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Amberlite XAD-4 modified electrodes for highly sensitive electrochemical determination of nimesulide in human urine
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Amberlite XAD-4 modified electrodes for highly sensitive electrochemical determination of nimesulide in human urine Nagaraj P. Shettia,b, , Mahesh M Shanbhaga,b, Shweta J Malodea,b, Rajesh K Srivastavac, ⁎ Kakarla Raghava Reddyd, ⁎
a
Center for Electrochemical Science and Materials, Department of Chemistry, K.L.E. Institute of Technology, Hubballi 580030, Karnataka, India Visvesvaraya Technological University, Belagavi 590018, Karnataka, India c Department of Biotechnology, GIT, Gitam Institute of Technology and Management (GITAM) (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India d School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia b
ARTICLE INFO
ABSTRACT
Keywords: Electrochemical sensor Urine Modified electrodes Voltammetry Electrochemical methods Biological samples
A Simple technique has been developed for electrochemical oxidation and determination of nimesulide (NIM) drug-using voltammetric techniques in phosphate buffer solutions. The modified sensor showed good stability, sensibility, and enhancement in the peak current with good reproducibility. Based on the variation of parameters and their results, the heterogeneous rate constant value was also calculated. The proposed sensor can be utilized for the analysis of the drug in biological and pharmaceutical samples with good recovery values. A suitable electrooxidation mechanism was proposed. The proposed technique was successfully employed for the determination of NIM in biological samples with good recovery results.
1. Introduction For the past few decades, more emphasis has been given out on research work. The research field is one of the immense disciplines in Science and Technology. In this area of investigation, pharmaceutical research is a fascinating area of the piece of research, which involves the discovery and development of new drugs and its control. There is a requirement for the exploration and improvement of a reliable analytical or diagnostic operation. As yet partition approaches, HPLC and its various techniques and electrochemical methods are utilized for the analyzing and the determination of the pharmaceutical drugs [1–5] Pharmaceutical, horticultural, food industry and environmental investigations have been developing quickly, because of advances in electrochemical sensing systems. Electrochemical sensors are the devices consisting of electrochemical transducers which generate the analytical data from the developed electrochemical information. They give quantitative and semiqualitative analytical details. The changes in electrical signals due to the reduction or oxidation reactions of analyte can be examined by several techniques. In this method current or potential is the measured assets. The electrochemical methods of investigation are getting more relevance in pharmaceutical research as a consequence of its extensive application. The high reproducibility of electroanalytical techniques
⁎
can offer an exact outcome when contrasted with different strategies [6]. The scope of this method is, the estimated electrical properties can be evaluated with techniques like conductometry, amperometry, potentiometry, and voltammetry, etc. The main importance or advantages of the electrochemical method in analysis is, it provides the devices with short analysis time, low costs, satisfactory detection limits, portability probability, etc, as it in was in case of pregnancy test glucose meters. Numerous electrochemical sensors have discovered everyday appliances, not only in laboratory purposes. The main priority of sensors or biodevices is to be actualized in healthcare applications [7–9] in the medical field, it means illness, mutation, infection at the first stages, etc. Early diagnosis is one of the strongest prevention methods, but still challenging due to high costs, strict sample preparation mechanism, and long-term analysis. Modern electrochemical technology can overcome these drawbacks by device miniaturization or rapid data output. Some sensitive and selective sensors were developed for the detection of biomolecules [10–13], biochemical species [14–16], and also employed these techniques in simultaneous determination of pharmaceutical drugs [17] or ion-selective sensors for determination pharmaceutical dosages [18,19] were found to be one of the great contributions towards developmental research. There are various kinds of voltammetric strategies that were utilized
Corresponding authors. E-mail addresses: [email protected] (N.P. Shetti), [email protected] (K.R. Reddy).
https://doi.org/10.1016/j.microc.2019.104389 Received 4 September 2019; Received in revised form 2 November 2019; Accepted 2 November 2019 0026-265X/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Nagaraj P. Shetti, et al., Microchemical Journal, https://doi.org/10.1016/j.microc.2019.104389
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training. Thus, a quick, simple and exact strategy with high sensitivity is relied upon to be established. From literature survey, we noted that early reported electrochemical methods used for the determination of NIM, which include utilization of mercury electrode [23], polarographic method [38], amperometric method [39, 40], carbon nanotubes and cysteic acidbased composite thin-film material at glassy carbon electrode [31], boron-doped diamond electrode [41], glassy carbon electrode utilized in which multiwalled carbon nanotubes used as modifier [32], TiO2 nanostructure modified carbon paste electrode [42], rGO and PEDOT: PSS modified sensor [43] and carbon black within dihexadecylphosphate modified sensor [44], spectrophotometric method [45] and potentiometric sensor [46]. The electrochemical analysis/determination of NIM at amberlite XAD-4 modified carbon paste electrode (CPE) has not been studied. By looking at the importance of NIM determination, we have constructed an amberlite XAD-4 resin-modified carbon paste electrode (XAD/CPE). We successfully applied the self-prepared modified electrode to determine NIM in the real samples. 2. Experimental
Fig 1. Chemical structure of NIM.
