Sensors and Actuators B 109 (2005) 278–284

Carbon-paste electrode modified with cobalt-5-nitrolsalophen as asensitive voltammetric sensor for detection of captopril

Saeed Shahrokhiana,∗, Mohammad Karimia, Habibollah Khajehsharifib

a Department of Chemistry, Sharif University of Technology, Tehran 11365-9516, Iranb Department of Chemistry, Yasouj University, Yasouj, Iran

Received 6 September 2004; received in revised form 19 December 2004; accepted 29 December 2004Available online 30 January 2005

Abstract

The electrochemical behavior of captopril at the surface of a carbon-paste electrode (CPE) modified with cobalt-5-nitrolsalophen (CoNSal)is described. The prepared electrode shows an excellent electrocatalytic activity toward the oxidation of captopril, which is leading to markedlowering in the anodic overpotential and considerable improvement of sensitivity (anodic current). Whereas at the surface of unmodifiedelectrode an electrochemical activity for captopril cannot be observed, a very sharp anodic wave with an anodic peak potential about 650 mV( (II) redoxc ak currentf elopmento rminationo ) and verys©

K etry

ChwRpa[dtrebsb

ica-nsti-taste,leed-esseet,dys-

rted

nivingthe

liq-

s

0d

versus Ag/AgCl) is obtained using the prepared modified electrode. This catalytic wave is assigned to mediating of Co(III)/Coouple in the anodic oxidation of captopril. The substantial decrease in the overvoltage and significant improvement of anodic peor captopril associated with high stability of CoNSal in the matrix of modified CPE (compared to cobalt salophen); allow the devf a highly sensitive voltammetric sensor for the detection of captopril. The resulted electrode is used for the voltammetric detef captopril pharmaceutical and clinical (human serum) preparations. The results show that a very good precision (R.S.D. < 2.5%table voltammetric response toward captopril.2005 Elsevier B.V. All rights reserved.

eywords:Cobalt-5-nitrolsalophen; Electrocatalysis; Modified electrode; Carbon paste; Captopril; Cyclic voltammetry; Differential pulse voltamm

aptopril is an angiotensin converting enzyme (ACE) in-ibitor. This medication work to block an enzyme system,hich causes artery walls to relax, reducing blood pressure.elaxing the arteries, and as a consequence lowering of bloodressure, improves the pumping efficiency of a failing heartnd improves cardiac output in patients with heart failure

1,2]. Other uses of captopril have also reported including,ecreasing high blood pressure caused by blood vessels in

he kidneys, decreasing symptoms of cystinuria, reducingheumatoid arthritis symptoms, treating Raynaud’s phenom-na and progression of kidney disease in peoples with dia-etes[1–3]. Captopril is generally well tolerated and someide effects are reported for it. A dry, persistent cough haseen reported with the use of captopril and other ACE in-

∗ Corresponding author. Tel.: +98 21 6005718; fax: +98 21 6012983.E-mail address:shahrokhian@sharif.edu (S. Shahrokhian).

hibitors. Coughing resolves after discontinuing the medtion. Other side effects are include abdominal pain, copation, diarrhea, dizziness, fatigue, headache, loss ofloss of appetite, nausea and vomiting, easy bruising or bing, chest pain, chills, difficulty breathing, severe dizzinor fainting, fever, numbness or tingling in the hands or frash, and a sore or swollen throat. In rare instances, liverfunction and skin yellowing (jaundice) have been repowith captopril[1–3].

Captopril (1-(3-mercapto-2-methyl-1-oxopropyl)-l-pro-line) with a thiol ( SH) functional group and was showthat may also act as a scavenger of free radicals in lsystems[4–6]. Several methods have been applied fordetermination of captopril, including high performanceuid chromatography[7–10], photometry[5,11], fluorometry[12], capillary electrophoresis[13], flow injection analysi(FIA) [14] and sequential injection analysis (SIA)[15].

