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PVC membrane Sensor Immobilized with Clopidogrel-Tetraiodo Bismuthate for the Potentiometric Determination of Clopidogrel from Pharmaceutical Formulations
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ScienceDirect Materials Today: Proceedings 5 (2018) 17812–17819
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ICMPC_2018
PVC membrane Sensor Immobilized with Clopidogrel-Tetraiodo Bismuthate for the Potentiometric Determination of Clopidogrel from Pharmaceutical Formulations Santhy A ,Beena Saraswathyamma*, , Uma Sankar P,Vidya R and Rejithamol R Department of Chemistry, Amrita Vishwa Vidyapeetham, Amritapuri, India
Abstract This paper describes the fabrication of potentiometric PVC membrane for clopidogrel bisulphate and its successful utilization in the determination clopidogrel from clopilet tablet. Effect of PVC membrane matrix were studied and optimized membrane composition which ensued a Nernstian slope of 58.83±0.340mV/decade was found to be PVC 32%, ion association 3%,NaTBP 2% and DBP 63 % respectively. Sensor revealed a fast response time of 3s in the concentration range 1×10-2 -1×10-6 M with a lower detection limit of 9.12 ×10-7M. Working pH range and response time was found to be 2.0 - 4.5 and 5s respectively. Comparative studies on the various parameters that depend on the potential response of the present sensor with that of the literature reports were also included. © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of Materials Processing and characterization. Keywords:Potentiometry; clopidogrel; clopidogrel-tetraidobismuthate; PVC membrane sensor
1. Introduction Clopidogrel bisulphate (Fig.1) is an antiplatelet agent belonging to the class of thienopyridine [1-2]. It is one of the most effective and safe medicine that has been given to the stroke and heart patients to reduce the risk of these events. Clopidogrel irreversibly impedes the platelet aggregation, thereby lowers the chance of heart attacks and stroke [3-4]. It is also given as an alternative antiplatelet drug for patients allergic to aspirin or, in
* Corresponding author. Tel.: 09495188217. Email [email protected] 2214-7853© 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of Materials Processing and characterization.
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combination with aspirin, for the prevention of thrombosis [5-7]. UV spectrophotometry [8-10], 1H-NMR and a chiral HPLC [11], HPLC [12-14], HPTLC [15-16], HPLCMS/MS [17] and capillary electrophoresis [18-20] are the some of the analytical methods reported in literature for the trace level determination of clopidogrel. Major draw backs of these methods are expensive, required multiple sample preparation and qualified operators are required. On the contrary potentiometric sensors offers a highly selective, sensitive and economical method for the analysis pharmaceuticals. They are also well suited for the miniaturization. In continuation to the fabrication of potentiometric sensors for metal ions and pharmaceuticals [21-24], this work describes the fabrication of highly sensitive and selective potentiometric PVC membrane sensor for clopidogrel. CLOP-tetraiodo bismuthate ion association is used as the sensing material for the construction of this novel sensor.
Fig. 1. Structure of clopidogrel bisulphate
2. Experimental 2.1. Materials and chemicals Bis(ethylhexyl) phthalate (DOP), di-n-butyl phthalate (DBP), di-n-butyl sebacate (DBS) and Benzyl butyl phalate (BBP) were procured from Alfa Aesar (USA) and were used as such. Potassium iodide, bismuth nitrate, ascorbic acid, urea, glucose, maltose and all other metal salts were procured from Merck. Clopidogrel bisulphate and its dosage form are obtained as gift from KVSR Siddhartha College of Pharmaceutical Sciences, India. Stock solution of 10-2 M clopidogrel solution was prepared by transferring 0.419g of clopidogrel bisulphate to 100mL standard flask and made up to the mark with double distilled water. Serial dilution of stock solution and all other solutions were prepared in double distilled water. 2.2. Fabrication of PVC membrane electrode Preparation of CLOP-tetraiodo bismuthate association was achieved by mixing equal proportions of tetraiodo bismuthate solution and CLOP in water. Dark orange coloured precipitate formed is filtered, washed and dried. PVC membrane incorporating ion association (3%), PVC (32%), DBP (63%) and NaTBP (2%) was prepared by dissolving respective matrix components in 10ml tetrahydrofuran. The resulting solution is poured in to petri dish (7cm diameter) and kept overnight for evaporation of the solvent. Thin (ᵙ 0.1mm thickness) transparent membrane acquired is cut to size and pasted to one end of a glass tube. 1×10-2 M CLOP solution was taken in the tube as internal solution and the electrode was conditioned by dipping in 10-2 M CLOP solution for one day. Silver-silver chloride electrode was used as internal reference electrode and electrode was kept in the same analyte solution when not in use.