2.1. Chemicals and reagents
to determine the analyte under the test, out of which cyclic voltammetric procedure is enormously utilized technique, because of its peculiarities such as its ease, high affectability, selectivity, reproducibility, and quick dissecting capacity. The enhancement in the analyte and electrode superficial area collaboration is done by building up a modified electrode due to which above peculiarities can be improved. The modified electrodes as sensors are most ordinarily utilized in different electrochemical procedures because of incomparable properties, for example, huge focused area, great conductivity, and stability. Inflammation is a defensive response to crash the harmful upgrades and start the mending procedure. Intense inflammation leads to pain, warmth, rash, and swelling. Commonly inflammation effectuated by means of prostaglandin, they were created from arachidonate by the action of cyclooxygenase coenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory including those specific for limitation of cyclooxygenase-2 [20]. N-(4-nitro-2-phenoxyphenyl)methanesulfonamide, IUPAC name of NIM (C13H12N2O2S) (Fig. 1) is a decently recent non-steroidal anti-inflammatory drug (NSAID) with painrelieving and fever-lessening properties. Employed in the healing of intense pain, initial stages of dysmenorrhoea, the symptomatic remedy for osteoarthritis and rheumatoid arthritis [21,22]. It can lessen the rate of the arrangement of gastrointestinal ulcers. NIM, pKa estimation of 6.85 is significant for gastric acceptability, as it prevents the back diffusion of hydrogen ion in charge of tissue harm [23]. The half-life of NIM shifted from 1.8 - 4.7 hours. It is to a great extent eliminated by means of its metabolic form, 4-hydroxy derivative (M1), however minor metabolite type of NIM can be identified in urine and feces, essentially in conjugated form. The percentage of NIM (M1) discharged through urine and feces is observed to be 50.5 - 62.5% and 17.9 - 36.2% respectively for an orally administrated dose [22]. The metabolite may accumulate gradually in patients, which may cause renal or hepatic issues [24,25]. In this manner, its significance as bioactive molecules forces its examination, investigation in biological and clinical samples. NIM has been acknowledged by spectrometry [26,27], chromatography [28–30], electrochemical method [31,32], capillary zone electrophoresis [33,34], HPLC with monolithic column [35] and at glassy carbon electrode [36] as a detector and with tandem mass spectrometry [37]. For biofluid trials, a technique of thin-layer chromatographic was utilized for the assurance of moiety in plasma. There were two HPLC strategies to identify NIM in plasma and human urine samples. Additionally, a considerable lot of the techniques referenced above are tedious, control steps, modern instruments, and required special
Unadulterated NIM and pure XAD-4 resin bought from SigmaAldrich for the analysis and utilized as it is received. A standard true solution of NIM of 1.0 mM concentration was produced with the help of HPLC grade ethanol solution. The phosphate buffer solutions (PBS) comprising ionic strength of 0.2M has been set up as reported in the literature [47,48], extending the pH from 3.0 to 11.2, utilized as supporting electrolyte in which electrochemical estimations were conducted. Other reagents were employed in analytical quality and doubly purified water was used in the entire experiment. 2.2. Instrumentation Electrochemical analyzer, Model; D630 CHI company (USA) was employed in electrochemical measurement. 10.0 ml glass compartment was utilized for the voltammetric estimation, employing a three-electrode arrangement wherein saturated silver/silver chloride electrode used as a reference electrode, platinum filament acts as an auxiliary electrode and the self-constructed, XAD resin amended CPE utilized as the working electrode. LI120, Elico model pH meter used for the measurement of the pH of developed phosphate buffer solutions and AFM instrument used for the characterization of the modified electrode. 2.3. Preparation of working electrode To develop XAD modified CPE, the process was set up by the blending of graphite powder (1.0 g), amberlite XAD-4 resin (0.05 g) as a modifier and paraffin oil (0.5 mL) in a small agate mortar, to ger homogenized paste. A uniformly mixed paste filled in the empty space present in the polytetrafluoroethylene tube (PTFE) furnished with copper string for an outer electrical connection. The developed electrode used to be cleaned or smoothened to get a sparkly surface and was actuated in a phosphate buffer solution in the ideal pH worked in the range of 0.6 V to 1.2 V till a balanced voltammogram is accomplished, using this activated electrode the sample under the investigation was carried out. For new sample study, the calibrated paste was disposed-off and the new paste was refilled into PTFE. The derived electrode was employed as XAD/CPE. Likewise, pure CPE was set up without the addition of modifiers. 2.4. Analytical methodology The modified CPE was firstly actuated in PBS (0.2M, pH 7.0) by the 2
