A new coated-wire electrode based on clopidogrel-hexathiocyanato
ferrate (III) ion-pair

 

Ryad Kassab*, Mahmoud Aboudan

Department of Analytical Chemistry, Faculty of Sciences, University of Aleppo, Aleppo, Syria.

*Corresponding Author E-mail: ryadchem88@gmail.com

 

ABSTRACT:

A plasticized coated-wire PVC-membrane electrode for determination of clopidogrel bisulfate (CLPB), based on the formation of CLP-hexathiocyanato ferrate (III) ion-pair, was constructed and studied. The effect of different parameters including membrane composition, temperature, conditioning time, pH of the test solution, response time, and interferent species on the electrode performance, was also studied. The optimum electrode performance was accomplished with a membrane composition of 49.38% PVC and DOP, and 1.25% ion-pair complex. This electrode showed a linear response with a Nernstian slope of 59.58±1.19mV/decade over the concentration range 1.0×10-4 – 5.0×10-2M and was usable within the pH range 1.1–2.8. This sensor exhibited a relatively fast response time (about 22 s), a low detection limit (6.48×10-5 M), a long lifetime (>4 months, 2 h a day) and good thermal stability. The standard electrode potentials, E°, were determined at 25 – 80°C and used to calculate the isothermal temperature coefficient (dE°/dT) of the electrode. The highly selective electrode was successfully applied for the determination of clopidogrel bisulfate both in pure and pharmaceutical forms using potentiometric measurements. The obtained results were statistically analyzed in regards to both accuracy and precision and were compared to the U.S. pharmacopeial method where there no significant difference was observed.

 

KEYWORDS: Coated-wire electrode, Hexathiocyanato ferrate (III), Clopidogrel bisulfate, Ion-associate, Nernstian response.

 

 


INTRODUCTION: 

Ion-selective electrodes (ISEs) are electrochemical sensors that allow the potentiometric determination of particular ions’ activity in presence of other ions1,2 in both aqueous or mixed solvents2. Since they have been introduced to the field of pharmaceutical analysis, ISEs significantly led to increasing number of compounds that are determined potentiometrically.

 

Based on the membrane’s material, ion-selective electrodes are classified into glass, crystalline, and polymeric electrodes. Poly (vinyl chloride) (PVC) is the most popular polymer used in preparing polymeric ISE membranes3.

 

 

The conventional construction of ISEs usually consists of an internal solution, an internal reference electrode (often Ag/AgCl), and a sensing membrane that is in contact with the internal solution and the test solution.It is difficult to make small-size conventional electrodes with an internal solution and an internal electrode, and this will restrain their applications to the samples of small volumes such as the clinical and biological samples. For this reason, the researchers tried to eliminate both the internal solution and the internal electrode and replaced them with the so-called “solid- contact”3 that were first suggested by Hirata and Date4. Polymeric coated-wire electrodes (CWEs) refer to a type of solid-contact ion-selective electrode in which an electroactive species is incorporated in a thin polymeric film coated directly to a metallic conductor5. Due to their simplicity, ease of production, and small size construction, CWEs are of great interest for application in biology and medicine6.

 

 

If either the substance determined or the titrant (or both) have an adequate lipophilic character, a limited water-soluble ion-pair will be precipitated, this electroactive substance is extractable with organic solvents 6, and the sensed ion is in ion-exchange equilibrium with the electroactive material7.

 

Clopidogrel bisulfate (figure 1); C16H16ClNO2S.H2SO4 (Mw 419.9 g/mol); Thieno[3,2-c]pyridine-5(4H)-acetic acid, α-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (S)-, sulfate (1:1)8; is a thienopyridine antiplatelet drug used in thromboembolic disorders. It is a platelet P2Y12 -receptor antagonist that acts by inhibiting adenosine diphosphate-mediated platelet aggregation9.

