curve. The LOD and LOQ values are shown in Table 2. The repeatability and reproducibility of peak potentials and peak currents were tested by repeating six experiments on 4 . 1024 M CPM, TR, or PRC for both techniques. The selected concentrations were assayed with related calibration curves to determine within-day (repeatability) and between-day (reproducibility) variability. The within-day and between-day precision, accuracy, and reproducibility were determined as the R.S.D.% and results are shown in Table 2. Results shown in Table 2 demonstrate good precision, accuracy, and reproducibility of the proposed procedures.

Assay of Chlorpromazine, Thioridazine in Tablets The proposed methods were applied to the direct determination of chlorpromazine and thioridazine in pharmaceutical dosage forms. These procedures were successfully applied to the analysis of Promazinw and Thioridazinw tablets without the need for any pretreatment step prior to analysis. Ten capsules were analyzed by the procedure described in the experimental section. Well-defined differential pulse and square-wave peaks were obtained and no interferences were observed. The amounts of chlorpromazine Table 3. Comparative CPM and TR studies from pharmaceutical dosage forms Chlorpromazine HCl

Labeled claim (mg) Amount found (mg)a R.S.D.% 95% Confidence limit Bias% Added (mg) Found (mg)a Recovery% R.S.D.% of recovery Bias% a



Official methodb



Official methodc













0.315 0.097

0.177 0.055

0.170 0.054

0.204 0.063

0.261 0.081

0.201 0.059

0.48 1.776 1.766 99.45 0.963

0.44 1.776 1.782 100.35 0.751

0.40 1.776 1.780 100.4 0.758

0.20 2.035 2.026 99.57 0.498

0.36 2.035 2.020 99.27 0.717

0.12 2.035 2.024 99.55 0.654



– 0.225




Each value is the mean of five experiments. European Farmacopoeia Fourth Edition 2001. c Polish Farmacopoeia VI 2002. b

Thioridazine HCl

802 Table 4.

K. Mielech-Łukasiewicz et al. The effect of interference on the determination of phenothiazine derivativesa

Tolerance ratio 200 100 50

Compounds added microcrystalline cellulose, lactose, glucose, starch, tartaric acid, Mg2þ Ca2þ, Cu2þ, citric acid, magnesium stearate, Pb2þ, Cd2þ, Zn2þ, Fe2þ


The tolerance limit was taken as the concentration causing an error + 5%.

or thioridazine in tablets was calculated by reference to the appropriate calibration plots. The results obtained are given in Table 3. Due to the accuracy of the developed methods, we also carried out a recovery study. For the recovery studies, the standard addition method was used. The results in Table 3 demonstrate the validity of the proposed techniques for the determination of chlorpromazine and thioridazine in pharmaceutical dosage forms. The proposed DPV and SWV techniques proved to be sufficiently precise and accurate for reliable analysis of studied substances. Moreover, several excipients used in the pharmaceutical formulations, reducing compounds, and electroactive ions were investigated for their interference for the determination of 1 . 1024 M studied phenothiazine derivatives. The tolerance limit was taken as the concentration causing an error + 5%. The results are shown in Table 4. Excipients presented in tablets do not interfere with analysis, except for some electroactive ions (e.g., Pb2þ, Cd2þ), which are similar in anodic peak potential to studied phenothiazines. Promazinw and Thioridazinw are single-component preparations (one biologically active substance). The ingredients contained within a tablet mass, as given by the manufacturer, do not disturb the determination of a main constituent in optimal conditions. The CPM and TR pharmaceutical dosage forms were also determined with official pharmacopoeial methods, which are proposed for comparison with the DPV and SWV techniques. The results obtained for the pharmaceutical dosage forms by electroanalytical and official methods are listed in Table 3. The results show no significant difference between pharmacopoeial and proposed methods with regard to precision and accuracy, but voltammetric assays are more sensitive, simple, and rapid than official methods, without the need for any pretreatment step prior to analysis.

CONCLUSION This paper, on the electrochemical behavior of some 2, 10-disubstituted phenothiazines (chlorpromazine, thioridazine, and propericiazine) at glassy carbon electrode, has described how the compounds are reversibly oxidized

Voltammetric Determination in Pharmaceuticals


at about 0.59 –0.75 V potentials. Cyclic voltammetric measurements showed a reversible oxidation of studied compounds at all studied pH values and buffers investigated. Two voltammetric techniques—DPV and SWV—have been developed for the determination of PF in pharmaceutical dosage forms. The developed determination methods of PF are based on electrochemical oxidation of these substances to cation radicals. The direct oxidation of phenothiazine derivatives at bare glassy carbon electrode is simple and the electrode does not foul the oxidation product, therefore it is not necessary to use a modified electrode. Using the proposed procedures, it takes less than 5 min to run samples. The analyses were performed without any interference from additives present in the tablets. The methods are simple, sensitive, and do not require the expensive grades of solutions that are needed for HPLC procedures.

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Voltammetric Determination in Pharmaceuticals


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