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cyclic voltammetric technique in the potential range of 0.0 V and 1.4 V until a reproducible voltammogram was acquired. Then electrode was moved into the cell containing PBS (10.0 mL) with an appropriate quantity of NIM. After that, the potential scan was started, and cyclic voltammograms were recorded between 0.6 and 1.2 V with a 50.0 mVs−1 of scan rate. All investigations were carried out at room temperature of 25.0 ( ± 0.1) °C. The experimental criteria for SWV were; final potential: 1.2 V, initial potential: 0.6 V, amplitude: 25.0 mV, frequency: 15.0 Hz, scan rate: 50.0 mVs−1 and sensitivity: 1.0 × 10−4A/V.
3.2. Electrochemical behaviour of NIM The cyclic voltammetric method was utilized to study the electrochemical response of NIM at the electrodes at PBS (pH 7.0). We obtained the cyclic voltammograms, at scan rate 50.0 mVs−1 for NIM solution (1.0 mM) for both bare CPE and modified XAD/CPE. On comparing the voltammograms. We observed that there is a drastic change in the behaviour of the NIM at the electrodes, which indicates the effective modification of the electrode due to which sensing area of the revised electrode was increased and also there was a recognizable increase in the sensitivity and selectivity. From a voltammogram (Fig. 3). it is clearly observed that the modified electrode has enhanced anodic peak current, in comparison with the unmodified CPE. So modified electrode used for further investigations. There was no reduction peak perceived in the reverse scan, which suggests that the irreversible process of NIM at the electrode.
2.5. Preparation of sample Eight to ten bits of NIM tablets were blended in an agate mortar. A weight relating to a 0.1 mM standard solution was taken in a 100.0 ml standard graduated flask and made to the mark with doubly purified water. Complete dissolution is achieved by sonicating for ten minutes, then phosphate buffer solution (pH 7.0) was used to dilute the suitable aliquots of clear supernatant liquid to prepare appropriate solutions. Every prepared sample solution was moved to a voltammetric vessel and examined by a standard addition method. Square wave voltammograms were noted between the potentials of 0.6 V to 1.2 V with 0 second accumulation time, and the oxidation peak current of NIM was estimated. To consider the accuracy of the proposed approach, and to inspect the excipients interference which was implemented in the dosage forms and by using the standard addition method, recovery experiments were done. This study was executed by the inducing precise quantity of NIM to a known concentration of the tablets. The obtained mixture was examined as in pure NIM.
3.3. Accumulation time effect One of the factors which play a significant role in the electrochemical study is accumulation time (tacc), it is the time in which the transport of the molecule or adsorption of the molecule from the mother liquor is more to the active area of the electrode, this part has an affect on the sensor's sensitivity and selectivity. The cyclic voltammetric strategy was employed for the investigation. Voltammograms were obtained for NIM solution (1.0 mM) in the time range of 0–120 s on the oxidation of the NIM. From the plot of accumulation time (tacc) Vs. peak current (Ip) shown in Fig. 4. we noticed that the peak current was a progressively declined from 0 to 30 s, also peak current slightly increased at 45 s and slightly decreased at 60 s, beyond the 60 s peak current was slowly increased. From this plot, at XAD/CPE, the highest value of peak current was at 0 s of accumulation time and was optimum for further studies.
2.6. Human urine sample analysis
3.4. Effect of variation of pH
Biological samples gathered from healthy individuals, spiked with a known amount of NIM to the diluted form of these samples were subjected to investigation. For these spiked urine samples, a square wave voltammetry technique has been applied to determine the NIM content. Recovery values were in great concurrence with the concentration of NIM (0.1 mM) spiked, also recovery values at ambient temperature i.e., 25.0 ± 0.1 °C.