 

Several analytical techniques have been reported for the determination of clopidogrel bisulfate including spectrophotometry10-19, high performance liquid chromatography (HPLC)20-31, and voltammetry32. CLP-silicotungstate, CLP-silicomolybdate, CLP- tetraphenylborate33, CLP-phosphotungstate, CLP-phosphomolybdate, and CLP-reineckate33,34 ion-pair compounds have been used for the potentiometric determination of clopidogrel bisulfate.

 

Figure 1: Chemical Structure of CLPB

 

Since CLPB carries a positive charge on the nitrogen atom (figure 1), the aim of this study was to use the negatively charged coordinate complex [Fe(SCN)6]3- as a new ion-pairing agent to the drug, consequently leading to be held together by electrostatic attraction forming the ion-pair precipitate CLP2[Fe(SCN)6] and hence determining CLPB selectively despite the presence of any interfering species. To achieve this, the prepared electroactive associate has been incorporated into a PVC matrix plasticized with dioctyl phthalate (DOP) to construct a new coated-wire selective electrode to the drug clopidogrel bisulfate. All affecting parameters on the electrode performance were thoroughly investigated.

 

MATERIALS AND METHODS:

Materials:

Clopidogrel bisulfate was provided by Cadchem Laboratories LTD (India). All chemicals and excipients were of analytical or pharmaceutical grade. All aqueous solutions were prepared using bi-distilled water. Tetrahydrofuran (THF) was from Riedel-de Haën, dioctyl phthalate (DOP) from Merck, and PVC of relatively high molecular weight was from Fluka.

 

Apparatus:

Potentiometric measurements were carried out using digital Multimeter (UNI-T, China) with an accuracy of ±0.1 mV. pH meter (Sartorious, Germany). Electronic balance with an accuracy of ±0.1mg (Sartorious, Germany). Ultrasonic waves apparatus (Wisd, Korea). HPLC instrument with an autosampler (Agilent 1200, USA). Magnetic stirrer with hotplate (Wisd, Korea).

 

Standard solutions:

A stock solution of clopidogrel bisulfate (0.1M) was prepared by dissolving an appropriate amount of the substance in hydrochloric acid (HCl, pH 1.0) and then sonicated until the drug was completely dissolved. Other dilute solutions (0.7×10-1 – 1.0×10-5 M) were prepared by serial dilution.

 

Preparation of the electroactive material:

A 50mL of the coordinate complex [Fe(SCN)6]3- (0.0625M), was first prepared by adding 20.625mmol (10% excess) of KSCN solution to 3.125 mmol of FeCl3 solution.The ion-pair complex CLP-[Fe(SCN)6] was prepared from an aqueous medium by adding (50ml, 0.0625 M) [Fe(SCN)6]3- complex solution to 6.25mmol clopidogrel bisulfate solution (100mL, 0.0625M) prepared in HCl as described previously to yield a deep red precipitate, which was filtered, washed thoroughly with distilled water, and finally dried at room temperature. The predicted composition of the ion-associate complex has a molar ratio of 1:2 and a suggested formula of CLP2[Fe(SCN)6]. This composition was predicted using the complete precipitation method; in brief, increasing known amounts of complex solution were added to the drug solution, and the precipitate was filtered after each addition until complete precipitation is achieved.

 

Coating solution preparation and CWE construction:

The polymeric matrix solution was prepared by dissolving equal weights of PVC and the plasticizer (DOP) in an adequate amount of THF solvent. The matrix was mixed with the ion-pair complex (IP) dissolved in a minimum amount of THF. The solvent was allowed to evaporate until a thick solution is obtained.