925-4005/$ – see front matter © 2005 Elsevier B.V. All rights reserved.oi:10.1016/j.snb.2004.12.059

S. Shahrokhian et al. / Sensors and Actuators B 109 (2005) 278–284 279

Captopril with its thiol group can undergoes in elec-trochemical oxidation at the surface of various electrodes[14–16]. Electrochemical oxidation of this compound us-ing boron-doped electrodes has been performed in alka-line medium and a relatively broad and irreversible anodicpeak has been obtained at∼0.8 V versus Ag/AgCl. At thesurface of glassy carbon (GC) as working electrode, how-ever, an ill-defined irreversible oxidation peak is reported[14].

Chemically modified electrodes (CMEs) have continuedto be of major concern during the past decade and a rela-tively large amount of electrochemical research has been de-voted to the development and applications of different typesof CMEs [17–20]. Modification of electrodes with suitablebiocompatible materials enables the electrochemistry of theredox biological compounds to proceed without hindrance[21–23]. This phenomenon generally results in increased se-lectivity and sensitivity of the determinations[24–26]. It hasbeen known for a number of years that certain transitionmetal complexes with phthalocyanines[18,27], porphyrins[28,29] and Schiff bases[19] can catalyze, via reduction oftheir central metal ions, the electro-oxidation of some chem-ical and biological important compounds. A number of thesecompounds, as mediators in modified electrodes, have beencharacterized for electrocatalysis of sulfhydryl compoundssuch as cysteine and its derivatives[17], glutathione[30], 2-to c-t ility,a eenw ifiede cur-r odes[

al)w oxi-d rode( re-a etryi elec-t ptabler olara ara-t

1

1

,2-p om-pn ide( andp

structure of synthesized complex was performed by IR,1Hand 13C NMR, UV–vis and elemental analysis. Graphitepowder and spectroscopic mineral oil (Nujol) were purchasedfrom Merck. N-[(S)-mercapto-2-methyl]-l-proline (Capto-pril) was prepared from Fluka. All other chemicals wereof analytical reagent grade from Merck. Tablets of captoprilwere prepared from Exir pharmaceutical Company (Tehran,Iran). A carefully weighted amount of tablets (100 mg) wasdissolved in 1 l appropriate buffer solution (0.1 M acetatebuffer with pH 5.0) and 20.00 ml of this was applied forvoltammetric determination by DPV techniques in the stan-dard addition mode. All aqueous solutions were preparedwith doubly distilled deionized water. Human serum sam-ples for recovery tests were prepared from Razi vaccine andserum institute (Tehran, Iran). In order to evaluation of theaccuracy of method, 10.00 ml of human serum sample wasdiluted to 100.0 ml (with 0.1 M acetate buffer with pH 5.0)and 20.00 of the diluted solution were spiked with differentamounts of captopril solution.

Stock solutions of captopril were freshly prepared as re-quired in 0.10 M phosphate or acetate buffer at the desiredpH (3.0–7.0) and purged with pure nitrogen gas (99.999%)for 5 min before the voltammetric measurements. Voltam-metric experiments were carried out in the buffered solutionsof cysteine and ascorbic acid, deoxygenated by purging thep ringt ace oft thes

1

aM VA.A ith ac ed),a e ast er-S uffers te inv

1

d bym eralo es-t urew i.d.).E owni odi-fi ositew eingd by am hen,

hioglycolic acid[18], penicillamine[19], captopril[14] andther sulfhydryl compounds[20,31,32]. Carbon-paste ele

rodes, due to the ease of their construction, renewabnd compatibility with various types of modifiers, have bidely used as a suitable matrix for preparation of modlectrodes. Further, they show rather low backgroundent compared to solid graphite or noble metal electr33].

In the present work, cobalt(II)-5nitrosalophen (CoNSas used as a very efficient catalyst in electrochemicalation of captopril using a modified carbon-paste electCPE). Preliminary studies in order to appointment ofction mechanism were carried out by cyclic voltamm

n various pHs and potential sweep rates. The modifiedrode was applied as a very sensitive sensor with an acceeproducibility and accuracy in the detection of micrommounts of captopril in pharmaceutical and clinical prep

ions using differential pulse voltammetry (DPV).