The reaction at the electrode surface may be influenced by the pH of the medium. Effect of variation of pH investigated between pH 3.0 to pH 11.2 using 0.2M PBS by cyclic voltammetry. Cyclic voltammograms were noted in the range of potential from 0.6 V to 1.2 V for the modified sensor. From the voltammograms (Fig. 5). it was observed that, as pH of PBS values increases, potential peaks are slightly moved towards the less positive values, this is due to the involvement of the H+ ion at electrode reaction. Ep = K- (0.059 y/n) pH, where ‘y’ value indicating a number of H+ ions involved and the number of electrons designated by ‘n’. pH-dependent potentials of organic compounds, during its oxidation they were undergoing for deprotonation reaction [49]. Up to pH 7.0, the peak potentials are moved towards the lesser value after pH 7.0 they became pH-independent (Fig. 5A). From (5A) we noticed that the pH-independent peak potential shows a slope of 7.5 mV/pH in the range of pH 7.0 to pH 11.2. The dependence of pH which were in between pH 3.0 to 7.0 has a slope of 57.8 mV/pH, implies the slope value i.e. 57.8 mV/pH being close to the Nernstian value of 59 mV/pH, indicating that same number of protons and electrons were get participated [50] in the oxidation reaction of the NIM at the electrode and we got the linear equation; Ep = 0.0564 pH + +1.3102; R² = =0.9806. Weak acid or weak base involved in the electrode process has potential-pH variation, it shows the change in slope at pH = =pKa, the point of intersection of lines at pH 6.8 refers to the pKa value of NIM, i.e. 6.86 [51]. We got the highest peak current at pH 7.0 (5B). For the determination of NIM and further investigation PBS (pH 7) was used.
3. Results and discussion 3.1. The surface area of the electrode By means of a cyclic voltammetric (CV) strategy, the area of the electrode was achieved by utilizing K3Fe(CN)6 solution (1.0 mM) in KCl solution (0.1M) by filing the current-potential curves at distinct sweep rates. For a reversible process, the sensing electrodes active area was studied at T = =298 K, peak current (Ip) using the Randles Sevcik equation.
Ip=(2.69 × 105)n3/2A0D01/2
1/2C0
(1)
In Eq. (1) for K3Fe (CN)6 solution (1.0 mM) and KCl (0.1 M) as supporting electrolyte, D0 = =7.6 × 10−6 cm2 s−1 and n = =1. And by the help of the slope of the plot, Ip vs. υ1/2, A0 (surface area of the electrode) calculated, and values were found to be 0.040 cm2 and 0.081 cm2 for bare carbon paste electrode and XAD modified carbon paste electrode respectively. The enhancement in the surface area of the modified electrode is evidence for the effectual amendment of the electrode. AFM was employed for the characterization of the base of the modified electrode. From the investigation of AFM, the coarseness of the electrode and the delta Z values were received. Visual of AFM of XAD/CPE has shown in Fig. 2.
3.5. Effect of scan rate variation Physiochemical properties such as transfer coefficient, a number of 3
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Fig 2. AFM image of XAD/CPE.
Fig 3. Voltammetric behaviour of 0.1 mM of NIM in pH 7.0 PBS (I = 0.2 M); υ = 0.05 Vs−1. (A) Variation of peak current (Ip/μA) at bare electrode (CPE), and amberlite XAD modified electrode (XAD/CPE).
from10.0 mVs−1–230.0 mVs−1, scan rate. We obtained the linear relationship between peak current and the square root of the scan rate (6A) with linear regression equation: Ipa = =63.631ν1/2–3.2722; R2 = =0.9737, and it suggests that the diffusion-controlled oxidation process of NIM at XAD/CPE. When the observation done on the graphical representation of log Ip Vs log ν; (6B) linear regression equation obtained as follows: log Ip = =0.5912 log ν + +1.8085; R2 = =0.9734. The theoretical value for an ideal reaction controlled by diffusion reported to be 0.5 and from this plot the slope value, 0.5912 was close to that of the theoretical value [52]. When we calibrate the plot of Ep Vs log ν (6C), we noted that peak potential value shifting towards positive value as the scan rate increases, indicating the electrode process was irreversible. A great linear relationship with regression equation was received for the peak current and log of scan rate; Ep = =0.047 log ν + +0.9892; R2 = =0.9927. Leviron's equation [53] for an irreversible reaction at electrode process given as follows:
Fig 4. Preconcentration time of 0.1 mM NIM at XAD/CPE.
electrons involved in the mechanism and heterogeneous rate constant of a reaction at the electrode can be determined by varying the scan rate. In this, the peak current is proportional to the applied scan rate (Fig.6). The experiment was performed in the range of the scan rate
EP = E + 4
2.303 RT RTk log nF nF
+
2.303 RT logv. nF
(2)
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Fig 5. Cyclic voltammograms obtained for 0.1 mM NIM in buffer solution of different pH at XAD-CPE; υ = 0.05 Vs−1; tacc = 0s: (a) 3.0; (b) 4.2; (c) 5.0; (d) 6.0; (e) 7.0; (f) 8.0; (g) 9.2; (h) 10.4; (i) 11.2. (A) Influence of pH on the peak potential Ep/V of NIM. (B) Variation of peak currents Ip/µA of NIM with pH.