 

The coated wire was prepared as described in Ref 5. The exposed Ag wire was firstly washed with suitable detergent and water, then it was dried with acetone, and finally rinsed with chloroform and allowed to dry. The Ag wire was placed vertically to achieve a uniform coating. The wire was coated by quickly dipping about 2 cm of the exposed Ag wire into the coating solution several times and then the film of PVC solution was left on the wire to dry in air for about 1min. The dipping and drying procedure is repeated until a plastic bead, with an approximate diameter of 2mm, is obtained. The coated membrane was allowed to dry in air for a few hours, then the coated wire was installed in the electrode’s body which in turn was in conjunction with an external Ag/AgCl reference electrode that is immersed into 1M KCl electrolyte. The constructed CWE electrode is represented as follows:

 

Ag ǀ Membrane ǀ Test solution ǀ KCl 1M solution ǀ AgCl, Ag

 

Selectivity of the electrode:

The selectivity of the electrode was studied in presence of some inorganic ions, excipients and pharmaceuticals that may be included in the pharmaceutical formulations of the drug. We used the matched potential method (MPM) that has been advocated by IUPAC in a technical report35 to calculate the selectivity coefficients . In this method, a specific amount of primary ion (àA) is added to a reference solution (aA) and the membrane potential is measured. In a separate experiment, interfering ions (aB) are successively added to an identical reference solution until the membrane potential matches the one obtained before with the primary ion. The selectivity coefficient is then defined by the ratio of the primary ion and interfering ion activity increases in both experiments36:

 

Results and discussioN:

Pre-conditioning the electrode:

The response of the freshly prepared electrodes is usually slow and hard to reproduce. Hence, proper function of ISEs requires pre-conditioning. This process usually involves soaking the electrode into a solution of the ion to be sensed, followed by repeated measurements until the response is rapid and reproducible 37. The electrode after removing from the conditioning solution, should be rinsed and soaked for 10 – 20 min in deionized water prior to calibration5.

 

The prepared sensor was soaked into a solution of 0.01M CLPB at different times and the calibration graphs were plotted. The membrane required very short soaking time and was found to be 1 hour to get Nernstian response within the concentration range of 1.0×10-4 – 5.0×10-2 M.

 

Optimum membrane composition and electrode characteristics:

Different compositions of coating solution were prepared. These membranes have variant percentages of ion-pair substance (0.5 – 3.0 %) and equal amounts of PVC and DOP plasticizer. The calibration curve of E, mV vs. the negative logarithm of the drug concentration (pCdrug) of each composition was constructed. The slope, linear range, limit of detection, and correlation coefficient were determined from the corresponding calibration curve and are given in (Table 1). The electrode No. 3 showed the best Nernstian response with a slope of 59.58±1.19mV/decade, where it was chosen for the latter study of further parameters.

 

Table 1: Composition and analytical characteristics of the prepared electrodes

No.

Coated membrane %

Slope, mV/decade

R2

Linear range, M

LOD, M

PVC and DOP

IP

1

49.75

0.5

55.08

0.9992

1.0×10-4 – 2.5×10-2

8.01×10-5

2

49.50

1.0

57.91

0.9995

1.0×10-4 – 5.0×10-2

7.91×10-5

3

49.38

1.25

59.58

0.9998

1.0×10-4 – 5.0×10-2

6.48×10-5

4

49.25

1.5

60.04

0.9995

1.0×10-4 – 5.0×10-2

6.98×10-5

5

49.00

2.0

56.79

0.9991

1.0×10-4 – 5.0×10-2

7.07×10-5

6

48.75

2.5

52.22

0.9990

1.0×10-4 – 2.5×10-2

8.45×10-5

7

48.50

3.0

47.31

0.9988

1.0×10-4 – 2.5×10-2

8.74×10-5

 

Effect of pH:

The effect of pH of the drug solution on potential measurements was investigated by adding very small volumes of concentrated HCl or NaOH solutions to the test solution. The potential readings were plotted against the pH-values within the concentration range 1.0×10-3 – 1.0×10-4 M, (figure 2). Practically, the potential values were found to be independent from pH values over the range of 1.1 – 2.8 and hence the sensor can be safely used for determination of CLPB within the suggested working pH range. At low pH values, the potential response is often affected by the interference of hydrogen ions. Whereas at pH values higher than 2.8, the CLPB solution starts to precipitate and the emf readings considerably decrease leading to the fact that the practical pH range is limited to the drug solubility.