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2.3 Apparatus Emf measurements were carried out in a Metrohm 781 ion meter at 250.1C with Ag/AgCl as reference electrode. The cell assembly involved the measurements is given as Ag/AgCl| KCl || test solution |membrane | internal solution (10-2M CLOP) || KCl | AgCl/Ag. 2.4. Characterization of Ion association CLOP-tetraiodo bismuthate ion association was characterized by CHN analysis. The data is given in table 1.The experimentally obtained CHN values are in close agreement with theoretically calculated results which confirms the formation of ion association in 1:1 ratio. Table 1.CHN Data of CLOP-Tetraiodobismuthate ion association CHN Data
Experimental
Calculated
C%
16.7
16.91
N%
1.2
1.23
H%
1.4
1.60
2.5 Construction of Calibration Graph 25 mL of clopidogrel solution of varying concentration, 1×10-2 - 1×10-7 M was transferred to 50 mL beakers. Cell assembly was completed by immersing CLOP-tetraiodo bismuthate based PVC membrane sensor and Ag/AgCl reference electrode. EMF readings were noted after stabilization to ±0.2mV.Calibration graph was developed by plotting EMF against –log [CLOP]. 2. Result and Discussion Clopidogrel reacted readily with tetraiodo bismuthate solution to give an orange solid. The formation of CLOPtetraiodo bismuthate ion association is confirmed by CHN analysis. Data analysis showed that composition is 1:1 CLOP:tetraiodo bismuthate. 3.1. Optimization of membrane composition Nature and amount of sensor matrix components such as PVC, electro active component, plasticizer and additive are found to influence on the response characteristics of the sensor. Primarily, to understand the effect of plasticizer on the sensitivity and selectivity of the membrane sensor, four different plasticizers were tested and results obtained are compiled in the fig 2. Electrode based on DBP exhibited best Nenrstian response and hence further studies were carried out with this plasticizer. Effect of NaTBP as additive on the performance of the developed sensor was studied and results are shown in table 2. From the table 2 it is obvious that inclusion of 2 % NaTBP as additive in the sensor matrix improves the linear concentration range of the sensor from 10-5 to 10-6. It not only increases the concentration range but also improves response time and reproducibility of the sensor. Optimized amount was found to be 2%. .
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Fig. 2.Effect of plasticizer on the potential response of the PVC membrane sensor
Table 2. Optimization of PVC matrix based on CLOP-Tetraiodo bismuthate ion Association Sensor No. Ion association
Compositi on (%) PVC
Plasticizer
1
3
32
DOP 65
2
3
32
DBS 65
3
3
32
DBP, 65
4
3
32
BBP,65
Concentration range(M)
Slope (mV/decade)
1×10-4 -1×10-7
71.9±0.65
NaTBP
Not straight line 1×10-2 -1×10-5
40.70±0.54 Not straight line
1×10-2 -1×10-6
58.67±0.51
2
1×10-2 -1×10-6 1×10-2 -1×10-6
70.34±0.65 50.67±0.45
1
1×10-2 -1×10-6
52.37±0.55
5
3
32
DBP, 63
2
6
4
32
DBP, 62
2
7
2
32
DBP, 64
8
3
32
DBP, 64
Percentage of ion association in sensor matrix also varied and results are given in the table 2. Senor membrane incorporating 3 % ion association has given a slope of 58.6 mV/decade in the concentration range1×10-2 - 1×10-6 M. The lower detection limit is found to be 9.12×10-7 M (sensor no.5). The optimized membrane composition which exhibited best response in terms of slope and linear concentration range was found to be 3% ion association, 32% PVC, 2% NaTBP and 63% DBP (sensor No.5). The calibration graph obtained with the sensor 5 is shown in fig. 3 and response characteristics of the sensor is compiled in table 3.
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Fig.3.Calibration graph for the clopidogrel senor
Table 3. Response characteristics of the PVC membrane sensor Parameters
Response of the PVC membrane electrode
Working conc. range (M)
1×10-2 -1×10--6 M
pH
2.0 – 4.5
Response time(s)
5s
Slope (mV/decade)
58.670±0.51
Detection limit
9.12×10-7 M
Shelf life
7 weeks
Standard deviation
±0.51
3.2. Dynamic response time and reproducibility Response time of the developed sensor is recorded after the successive immersion of the sensor in clopidogrel solution of varying concentration from 1×10-2 - 1×10-7 M. Response time of the sensor to attain a stable potential within ±1mV is found to be 5s .