. Experimental

.1. Reagents

Cobalt(II) chloride, 5-nitrosalicylaldehyde and 1henylenediamine for synthesis of the Schiff base clex were prepared from Merck. The complexN,N′-bis(5-itrosalicylidene)-1,2-phenylenediamino-cobalt(II) chlorcobalt(II)-5-nitrosalophen, CoNSal), was synthesizedurified as reported previously[34–36]. Identification of the

ure nitrogen (99.999% from Roham Gas Company). Duhe experiments, nitrogen gas was passed over the surfest solutions in order to avoid entrance of oxygen intoolution.

.2. Apparatus

Voltammetric experiments were performed withetrohm Computrace Voltammetric Analyser model 757conventional three-electrode system was used w

arbon-paste working electrode (unmodified or modifisaturated Ag/AgCl reference electrode and a Pt wir

he counter electrode. A digital pH/mV/Ion meter (Cybcan model 2500) was applied for the preparing of the bolutions, which were used as the supporting electrolyoltammetric experiments.

.3. Preparation of modified electrode

The unmodified carbon-paste electrode was prepareixing graphite powder with appropriate amount of minil (Nujol) and thorough hand mixing in a mortar and p

le (∼75:25, w/w), and a portion of the composite mixtas packed into the end of a Teflon tube (ca. 2.5 mmlectrical contact was made by forcing a copper pin d

nto the Teflon and into the back of the composite. The med electrode was prepared by mixing unmodified compith CoNSal (2%, w/w) and then the composite was bissolved in dichloromethane. The mixture was stirredagnetic stirrer till the solvent evaporated, completely. T

280 S. Shahrokhian et al. / Sensors and Actuators B 109 (2005) 278–284

the modified composite was then air dried for 24 h and usedin the same way as unmodified electrode.

2. Results and discussion

2.1. Cyclic voltammetric studies of captopril

Fig. 1shows the cyclic voltammograms for 1 mM capto-pril in buffered solution with pH 5.0 (0.1 M acetate) at thesurface of unmodified (dashed line) and modified CPE withCoNSal (solid line) in the potential range of 0.3–0.8 V versusAg/AgCl. A well-defined and very sharp irreversible oxida-tion peak at∼600 mV is obtained using modified CPE asworking electrode, whereas, at the unmodified electrode ananodic peak cannot be observed for captopril. This signifi-cant improvement of peak current together with the sharp-ness of anodic peak may be related to a remarkable reductionin the anodic overpotential of the process at the surface ofmodified electrode. Observation of such behavior for cap-topril, which is observed in different concentrations (in therange of 1× 10−4 to 1× 10−3 M) and also various poten-tial sweep rates between 10 and 100 mV s−1, clearly demon-strate that CoNSal acts as an efficient electron mediator in theelectrocatalytic oxidation of captopril, leading to a consid-e ently,i ity).A rvedo nge.T itha ofp ap-t

F od-i .1 Ma

Fig. 2. (A) Variation of anodic peak potential with the pH of buffer solution atthe modified electrode for 1 mM of captopril in a sweep rate of 100 mV s−1.(B) Differential pulse voltammograms for 0.1 mM captopril in various pHsof the buffered solutions; (—) pH = 3.0. (· · ·) pH = 4.0, (– – –) pH = 5.0 and(– ·· – ·· –) (0.1 M acetate is used for pH 4, 5 and 0.1 M phosphate is used forpHs 3, 6).

The effect of the pH of buffer solution on the electrochem-ical oxidation of captopril was investigated in the pH rangeof 3.0–7.0. As can be seen inFig. 2(A), a cathodic (negative)shift in anodic potential peak is occurred by increasing of thepH of buffer solution. The calibration curve ofEp,aversus pH,in the pH range of 4.0–7.0, has a slope of−37.4 mV pH−1

and a correlation coefficient of 0.9982. With respect to loss ofan electron in the electro-oxidation of captopril, contributionof a proton is accepted in the process. Captopril is a dibasicacid having dissociation constants pk1 = 3.7 (carboxyl group)and pk2 = 9.8 (thiol group)[37]. Therefore, in solutions withpH less than 3.7 it can be observed that a clear inflection pointfor variation of anodic peak potential. The differential pulsevoltammetric results for 0.1 mM captopril in various pHs,which is shown inFig. 2(B), showed that upon raising of the

rable decreasing in anodic overpotential and consequmprovement of anodic peak current (analytical sensitivt all potential sweep rates, no cathodic peak was obsen the reverse scan within the investigated potential rahis voltammetric behavior implies an EC mechanism wn irreversible following chemical reaction (dimerizationroduced thiol radical) during the electro-oxidation of c

opril.