 

Figure 2: Effect of pH of the test solution on the potentiometric readings

 

Lifetime of CWE:

It is well-established that the loss of plasticizer, carrier, or ionic site from the polymeric film due to leaching into the sample is a primary reason for limited lifetimes of carrier-based sensors36. This usually leads to a slow decrease in slope over the ISE lifetime3. The operational lifetime of the prepared sensor was estimated by continuous soaking of the electrode into a 0.01M solution of CLPB at room temperature and thereafter, the calibration graphs of E, mV vs. pCCLPB were plotted. The slopes of calibration curves were Nernstian even after soaking the electrode continuously for 240 hours with no change in the linear concentration range, so the constructed CWE can be used for at least 10 days (4 months, 2 h/day) with no noticeable decrease in slope.

 

Response time:

The response time of ISE is the length of time which elapses between the instant at which an ion-selective electrode and a reference electrode are brought into contact with a sample solution and the first instant at which the potential of the cell becomes equal to its steady-state value within 1mV38. In this study, the practical response time was recorded for different concentrations of CLPB solution within 1.0×10-4 to 1.0×10-2 M starting from the lower to the higher concentration. The plot of the potential readings vs. time for the response of the CLP-Fe(SCN)6 electrode, is shown in (figure 3), where the sensor reaches the equilibrium response in about 22 ± 2 sec.

 

Figure 3: Potential-time curve for response time of CLBB electrode


Temperature coefficients:

To study the thermal stability of the prepared sensor, the calibration curves of the potential E, mV vs. pCdrug at different temperatures of the test solution ranging from 25℃ to 80℃, were plotted. The slopes and standard electrode potentials were directly determined from the calibration curve where E° was obtained as intercept when pCdrug = 0, (Table 2). Later, E° values at different temperatures were plotted vs. (t-25), where t is the temperature of the test solution. A straight-line plot was obtained according to the following Antropov equation39:

 

The slope of E° vs. (t-25) plot represents the isothermal coefficients dE°/dT of the sensor (figure 4), which is equal to 1.44 mV/℃ amounting to 1.44×10-3 V/℃ within 25 – 60℃ temperatures range. This small value reveals a good thermal stability of the electrode. However, unlike to the conventional type of PVC membranes, this CWE electrode showed better thermal resistance and still useful to be used, with near Nernstian response at higher temperatures up to 80 ℃.

 

Table 2: Response characteristics at different temperatures

Temperature (℃)

Slope (mV/decade)

E° (mV)

25

55.28

111.69

30

56.21

121.98

40

59.57

137.01

50

61.74

153.07

60

60.88

161.47

65

56.39

153.26

70

54.86

147.77

80

53.85

143.48

 

Figure 4: Standard potentials at different temperatures

 

Selectivity:

The selectivity coefficients presented in (Table 3) showed that the prepared sensor is highly selective to clopidogrel cation CLP+ in presence of common inorganic ions where some of them may coordinate to complexes with electroactive components. The results reveal that the sugars, which are usually formulated in pharmaceutical preparations, and aspirin which is combined with clopidogrel in some dosage forms also do not interfere.

 

Table 3: Potentiometric selectivity coefficients determined by MPM method at 25℃

Interferent

Interferent

K+

2.18×10-3

Zn2+

1.48×10-4

Na+

3.15×10-3

Fe3+

9.30×10-5

NH4+

7.97×10-4

SCN-

2.18×10-3

Ca2+

9.70×10-4

NO2-

5.18×10-3

Mg2+

7.03×10-4

Aspirin

7.62×10-3

Ni2+

9.39×10-5

Lactose

1.68×10-4

Cu2+

7.64×10-5

Mannitol

1.07×10-4

Co2+

7.30×10-5

Sucrose

1.27×10-4

 

Characteristics of the electrode:

The response and performance characteristics of the fabricated coated-wire electrode under the aforementioned experimental conditions are summarized in (Table 4), while the calibration curve of the optimal membrane electrode is shown in (figure 5).