Fig 6. Cyclic voltammograms of 0.1 mM NIM in buffer solution of pH 7.0 (I = 0.2 M) at scan rate of : (a) blank; (b) 0.01; (c) 0.03; (d) 0.05; (e) 0.06; (f) 0.07; (g) 0.11; (h) 0.15; (i) 0.17; (j) 0.21; (k) 0.23 V s−1. (tacc = 0 s). (A) Dependence of peak current (Ip/µA) on the scan rate (υ/Vs−1). (B) Influence of logarithm of peak current (log Ip/µA) on the logarithm of scan rate (log υ/Vs−1). (C) Influence of peak potential (Ep / V) on the logarithm of scan rate (log υ/Vs−1).
where Ep is peak potential, n is a number of electrons transferred, k0 is the standard heterogeneous rate constant, α is the transfer coefficient, E0 is the formal redox potential, ν is the scan rate and other terms have their standard meanings.
The value of αn can be easily calculated by using the slope value of Ep versus log ν. For NIM at the modified electrode, the slope is 0.05, then αn determined to be 1.1828 by taking T = =298K, R = =8.314 JK−1 mol−1, and F = =96480 C mol−1. The value of ‘α’ 5
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found to be 0.56 by using the Bard and Faulkner [3,54] equation, as follows:
Ep = E p
Ep/2 = 47.7mV.
(3)
In (3), Ep/2 is the potential where the current is at exactly half of its peak value. There is a formula given for irreversible reaction; dEp/ dpH = =0.059X/αn, in which ‘X’ is the proton number involved during the reaction. And we obtained the solved equation as αn = =0.4595X and by substituting α and n values, X value found to be 2. The k0 value calculated as, 3.43 × 103 s−1. Therefore the number of protons and the number of electrons participated in the reaction mechanism of the NIM at XAD/CPE was found to be two. 3.6. Probable electrode mechanism of NIM While studying the effect of pH we noted that for all pH range we got one well defined anodic signal for the oxidation of NIM. The ionized and non-ionised form of NIM found to exist due to its pKa value of 6.85. we may predict, neat pH 7.0 the different forms of NIM to be obtained according to the equilibrium [38] shown in Scheme 1. The proton-dependent mechanism for NIM appears in acidic medium while the mechanism of proton independent reaction appears in the basic medium in the rate-determining steps or before. From the pH study, the number of electrons and protons that participated in the reaction was found to be two. In the acidic pH; as pH increases, peak current also increases and in case of basic medium peak current decreases as pH increases. From this the resolved oxidation peak could be ascribed most likely to the methyl sulphonamide group oxidation contained in the structure of NIM as similar to that of earlier reports [38,44]. On the basis of all these considerations, we proposed the probable mechanism as presented in Scheme 1.
Fig 7. SWVs with increasing concentrations of NIM in pH 7.0 phosphate buffer solution at XAD-CPE. (tacc = 0 s): (a) blank; (b) 1.0; (c) 3.0; (d) 5.0; (e) 8.0; (f) 10.0; (g) 20.0; (h) 30.0; (i) 40.0; (j) 50.0 μM; (A): Plot of concentration (C/μM) versus peak current (Ip/µA). Table 1 Characteristics of NIM calibration plot using square wave voltammetry at XAD/ CPE. Linearity range (M) Slope of the calibration plot (μA M−1) Intercept (μA) Correlation coefficient (r) RSD of slope (%) RSD of intercept (%) Number of data points LOD (M) LOQ (M) Repeatability (RSD%) Reproducibility (RSD%)
4. Analytical applications 4.1. Effect of concentration variation Calibration curves were obtained by using a square wave voltammetric (SWV) technique by varying the concentration from 1.0 μM to 50.0 μM at pH 7.0. The SWV technique was restrained the immense capacitive current and provides enhanced resolution. We obtained the voltammograms as shown in Fig. 7. From the plot of peak current (Ip) versus Concentration (7A), we derive the linear regression equation and given as follows: Ip = =3.694C + +0.1646; R2 = =0.9941. For higher concentrated solutions, deflection in linearity was observed due to the adsorption of the NIM or its oxidative products on the modified electrode surface. By using the limit of detection (LOD) equation and limit of quantification (LOQ) equation, the values were calculated to be 1.28 × 10−8 M and 4.28 × 10−8 M respectively [42]
LOD=3S/M.