ig. 1. Cyclic voltammograms of 1 mM captopril at the surface of unmfied CPE (dashed lines) and CoNSal-modified CPE (solid line), in 0cetate buffer solution with pH 5.0. Sweep rate was 100 mV s−1.

S. Shahrokhian et al. / Sensors and Actuators B 109 (2005) 278–284 281

Fig. 3. (A) Cyclic voltammograms of 1 mM captopril at CoNSal-modifiedelectrode in various sweep rates. (B) Variation of anodic peak current withpotential sweep rate (υ). Electrolyte was 0.1 M acetate buffer solution withpH 5.0.

pH of solution, up to 5.0, the anodic peak current is increasedand after with a obvious decreasing is resulted. Therefore,the pH 5.0 was selected as an optimum condition in order toobtain maximum sensitivity in quantitative analytical mea-surements. Such a behavior can be related to instability ofcaptopril in higher pH values and its graduate atmosphericoxidation caused to dissolved oxygen. Like behavior havebeen already reported for other sulfhydryl compounds e.g.cysteine, penicillamine, 2-thiouracil and 2-thiobarbituric acid[17,19,20].

Cyclic voltammograms of 1 mM captopril in buffered so-lution with pH 5.0 in various potential sweep rates wereshown inFig. 3(A). Peak current for anodic oxidation ofcaptopril (Ip,a) at the surface of modified electrode showsa linear variation with potential sweep rate (υ) in therange of 10–100 mV s−1 revealing an adsorption-like be-

havior of corresponding mechanism (Fig. 3). Statistical datafor this regression analysis (Ip,a=a+bυ) shows a slope of0.07�A mV−1 s andR2 = 0.9981. The results revealed thatthe electrocatalytic oxidation of captopril at the surface ofCoNSal-modified electrode may be proceed via the formationof an adsorbed adduct from axial coordination of the thiolateanion of captopril and the central metal cation (Co3+) in thecenter of planar Schiff base complex. Such a behavior, whichis observed also at other studied pH values (3.0–6.0), couldbe a sufficient reason for obtaining a very sharp anodic wavefor captopril oxidation using the modified electrode. Baldwinand co-workers has already observed such a behavior for theincorporation of the complexation step in the mechanism ofelectrocatalytic oxidation of cysteine, homocysteine and glu-tathione at modified CPE with CoPc, resulting of adsorption-like cyclic voltammograms[27].

Values ofαna (α is the transfer coefficient andna is thenumber of electrons involved in the rate-determining step)were calculated for the irreversible oxidation of captopril ac-cording to the equationαna = 0.0477/(Ep −Ep/2) [38]. Forthe compound, the value ofαna at the modified electrodeis obtained between 0.42 and 0.46 in the investigated po-tential sweep rate (10–100 mV s−1) and various pHs. In thisirreversible system, presume a value of 0.5 forα in this ir-reversible system, the results indeed suggest a one-electrontransfer process in the rate-determining step in the mecha-n

ch-a n ofc Theo utedt ap-tu :

C

R

2 )

R alo-c ctro-c o isc ox-i t inm cesst (II)s gCl).B ida-t ple( e re-s s, iti m-p ofc forc Cl),

ism of electrocatalytic oxidation of captopril.It results from the mentioned above, the following me

nism can be presented for the electrocatalytic oxidatioaptopril at the surface of CoNSal-modified electrode.verall oxidative reaction process can therefore be attribo first the initial one electron, one proton oxidation of copril (RSH) to generate the radical species RS• which canndergo rapid dimerization to form the disulfide (RSSR)

o(II)MSal → Co(III)MSal + e− (1)

SH + Co(III)MSal → RS• + Co(II)MSal + H+ (2)