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Reproducibility of the sensor is monitored by measuring the potential response of the sensor over the concentration range 1×10-2 - 1×10-7 M for a period of 8 weeks and slope of each calibration graph is evaluated. The slope of the calibration graphs were found to be reproducible to within ±1mV for a period of 7 weeks. After that the slope was found to decrease which may be due to the leaching of the membrane constituents. Hence the shelf life of the sensor was noted as 7 weeks and response characteristics of the sensor are compiled in table 3. 3.3. Effect of pH on the potential response of the sensor Variation in the Potential response of the sensor with respect to change pH of the analyte solution was studied by using 1×10-3 M and 1×10-4clopidogrel solution in the pH range 1 to 5 and results are shown as Figure 4. pH was brought down by adding small volume of 0.1 M HCl and increased by the drop wise addition of 0.1 M NaOH solution. It is obvious from the figure that sensor response remains constant over the pH range2.0 to 4.5. Increase in the electrode potential below 1.8 may be due to the response of sensor towards H+ and decrease in the potential value above pH 4can be ascribed to increase of OH- concentration [25].
Fig.4. Effect of pH on the response of the clopidogrel sensor
3.4. Selectivity Ability of the present sensor to discriminate between clopidogrel and other certain organic and inorganic compounds and ions was tested by separate solution method. The selectivity coefficients were calculated by the equation Log KPotCLOP, Jz+ = (E2-E1)/S+ Log [CLP] – Log [ Jz+]1/z [26-27]. Where Kpot is the selectivity coefficient, E1 is the potential response of the electrode in 1×10-3 M CLP solution, E2 is the electrode potential in 1×10-3 M solution of the interferent ion Jz+ and S is the slope of the calibration graph. The selectivity coefficients obtained are presented in table 4.The KPotCLP, Jz+ values shown in table 4 reveals that developed sensor is highly selective to clopidogrel in presence of other ions or compounds tested.
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Table 4. Selectivity Interferents
Selectivity coefficient, KpotCLOP,JZ+
Na+
2.53×10-4
+
3.51×10-4
NH4+
3.56×10-4
K
3+
Fe
5.70×10-5
Mn2+
1.87×10-5
Ni
2+
6.15×10-5
Mg2+
2.35×10-5
Glucose
3.68×10-3
Urea
2.34×10-3
Ascorbic acid
2.56×10-3
3.5.Analytical application The practical utility of the proposed sensor was tested by applying the electrode for the determination of clopidogrel in clopilet tablets. Standard addition method and calibration method were used for the clopidogrel determination and results are shown in table 5. It is obvious from the table that the proposed sensor can be successfully applied for the determination of clopidogrel in pharmaceutical formulations. Table 5. Determination of CLOP in Clopilet tablet by calibration method and standard addition method Taken(mg)
Weight of sample
% Recovery
RSD %
Standard addition
5.2mg
98.1
0.64
method
7.2 mg
98.5
0.53
10.5 mg
99.1
0.46
Calibration
5.2 mg
98.4
0.46
method
7.2 mg
98.1
0.74
10.5 mg
98.6
0.51
3.6. Comparative Study of the Developed Sensor with Some of the Reported Sensors Table 6 compares various parameters that affect the perfo rmance of the newly developed sensor with those of the literature reports. The sensor showed comparable working concentration range, pH and response time with respect to the other clopidogrel sensors reported in literature [3, 28-29]. Table 6. Comparative study of Performance Characteristics of the proposed sensor with that of the Literature reports Working conc.