 

Table 4: Performance and operating characteristics of CLPB electrode

Parameter

CLP-Fe(SCN)6 CWE

Composition, % w/w

Ion Pair 1.25, PVC and DOP 49.38

Slope, mV/decade

59.58 ± 1.19

R2

0.9998

Linear range, M

1.0×10-4 – 5.0×10-2

Detection Limit, M

6.48×10-5

Conditioning time, hour

1

Response time, sec

22 ± 2

Working pH range

1.1 – 2.8

Lifetime, months

> 4

 

Figure 5: Potentiometric response curve for optimum electrode

 

Analytical Application:

The present coated-wire electrode has been used successfully for potentiometric determination of clopidogrel bisulfate in pure form and in its dosage forms by applying the standard curve method. The potentiometric responses were plotted against pCCLPB within the linear concentration range. The mean recoveries as well the relative standard deviations that are given in (Table 5), were calculated after five replicates, where the results indicate to the good accuracy and precision of the proposed method as recoveries ranged from 97.13 to 102.81% with acceptable RSDs (1.91–3.29%).

 

The assay of clopidogrel CLP in its solid formulations has been performed. Clobeden 75mg tablets (Barakat Pharma) and the combined dosage form of clopidogrel with aspirin in Plavispirin 75/75 tablets (City Pharma) were purchased from local pharmacies. The results of five replicates of each pharmaceutical form are shown in (Table 6). The validity of the proposed method was tested by applying both Student’s t - and F-tests (at 95% confidence limit)40. The results show that the calculated t - and F-values did not exceed the tabulated values at the corresponding degrees of freedom asshown in (Table 6), and the assay results were in good agreement with those obtained by applying the official HPLC method.

 

Table 5: Statistical and analytical results for determination of clopidogrel bisulfate in pure solutions

Ctaken

Cfound± SD, mg/L

Recovery %

RSD %

M

mg/L

1.0×10-4

41.99

41.74 ± 1.37

99.40

3.29

5.0×10-4

209.95

215.85 ± 6.37

102.81

2.95

1.0×10-3

419.90

407.84 ± 12.31

97.13

3.02

5.0×10-3

2.100×103

2.111×103 ± 65.22

100.52

3.09

1.0×10-2

4.199×103

4.243×103± 81.04

101.05

1.91

2.5×10-2

1.050×104

1.051×104± 238.74

100.10

2.27

5.0×10-2

2.100×104

2.083×104± 455.39

99.19

2.19

Table 6: Assay results for determination of clopidogrel in tablets

Sample

± SD (mg/Tab)

Assay %

RSD %

t-value a

F-value b

Clopeden 75

77.36 ± 1.32

103.15

1.71

1.75

9.90

HPLC method

76.25 ± 0.42

101.66

   0.55 c

Plavispirin 75/75

79.21 ± 1.47

105.61

1.85

1.64

8.28

HPLC method

78.03 ± 0.51

104.41

   0.65 c

aTabulated t-value is ~ 2.57.

bTabulated one-tailed F-value (4, 2) is 19.25.

cAverage of three determinations.

 

Conclusion:

The fabricated coated wire electrode equipped with PVC membrane containing the co-ordinate complex hexathiocyanato ferrate (III) as a new ion-pairing agent has proven to be useful device for direct potentiometric determination of clopidogrel bisulfate in pure form and pharmaceutical products. It shows good accuracy and precision besides being of low cost, reliable, and easy to use tool without a need to complicated instruments. The sensor has good operating characteristics presented in Nernstian slope, short conditioning time, high thermal stability within wide range of temperatures, and relative long lifetime. The analytical results for the determination of CLP in Plavispirin tablets compared to the US pharmacopeial method reflects the high selectivity of the electrode in combined dosage formulations of clopidogrel with aspirin.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

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Received on 14.11.2022            Modified on 31.01.2023

Accepted on 21.03.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(9):4329-4335.

DOI: 10.52711/0974-360X.2023.00709