RS• → RSSR (fast) (3

esults of previous studies on the catalytic effect of phthyanine and Schiff base complexes of cobalt in the elehemical oxidation of thiols have been shown that, Capable to catalyze the thiol oxidation in both 2+ and 3+dation state[18–20,27,31]. These results are shown tha

ore acidic conditions, the most probable oxidation prohat occurred, is referred to catalytic effect of Co(III)/Coystem (peak potentials greater than 0.6 V versus Ag/Aut, in neutral and some extent alkaline conditions, ox

ion of thiols is catalyzed by Co(II)/Co(I) mediator couwith a considerably less peak potential). Based on thults of the present work and also from previous studies confirmed that in the applied conditions, the Co(III) colex (CoIII MSal) catalyzes the electrochemical oxidationaptopril. The anodic peak potential, which is observedaptopril in the study (greater than 600 mV versus Ag/Ag

282 S. Shahrokhian et al. / Sensors and Actuators B 109 (2005) 278–284

Fig. 4. Differential pulse calibration curves for anodic current vs. captoprilconcentration in a background of 0.1 M acetate buffer (©), standard additionto a tablet sample buffered with 0.1 M acetate buffer with pH 5.0 (�).

is near to value that reported for Co(III)/Co(II) redox pair insome complexes of cobalt such as phthalocyanines[19,27].Remarkable decrease of voltammetric response of the modi-fied electrode upon the raising of pH can be related to lower-ing the catalytic activity of the mediator in these conditions.

2.2. Differential pulse voltammetric measurements

The DPV method was used as a very sensitive methodwith sub-micromolar detection limit for determination oftraces values of captopril. DPV waves for captopril wereobtained in 0.1 M acetate buffer (pH = 5.0) as backgroundelectrolyte. The calibration curve for these determinations,which is shown inFig. 4, exhibit a linear range of 4.0× 10−6

to 1.1× 10−4 M with a slope of 0.013�A �M−1 and a cor-relation coefficient of 0.9991 and a slope variation of 2.8%(n= 5). The detection limit for determination of captopril us-

ing this method was 1.1× 10−6 M (for S/N = 3). The detec-tion system is very stable and the R.S.D. (%) for the slopevariation, based on 10 measurements during 2 months, wasless∼4.2%.

The CoNSal-modified electrode was used as the workingelectrode for the determination of minor amounts of capto-pril in pharmaceutical preparations by DPV technique. Thestandard addition method was applied to drawing the currentdata for captopril concentrations added to the prepared tabletssamples. Linear calibration plot for this standard addition isshown inFig. 4. The precision of method for the determina-tion of captopril in the pharmaceutical preparations, based onfive replicates analysis, shows an R.S.D. of 3.5%. The meanvalue for captopril based on five replicates was 52 (±1) mg.

The prepared modified electrode was applied for obtain-ing the recovery results of the captopril added to the tabletand human serum samples. These results for various spikedamounts of captopril in acetate buffer (0.1 M, pH = 5.0) asbackground electrolyte were shown inTable 1. Experimen-tal conditions for these DPV measurements was similar asdescribed inTable 2. The excellent recovery results indicatethat the complex matrix of the human serum or pharmaceu-tical sample do not interfere with the detection of the minoramounts of captopril. Accuracy, detection limit and precisionin voltammetric measurements of captopril in the presentw duc-t altp withtp asp odifi-c aceb canb apto-p ari-s sm ofm itsv

Table 1Results of analysis of captopril tablets and recovery for added values of cap

Experiment Sample preparation Labeled vacaptopril (mg

)

1 Captopril tablet dissolved inbuffer solution, pH 5.0

50.0

2 Sample1 + 5 mgcaptopril –3 Sample 1 + 10 mg captopril –455678

d valuereplic

ith pH 5

Sample 1 + 15 mg captopril –Sample 1 + 20 mg captopril

c 10 ml serum + 1 mgcaptopril –c 10 ml serum + 3 mgcaptopril –c 10 ml serum + 8 mgcaptoprilc 10 ml serum + 10 mg captopril –a Amount of captopril (mg) in a powdered tablet containing a labeleb Values in parenthesis explain the standard deviation based on fivec Human serum samples containing 0.1 M acetate buffer solution w