(4)
LOQ=10S/M.
(5)
5.0 × 10−7 to 1.0 × 10−4 36.941 1.6458 0.9941 0.0052 0.0096 09 1.28 × 10−8 4.28 × 10−8 0.1176 0.1547
Table 2 Comparison of detection limits of NIM by other sensors utilized. Comparison with reported methods Method and Sensors utilized Capillary zone electrophoresis Flow amperometry Reverse phase liquid chromatography Electroanalytical method using carbon black within dihexadecylphosphate film as a sensor Micellar electro kinetic chromatography Novel potentiometric sensor HPLC method using short monolithic column Multiwalled carbon nanotubes modified GCEa Spectrophotometric method Ultra HPLC with tandem mass spectroscopy Cysteic acid and carbon nanotubes modified GCEa Amberlite XAD-4 modified CPEb
where ‘S’ is the standard deviation of the peak current of the blank (five replicates) and ‘m’ is the slope of the calibration curve. Table 1 gives information regarding the calibration plot characters at XAD/CPE and comparison with the pre-reported methods have been presented in Table 2.
LOD 2.00 3.10 2.30 1.60
(M) × 10−5 × 10−6 × 10−6 × 10−8
9.00 3.20 1.62 1.60 1.47 6.49 5.00 1.28
× × × × × × × ×
10−7 10−7 10−7 10−7 10−7 10−8 10−8 10−8
References [34] [40] [30] [44] [29] [46] [35] [32] [45] [37] [31] Present work
a = Glassy Carbon Electrode, b = Carbon Paste Electrode
4.2. Analysis of tablet sample
voltammetric technique was used for the tablet analysis by using the standard addition method. Recovery investigations were performed after the addition of the known amount of the drug to various preanalysed formulations of NIM. The outcome had great concurrency with the content on the label. The recoveries found to be in the range of 1.0 × 10−6 M to 8.0 × 10−6 M lies between 96.0 to 98.63% with RSD of 1.56% (Table 3).
The solution to be investigated was set up by dissolving a suitable measure of the powdered tablet (Nicip plus, 100.0 mg per tablet) with respect to the true solution in 100.0 mL graduated flask by using ethanol. The tablet solution was diluted by using a pH 7.0 buffer solution to prepare the required concentration of the sample. Square wave 6
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4.4. Investigation of spiked human urine samples
Table 3 Application of SWV technique for the determination of NIM in tablet samples at XAD-CPE and recovery test. Labelled claim (mg) Amount found (mg)* RSD (%) Added (mg) Found (mg)* Recovered (%) RSD (%) * Average of five determination
We employed square wave voltammetry for the detection of NIM in spiked urine samples. We collected the urine samples from healthy volunteers. These drug-free urine samples are screened through a filter paper and store in frosty conditions until the assay. We added a known measure of NIM to drug-free urine sample for the estimation of the recovery. A known quantity of drug-spiked into the urine sample diluted a hundred folds with the PBS before investigation without further pre-treatments. NIM in the urine sample was determined from the calibration graph. The detection result of three urine specimens obtained and recorded in Table 5. The recovery values were found within the interval of 90.0 to 97.4% and RSD was 4.33%. Good recoveries of NIM were achieved, which indicates the applicability of the proposed approach to the analysis of NIM in biological samples like plasma and urine samples.
Nicip plus 100.00 98.20 1.43 1.00 0.96 96.41 1.56
Table 4 Influence of potential interferents on the voltammetric response of 0.1 mM NIM. Interferent
Concentration (M)
Signal change (%)
Tartaric acid Citric Acid Ascorbic acid Lactose Sucrose Dextrose Starch Gum Acacia Glycine Urea
0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
−0.76 −0.8 −0.67 −0.72 −0.56 −0.72 −0.73 −0.76 −0.77 −0.81
4.5. Analyzing repeatability and reproducibility of the constructed electrode Repeatability of the XAD/CPE was examined to evaluate the efficiency and quality of steadiness. The electrode was conserved in an airtight container for about 10 days. We noticed that the electrode retained 95.7 to 97.8% of its original peak response for 0.1 mM NIM concentration. The results indicating the stability of the constructed electrode. To examine the electrode reproducibility of the modified electrode preparation methodology, a 0.1 mM NIM solution was estimated at amberlite XAD-4 resin amended carbon paste electrode (restored each time as in Section 2.3) with regular intervals within a day [55]. The RSD of the peak current was 2.58% (five replicates) recommending great reproducibility of NIM determination. The reproducibility of the electrode between days is the same as within a day if the temperature was kept practically steady. Due to the deposition of oxidative products on the peripheral area of the modified electrode, after the progressive usage of the electrode, the current response was diminished. For this reason, we have to refill the electrode as said in Section 2.3.