pH
range (M)
Response
Slope
time(s)
(mV/decade)
Shelf life/day
Detection
Reference
limit(mol/L)
1×10-2 -1×10-7
1.2- 4.6
20
55.97±0.460
25
5.01x 10-8
24
1×10-2 -1×10-7
1.2- 4.8
8
60.0±0.5
Fresh surface
3.4 x 10-8
25
1×10-2 -1×10-5
1.5- 4.0
-
61.7, 59.3
70
5.0 x 10-5, 4.0 x 10-5
26
1×10-2 -1×10-7
1.8-4.0
5
50.7±0.54
30
2.901x 10-8
CLOP
(CMCPE)
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Conclusion Clopidogrel-teraiodo bismuthate ion association based PVC membrane sensor has been fabricated for the determination of clopidogrel bisulphate. The sensor showed comparable working concentration range, pH and response time with respect to the other clopidogrel sensors reported in literature. Acknowledgments The authors are grateful to Dr. Devalo Rao, Principal, KVSR Siddhartha College of Pharmaceutical Sciences, India, for giving the clopidogrel bisulphate as a gift sample. References [1] S. Budavari, "The Merck Index” 13th Ed. Merck & Co. Inc., P. 856, 2011. [2] W. Henein, "ATLAS 2 everything about drugs from A to Z", Nobar publisher., 2006, P. 282. [3] S. F. bin-Ibrahim, N. A. Alarfaj and F. A. Aly, Journal of American Science. 8(2012) 276-283. [4] Y.Gomes, E. Adams, J. Hoogmartens, J.Pharma. Biomed. Anal. 34 (2004) 341-348. [5]S. Rossi, “Australian Medicines Handbook” 2006. Adelaide: “Australian Medicines Handbook”, ISBN 0-9757919-2-3, 2006. [6] M. D Randall, and Karen E Neil, “Disease management”, 2nd ed., London: Pharmaceutical Press. 159, 2004. [7]"Clopidogrel Bisulfate", The American Society of Health-System Pharmacists. Retrieved 8 December 2016. [8]N.S. Yogita Shete, Y.V. Mahajan, R.L. Pore, B.S. Kuchekar, Int. J. Chem. Sci. 7(2009) 216-218. [9]M.D. Game, K.B. Gabhane, D.M. Sakarkar, Ind. J. Phama. Sci. 72 (2010) 825-828. [10]S. Gurav, R. Tembare, V. Salunkhe, Devprakash, G.P. Senthilkumar, J. Pharma. Tech. Res. vol.1 (2011) 258-263. [11]M. Reist, M. Roy, J.P. Montseny, J.M. Mayer,Drug Metab. Dispos.28 (2000) 1405–1410. [12]A.L Saber, M.A. Elmosallamy, A.A. Amin, H. Killa, J. Food Drug Anal. 16 (2007) 11–18. [13]L. Shu-qin, L. Jian-wen, H. Ji, S. Xiao-fan, S. Jin, H. Zhong-qui, J. Shen. Pharma. Univ. 25 (2008) 983–986. [14]M. K. Javed, Z. Iqbal, A. Khan, Y. Shah, L. Ahmed, J. Liq. Chromatogr. Related Technol34 (2011) 2118–2129. [15]R. B. Petal, M.B Shankar, M. R. Petal, K. K. Bhatt, J. AOAC. Int. 91 (2008) 750–755. [16]P. K. Sinha, M. C. Damel, K. G. Bothara, J. Anal. Chem.vol. 4 (2009) 152–160,. [17]L. Silvestro, M. Gheorghe, A. Iorachescu, V .Ciuca, Anal. Bional. 401 (2011) 1023–1034. [18]A. S. Fayed, S.A. Weshahy, M. A. Shehata, N. Y. Hassan, J. Pharma. Biomed. Anal. 49 (2009) 193–200. [19] M. Karazniewicz, F. Glowka, G. Oszkinis, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 878 (2010) 1013–1018. [20]H. Serra, M. Bronze, B. Simplicio, J. Chromtogr. B Anal. Technol. Biomed. Life Sci. vol. 878 (2010) 1480–1486. [21]S. Beena, K. Girish Kumar,International Journal of Advanced Research in Chemical Science. 3 (2016) 30-37. [22]S. Beena, K. Girish Kumar, Asian Journal of Chemistry. 29 (2017) 1296-1300. [23]S. Beena, P.Marta, J. Radecki, M.Wouter, D. Wim, K.Girish Kumar, H.Redecka, Electroanalysis. 20 (2008) 2009. [24]S. Beena, A.Santhy, R.Vidya, P.Uma Sankar, R.Rejithamol, IEEE International (biennial) Conference on “Technological Advancements in Power & Energy- 2017" (accepted for publication). [25]A. Nawal Alarfaj, F. A. Aly, J. Chil. Chem. Socl. 57 (2012) 1140-1145. [26]A. N. Alarfaj, F. A. Aly, M. El-Tohamy, Sensor Lett. 9 (2011) 1-8. [27]P. B. Cholke, R. Ahmed, S.Z. Chemate, K. R. Jadhave, Arch. Appli. Sci. Res. 4 (2012) 59-64. [28]A. F. Khorshid, Arabian Journal of Chemistry. 5 ( 2014). [29]A. Lotfy Saber, M. Alaa Elmosallamy, A. Alside Amin, H. Mohmed Ahmed Killa,Journal of Food and Drug Analysis. 16 (2008) 11-18.