ork is comparable the previous report based on conive carbon cement matrix chemically modified with cobhthalocyanine as an amperometric detector coupled

he high performance liquid chromatography[40]. In com-arison to this method[40], the CoNSal-modified CPE herformance characteristics, ease of preparation and mation and also simplicity of the renewability of its surfy simple polishing. Therefore, this voltammetric sensore used as a very highly sensitive detection device for cril in clinical and pharmaceutical preparations. In compon to CPE modified with CoSalophen[19], CoNSal showore lipophilic properties and more stability in the matrixodified electrode, leading to higher long time stability in

oltammetric responses.

topril to tablet preparations and human serum samples

lue of/tablet)a

Amount found for PA(mg/tablet)b

Recovery (%

51.8 (±1.5) –

57.1 (±1.8) 103.862.1 (±2.2) 103.564.1 (±2.5) 98.668.5 (±2.7) 97.71.08 (±0.09) 108.03.13 (±0.16) 104.37.79 (±0.32) 97.4

9.81 (±0.44) 98.1

of 50.0 mg/tablet.ates..0 (100-fold diluted).

S. Shahrokhian et al. / Sensors and Actuators B 109 (2005) 278–284 283

Table 2Differential pulse voltammetric parameters and response properties for the determination of captopril in pure buffered solutions and standard addition topharmaceutical and human serum preparations

Experiment Peak potential (mV) Pulse amplitude (mV) Linear range (�M) Detection limit (�M) Slope variation (%R.S.D.,n= 5)

Ia 515 (±5) 50 4.0–110.0 1.1 2.6IIb 530 (±5) 50 4.0–53.2 1.5 2.8III c 525 (±5) 50 8.4–45.7 3.5 3.1

a The experiment is related to the captopril added to the 25.0 ml of acetate buffer solution.b The experiment is related to the captopril added to the 25.0 ml of dissolved tablet sample (each tablet in 1 l of acetate buffer) containing 0.1 M acetatebuffer

solution.c The experiment is related to the captopril added to the 25.0 ml of diluted human serum sample (100 times with acetate buffer) containing 0.1 M acetate

buffer solution.

3. Conclusions

The results of the present work, exhibits the effective ruleof cobalt-5-nitrolsalophene (CoNSal) as electron mediatorin the matrix of carbon-paste electrode toward the electro-catalytic oxidation of captopril. The mechanism of electro-oxidation of captopril has been investigated by the cyclicvoltammetric studies. This modified electrode has been suc-cessfully applied as a selective and very sensitive voltammet-ric sensor for the detection of micromolar amounts of capto-pril in pharmaceutical and clinical preparations using differ-ential pulse voltammetric method. High sensitivity and lowdetection limit together with the very easy preparation andeasy regeneration of the electrode surface and also long timestability (respect to modified electrode with CoSalophen) andreproducibility makes the discussed system useful in the con-struction of simple devices for the determination of captopril.

Acknowledgement

The authors gratefully acknowledge financial support ofthe Research Council of Sharif University of Technology.

R

rilphy

01)

in-etric

icaletec-med.

ski,mnrm.

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Biographies

Saeed Shahrokhianreceived his BS degree in 1990, MS degree in 1994and PhD degree in 1999 from Isfahan University, Isfahan, Iran. Now, heis Associate Professor of Chemistry at Sharif University of Technology,Tehran, Iran.

Mohammad Karimi received his BS degree in 2001 and MS degree in2004 from Sharif University of Technology, Tehran, Iran.

H anU rsity,S rbiatM

Analyst 119 (1994) 259–263.33] K. Kalcher, J.M. Kaufmann, J. Wang, I. Svancara, K. Vytras

Neuhold, Z. Yang, Sensors based on carbon paste in electrochanalysis: a review with particular emphasis on the period 1990–Electroanalysis 7 (1995) 5–22.

abibollah Khajehsharifi received his BS degree in 1990 from Isfahniversity, Isfahan, Iran and MS degree in 1994 from Shiraz Univehiraz, Iran. Currently, he is studying for the degree of PhD at Taodarres University, Tehran, Iran.