4.3. Excipients interference study For eventual systematic utilization of the proposed strategy, the interference of some common excipients utilized in the pharmaceutical formulation was inspected. The study of excipients was carried out by using a SWV method at the constructed electrode using NIM (0.1 mM) and the excipients of 0.01 M concentration. Thus to perceive the interruption on peak current and peak potential of NIM was conducted. From Table 4 it is observed that even 100 folds of excipients like tartaric acid, ascorbic acid, citric acid, lactose, dextrose, sucrose, starch, gum acacia, glycerine, and urea did not disturb the voltammetric signals of NIM and percentage signal change was below 0.1% (Fig. 8). In this manner, the methodology can be utilized for the detection of the NIM even though the excipients were present, and consequently, it was considered to be selective.
5. Conclusion The determination of NIM was examined at a bare CPE and XAD/ CPE surface by using a cyclic voltammetric method and square wave voltammetric techniques. From the voltammograms, we concluded that easy transfer of electrons and enhanced sensitivity took place at the modified electrode in comparison with bare carbon paste electrode. The study of pH revealed that the procedure increasingly reasonable at pH
Fig 8. Influence of potential interferents on the voltammetric response of 0.1 mM NIM at XAD-CPE. 7
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Scheme 1. Possible electrode reaction mechanism of NIM. Table 5 Application of SWV technique for the determination of NIM in spiked human urine samples at XAD/CPE. Urine Samples
Spiked (10−4 M)
Sample 1 Sample 2 Sample 3 Recovery (%)
0.1 0.0968 96.8 0.5 0.450 90.0 0.8 0.779 97.375 = =90.0–97.4; *Average five readings.
Detected* (10−4 M)
% age of Recovery
RSD
% RSD
0.04238 0.04558 0.04213
4.42376 4.55784 4.21264
[6] [7] [8]
[9]
7.0. The electro-oxidation of NIM was observed to be irreversible reaction involving an equal number of electrons and protons with a diffusion-controlled process. Physiochemical parameters were determined by studying the effect of scan rate. The detection limit (LOD) was found to be 1.28×10−8 M with good sensitivity and selectivity. Investigation of the excipients demonstrated that no interference of typically utilized additive and excipients in the formulation of medicines. Apart from this, the result acquired in the investigation of NIM in spiked urine samples and tablet analysis indicates the applicability of the technique for analysis of NIM in pharmaceutical and real biological fluids like plasma and urine samples.
[10]
[11]
[12]
[13]
Declaration of competing interests [14]
The authors of this manuscript declare no conflicts of interest.
[15]
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Amberlite XAD-4 modified electrodes for highly sensitive electrochemical determination of nimesulide in human urine Nagaraj P. Shettia,b, , Mahesh M Shanbhaga,b, Shweta J Malodea,b, Rajesh K Srivastavac, ⁎ Kakarla Raghava Reddyd, ⁎
a
Center for Electrochemical Science and Materials, Department of Chemistry, K.L.E. Institute of Technology, Hubballi 580030, Karnataka, India Visvesvaraya Technological University, Belagavi 590018, Karnataka, India c Department of Biotechnology, GIT, Gitam Institute of Technology and Management (GITAM) (Deemed to be University), Visakhapatnam, Andhra Pradesh, 530045, India d School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia b
ARTICLE INFO
ABSTRACT
Keywords: Electrochemical sensor Urine Modified electrodes Voltammetry Electrochemical methods Biological samples
A Simple technique has been developed for electrochemical oxidation and determination of nimesulide (NIM) drug-using voltammetric techniques in phosphate buffer solutions. The modified sensor showed good stability, sensibility, and enhancement in the peak current with good reproducibility. Based on the variation of parameters and their results, the heterogeneous rate constant value was also calculated. The proposed sensor can be utilized for the analysis of the drug in biological and pharmaceutical samples with good recovery values. A suitable electrooxidation mechanism was proposed. The proposed technique was successfully employed for the determination of NIM in biological samples with good recovery results.