ScienceDirect Materials Today: Proceedings 5 (2018) 17812–17819
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ICMPC_2018
PVC membrane Sensor Immobilized with Clopidogrel-Tetraiodo Bismuthate for the Potentiometric Determination of Clopidogrel from Pharmaceutical Formulations Santhy A ,Beena Saraswathyamma*, , Uma Sankar P,Vidya R and Rejithamol R Department of Chemistry, Amrita Vishwa Vidyapeetham, Amritapuri, India
Abstract This paper describes the fabrication of potentiometric PVC membrane for clopidogrel bisulphate and its successful utilization in the determination clopidogrel from clopilet tablet. Effect of PVC membrane matrix were studied and optimized membrane composition which ensued a Nernstian slope of 58.83±0.340mV/decade was found to be PVC 32%, ion association 3%,NaTBP 2% and DBP 63 % respectively. Sensor revealed a fast response time of 3s in the concentration range 1×10-2 -1×10-6 M with a lower detection limit of 9.12 ×10-7M. Working pH range and response time was found to be 2.0 - 4.5 and 5s respectively. Comparative studies on the various parameters that depend on the potential response of the present sensor with that of the literature reports were also included. © 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of Materials Processing and characterization. Keywords:Potentiometry; clopidogrel; clopidogrel-tetraidobismuthate; PVC membrane sensor
1. Introduction Clopidogrel bisulphate (Fig.1) is an antiplatelet agent belonging to the class of thienopyridine [1-2]. It is one of the most effective and safe medicine that has been given to the stroke and heart patients to reduce the risk of these events. Clopidogrel irreversibly impedes the platelet aggregation, thereby lowers the chance of heart attacks and stroke [3-4]. It is also given as an alternative antiplatelet drug for patients allergic to aspirin or, in
* Corresponding author. Tel.: 09495188217. Email [email protected] 2214-7853© 2018 Elsevier Ltd. All rights reserved. Selection and/or Peer-review under responsibility of Materials Processing and characterization.
Beena Saraswathyamma et al. / Materials Today: Proceedings 5 (2018) 17812–17819
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combination with aspirin, for the prevention of thrombosis [5-7]. UV spectrophotometry [8-10], 1H-NMR and a chiral HPLC [11], HPLC [12-14], HPTLC [15-16], HPLCMS/MS [17] and capillary electrophoresis [18-20] are the some of the analytical methods reported in literature for the trace level determination of clopidogrel. Major draw backs of these methods are expensive, required multiple sample preparation and qualified operators are required. On the contrary potentiometric sensors offers a highly selective, sensitive and economical method for the analysis pharmaceuticals. They are also well suited for the miniaturization. In continuation to the fabrication of potentiometric sensors for metal ions and pharmaceuticals [21-24], this work describes the fabrication of highly sensitive and selective potentiometric PVC membrane sensor for clopidogrel. CLOP-tetraiodo bismuthate ion association is used as the sensing material for the construction of this novel sensor.
Fig. 1. Structure of clopidogrel bisulphate
2. Experimental 2.1. Materials and chemicals Bis(ethylhexyl) phthalate (DOP), di-n-butyl phthalate (DBP), di-n-butyl sebacate (DBS) and Benzyl butyl phalate (BBP) were procured from Alfa Aesar (USA) and were used as such. Potassium iodide, bismuth nitrate, ascorbic acid, urea, glucose, maltose and all other metal salts were procured from Merck. Clopidogrel bisulphate and its dosage form are obtained as gift from KVSR Siddhartha College of Pharmaceutical Sciences, India. Stock solution of 10-2 M clopidogrel solution was prepared by transferring 0.419g of clopidogrel bisulphate to 100mL standard flask and made up to the mark with double distilled water. Serial dilution of stock solution and all other solutions were prepared in double distilled water. 2.2. Fabrication of PVC membrane electrode Preparation of CLOP-tetraiodo bismuthate association was achieved by mixing equal proportions of tetraiodo bismuthate solution and CLOP in water. Dark orange coloured precipitate formed is filtered, washed and dried. PVC membrane incorporating ion association (3%), PVC (32%), DBP (63%) and NaTBP (2%) was prepared by dissolving respective matrix components in 10ml tetrahydrofuran. The resulting solution is poured in to petri dish (7cm diameter) and kept overnight for evaporation of the solvent. Thin (ᵙ 0.1mm thickness) transparent membrane acquired is cut to size and pasted to one end of a glass tube. 1×10-2 M CLOP solution was taken in the tube as internal solution and the electrode was conditioned by dipping in 10-2 M CLOP solution for one day. Silver-silver chloride electrode was used as internal reference electrode and electrode was kept in the same analyte solution when not in use.
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2.3 Apparatus Emf measurements were carried out in a Metrohm 781 ion meter at 250.1C with Ag/AgCl as reference electrode. The cell assembly involved the measurements is given as Ag/AgCl| KCl || test solution |membrane | internal solution (10-2M CLOP) || KCl | AgCl/Ag. 2.4. Characterization of Ion association CLOP-tetraiodo bismuthate ion association was characterized by CHN analysis. The data is given in table 1.The experimentally obtained CHN values are in close agreement with theoretically calculated results which confirms the formation of ion association in 1:1 ratio. Table 1.CHN Data of CLOP-Tetraiodobismuthate ion association CHN Data
Experimental
Calculated
C%
16.7
16.91
N%
1.2
1.23
H%
1.4
1.60
2.5 Construction of Calibration Graph 25 mL of clopidogrel solution of varying concentration, 1×10-2 - 1×10-7 M was transferred to 50 mL beakers. Cell assembly was completed by immersing CLOP-tetraiodo bismuthate based PVC membrane sensor and Ag/AgCl reference electrode. EMF readings were noted after stabilization to ±0.2mV.Calibration graph was developed by plotting EMF against –log [CLOP]. 2. Result and Discussion Clopidogrel reacted readily with tetraiodo bismuthate solution to give an orange solid. The formation of CLOPtetraiodo bismuthate ion association is confirmed by CHN analysis. Data analysis showed that composition is 1:1 CLOP:tetraiodo bismuthate. 3.1. Optimization of membrane composition Nature and amount of sensor matrix components such as PVC, electro active component, plasticizer and additive are found to influence on the response characteristics of the sensor. Primarily, to understand the effect of plasticizer on the sensitivity and selectivity of the membrane sensor, four different plasticizers were tested and results obtained are compiled in the fig 2. Electrode based on DBP exhibited best Nenrstian response and hence further studies were carried out with this plasticizer. Effect of NaTBP as additive on the performance of the developed sensor was studied and results are shown in table 2. From the table 2 it is obvious that inclusion of 2 % NaTBP as additive in the sensor matrix improves the linear concentration range of the sensor from 10-5 to 10-6. It not only increases the concentration range but also improves response time and reproducibility of the sensor. Optimized amount was found to be 2%. .
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Fig. 2.Effect of plasticizer on the potential response of the PVC membrane sensor
Table 2. Optimization of PVC matrix based on CLOP-Tetraiodo bismuthate ion Association Sensor No. Ion association
Compositi on (%) PVC
Plasticizer
1
3
32
DOP 65
2
3
32
DBS 65
3
3
32
DBP, 65
4
3
32
BBP,65
Concentration range(M)
Slope (mV/decade)
1×10-4 -1×10-7
71.9±0.65
NaTBP
Not straight line 1×10-2 -1×10-5
40.70±0.54 Not straight line
1×10-2 -1×10-6
58.67±0.51
2
1×10-2 -1×10-6 1×10-2 -1×10-6
70.34±0.65 50.67±0.45
1
1×10-2 -1×10-6
52.37±0.55
5
3
32
DBP, 63
2
6
4
32
DBP, 62
2
7
2
32
DBP, 64
8
3
32
DBP, 64
Percentage of ion association in sensor matrix also varied and results are given in the table 2. Senor membrane incorporating 3 % ion association has given a slope of 58.6 mV/decade in the concentration range1×10-2 - 1×10-6 M. The lower detection limit is found to be 9.12×10-7 M (sensor no.5). The optimized membrane composition which exhibited best response in terms of slope and linear concentration range was found to be 3% ion association, 32% PVC, 2% NaTBP and 63% DBP (sensor No.5). The calibration graph obtained with the sensor 5 is shown in fig. 3 and response characteristics of the sensor is compiled in table 3.
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Fig.3.Calibration graph for the clopidogrel senor
Table 3. Response characteristics of the PVC membrane sensor Parameters
Response of the PVC membrane electrode
Working conc. range (M)
1×10-2 -1×10--6 M
pH
2.0 – 4.5
Response time(s)
5s
Slope (mV/decade)
58.670±0.51
Detection limit
9.12×10-7 M
Shelf life
7 weeks
Standard deviation
±0.51
3.2. Dynamic response time and reproducibility Response time of the developed sensor is recorded after the successive immersion of the sensor in clopidogrel solution of varying concentration from 1×10-2 - 1×10-7 M. Response time of the sensor to attain a stable potential within ±1mV is found to be 5s .
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Reproducibility of the sensor is monitored by measuring the potential response of the sensor over the concentration range 1×10-2 - 1×10-7 M for a period of 8 weeks and slope of each calibration graph is evaluated. The slope of the calibration graphs were found to be reproducible to within ±1mV for a period of 7 weeks. After that the slope was found to decrease which may be due to the leaching of the membrane constituents. Hence the shelf life of the sensor was noted as 7 weeks and response characteristics of the sensor are compiled in table 3. 3.3. Effect of pH on the potential response of the sensor Variation in the Potential response of the sensor with respect to change pH of the analyte solution was studied by using 1×10-3 M and 1×10-4clopidogrel solution in the pH range 1 to 5 and results are shown as Figure 4. pH was brought down by adding small volume of 0.1 M HCl and increased by the drop wise addition of 0.1 M NaOH solution. It is obvious from the figure that sensor response remains constant over the pH range2.0 to 4.5. Increase in the electrode potential below 1.8 may be due to the response of sensor towards H+ and decrease in the potential value above pH 4can be ascribed to increase of OH- concentration [25].
Fig.4. Effect of pH on the response of the clopidogrel sensor
3.4. Selectivity Ability of the present sensor to discriminate between clopidogrel and other certain organic and inorganic compounds and ions was tested by separate solution method. The selectivity coefficients were calculated by the equation Log KPotCLOP, Jz+ = (E2-E1)/S+ Log [CLP] – Log [ Jz+]1/z [26-27]. Where Kpot is the selectivity coefficient, E1 is the potential response of the electrode in 1×10-3 M CLP solution, E2 is the electrode potential in 1×10-3 M solution of the interferent ion Jz+ and S is the slope of the calibration graph. The selectivity coefficients obtained are presented in table 4.The KPotCLP, Jz+ values shown in table 4 reveals that developed sensor is highly selective to clopidogrel in presence of other ions or compounds tested.
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Table 4. Selectivity Interferents
Selectivity coefficient, KpotCLOP,JZ+
Na+
2.53×10-4
+
3.51×10-4
NH4+
3.56×10-4
K
3+
Fe
5.70×10-5
Mn2+
1.87×10-5
Ni
2+
6.15×10-5
Mg2+
2.35×10-5
Glucose
3.68×10-3
Urea
2.34×10-3
Ascorbic acid
2.56×10-3
3.5.Analytical application The practical utility of the proposed sensor was tested by applying the electrode for the determination of clopidogrel in clopilet tablets. Standard addition method and calibration method were used for the clopidogrel determination and results are shown in table 5. It is obvious from the table that the proposed sensor can be successfully applied for the determination of clopidogrel in pharmaceutical formulations. Table 5. Determination of CLOP in Clopilet tablet by calibration method and standard addition method Taken(mg)
Weight of sample
% Recovery
RSD %
Standard addition
5.2mg
98.1
0.64
method
7.2 mg
98.5
0.53
10.5 mg
99.1
0.46
Calibration
5.2 mg
98.4
0.46
method
7.2 mg
98.1
0.74
10.5 mg
98.6
0.51
3.6. Comparative Study of the Developed Sensor with Some of the Reported Sensors Table 6 compares various parameters that affect the perfo rmance of the newly developed sensor with those of the literature reports. The sensor showed comparable working concentration range, pH and response time with respect to the other clopidogrel sensors reported in literature [3, 28-29]. Table 6. Comparative study of Performance Characteristics of the proposed sensor with that of the Literature reports Working conc.
pH
range (M)
Response
Slope
time(s)
(mV/decade)
Shelf life/day
Detection
Reference
limit(mol/L)
1×10-2 -1×10-7
1.2- 4.6
20
55.97±0.460
25
5.01x 10-8
24
1×10-2 -1×10-7
1.2- 4.8
8
60.0±0.5
Fresh surface
3.4 x 10-8
25
1×10-2 -1×10-5
1.5- 4.0
-
61.7, 59.3
70
5.0 x 10-5, 4.0 x 10-5
26
1×10-2 -1×10-7
1.8-4.0
5
50.7±0.54
30
2.901x 10-8
CLOP
(CMCPE)
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Conclusion Clopidogrel-teraiodo bismuthate ion association based PVC membrane sensor has been fabricated for the determination of clopidogrel bisulphate. The sensor showed comparable working concentration range, pH and response time with respect to the other clopidogrel sensors reported in literature. Acknowledgments The authors are grateful to Dr. Devalo Rao, Principal, KVSR Siddhartha College of Pharmaceutical Sciences, India, for giving the clopidogrel bisulphate as a gift sample. References [1] S. Budavari, "The Merck Index” 13th Ed. Merck & Co. Inc., P. 856, 2011. [2] W. Henein, "ATLAS 2 everything about drugs from A to Z", Nobar publisher., 2006, P. 282. [3] S. F. bin-Ibrahim, N. A. Alarfaj and F. A. Aly, Journal of American Science. 8(2012) 276-283. [4] Y.Gomes, E. Adams, J. Hoogmartens, J.Pharma. Biomed. Anal. 34 (2004) 341-348. [5]S. Rossi, “Australian Medicines Handbook” 2006. Adelaide: “Australian Medicines Handbook”, ISBN 0-9757919-2-3, 2006. [6] M. D Randall, and Karen E Neil, “Disease management”, 2nd ed., London: Pharmaceutical Press. 159, 2004. [7]"Clopidogrel Bisulfate", The American Society of Health-System Pharmacists. Retrieved 8 December 2016. [8]N.S. Yogita Shete, Y.V. Mahajan, R.L. Pore, B.S. Kuchekar, Int. J. Chem. Sci. 7(2009) 216-218. [9]M.D. Game, K.B. Gabhane, D.M. Sakarkar, Ind. J. Phama. Sci. 72 (2010) 825-828. [10]S. Gurav, R. Tembare, V. Salunkhe, Devprakash, G.P. Senthilkumar, J. Pharma. Tech. Res. vol.1 (2011) 258-263. [11]M. Reist, M. Roy, J.P. Montseny, J.M. Mayer,Drug Metab. Dispos.28 (2000) 1405–1410. [12]A.L Saber, M.A. Elmosallamy, A.A. Amin, H. Killa, J. Food Drug Anal. 16 (2007) 11–18. [13]L. Shu-qin, L. Jian-wen, H. Ji, S. Xiao-fan, S. Jin, H. Zhong-qui, J. Shen. Pharma. Univ. 25 (2008) 983–986. [14]M. K. Javed, Z. Iqbal, A. Khan, Y. Shah, L. Ahmed, J. Liq. Chromatogr. Related Technol34 (2011) 2118–2129. [15]R. B. Petal, M.B Shankar, M. R. Petal, K. K. Bhatt, J. AOAC. Int. 91 (2008) 750–755. [16]P. K. Sinha, M. C. Damel, K. G. Bothara, J. Anal. Chem.vol. 4 (2009) 152–160,. [17]L. Silvestro, M. Gheorghe, A. Iorachescu, V .Ciuca, Anal. Bional. 401 (2011) 1023–1034. [18]A. S. Fayed, S.A. Weshahy, M. A. Shehata, N. Y. Hassan, J. Pharma. Biomed. Anal. 49 (2009) 193–200. [19] M. Karazniewicz, F. Glowka, G. Oszkinis, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 878 (2010) 1013–1018. [20]H. Serra, M. Bronze, B. Simplicio, J. Chromtogr. B Anal. Technol. Biomed. Life Sci. vol. 878 (2010) 1480–1486. [21]S. Beena, K. Girish Kumar,International Journal of Advanced Research in Chemical Science. 3 (2016) 30-37. [22]S. Beena, K. Girish Kumar, Asian Journal of Chemistry. 29 (2017) 1296-1300. [23]S. Beena, P.Marta, J. Radecki, M.Wouter, D. Wim, K.Girish Kumar, H.Redecka, Electroanalysis. 20 (2008) 2009. [24]S. Beena, A.Santhy, R.Vidya, P.Uma Sankar, R.Rejithamol, IEEE International (biennial) Conference on “Technological Advancements in Power & Energy- 2017" (accepted for publication). [25]A. Nawal Alarfaj, F. A. Aly, J. Chil. Chem. Socl. 57 (2012) 1140-1145. [26]A. N. Alarfaj, F. A. Aly, M. El-Tohamy, Sensor Lett. 9 (2011) 1-8. [27]P. B. Cholke, R. Ahmed, S.Z. Chemate, K. R. Jadhave, Arch. Appli. Sci. Res. 4 (2012) 59-64. [28]A. F. Khorshid, Arabian Journal of Chemistry. 5 ( 2014). [29]A. Lotfy Saber, M. Alaa Elmosallamy, A. Alside Amin, H. Mohmed Ahmed Killa,Journal of Food and Drug Analysis. 16 (2008) 11-18.