1. Introduction For the past few decades, more emphasis has been given out on research work. The research field is one of the immense disciplines in Science and Technology. In this area of investigation, pharmaceutical research is a fascinating area of the piece of research, which involves the discovery and development of new drugs and its control. There is a requirement for the exploration and improvement of a reliable analytical or diagnostic operation. As yet partition approaches, HPLC and its various techniques and electrochemical methods are utilized for the analyzing and the determination of the pharmaceutical drugs [1–5] Pharmaceutical, horticultural, food industry and environmental investigations have been developing quickly, because of advances in electrochemical sensing systems. Electrochemical sensors are the devices consisting of electrochemical transducers which generate the analytical data from the developed electrochemical information. They give quantitative and semiqualitative analytical details. The changes in electrical signals due to the reduction or oxidation reactions of analyte can be examined by several techniques. In this method current or potential is the measured assets. The electrochemical methods of investigation are getting more relevance in pharmaceutical research as a consequence of its extensive application. The high reproducibility of electroanalytical techniques
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can offer an exact outcome when contrasted with different strategies [6]. The scope of this method is, the estimated electrical properties can be evaluated with techniques like conductometry, amperometry, potentiometry, and voltammetry, etc. The main importance or advantages of the electrochemical method in analysis is, it provides the devices with short analysis time, low costs, satisfactory detection limits, portability probability, etc, as it in was in case of pregnancy test glucose meters. Numerous electrochemical sensors have discovered everyday appliances, not only in laboratory purposes. The main priority of sensors or biodevices is to be actualized in healthcare applications [7–9] in the medical field, it means illness, mutation, infection at the first stages, etc. Early diagnosis is one of the strongest prevention methods, but still challenging due to high costs, strict sample preparation mechanism, and long-term analysis. Modern electrochemical technology can overcome these drawbacks by device miniaturization or rapid data output. Some sensitive and selective sensors were developed for the detection of biomolecules [10–13], biochemical species [14–16], and also employed these techniques in simultaneous determination of pharmaceutical drugs [17] or ion-selective sensors for determination pharmaceutical dosages [18,19] were found to be one of the great contributions towards developmental research. There are various kinds of voltammetric strategies that were utilized
Corresponding authors. E-mail addresses: [email protected] (N.P. Shetti), [email protected] (K.R. Reddy).
https://doi.org/10.1016/j.microc.2019.104389 Received 4 September 2019; Received in revised form 2 November 2019; Accepted 2 November 2019 0026-265X/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Nagaraj P. Shetti, et al., Microchemical Journal, https://doi.org/10.1016/j.microc.2019.104389
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training. Thus, a quick, simple and exact strategy with high sensitivity is relied upon to be established. From literature survey, we noted that early reported electrochemical methods used for the determination of NIM, which include utilization of mercury electrode [23], polarographic method [38], amperometric method [39, 40], carbon nanotubes and cysteic acidbased composite thin-film material at glassy carbon electrode [31], boron-doped diamond electrode [41], glassy carbon electrode utilized in which multiwalled carbon nanotubes used as modifier [32], TiO2 nanostructure modified carbon paste electrode [42], rGO and PEDOT: PSS modified sensor [43] and carbon black within dihexadecylphosphate modified sensor [44], spectrophotometric method [45] and potentiometric sensor [46]. The electrochemical analysis/determination of NIM at amberlite XAD-4 modified carbon paste electrode (CPE) has not been studied. By looking at the importance of NIM determination, we have constructed an amberlite XAD-4 resin-modified carbon paste electrode (XAD/CPE). We successfully applied the self-prepared modified electrode to determine NIM in the real samples. 2. Experimental
Fig 1. Chemical structure of NIM.
2.1. Chemicals and reagents
to determine the analyte under the test, out of which cyclic voltammetric procedure is enormously utilized technique, because of its peculiarities such as its ease, high affectability, selectivity, reproducibility, and quick dissecting capacity. The enhancement in the analyte and electrode superficial area collaboration is done by building up a modified electrode due to which above peculiarities can be improved. The modified electrodes as sensors are most ordinarily utilized in different electrochemical procedures because of incomparable properties, for example, huge focused area, great conductivity, and stability. Inflammation is a defensive response to crash the harmful upgrades and start the mending procedure. Intense inflammation leads to pain, warmth, rash, and swelling. Commonly inflammation effectuated by means of prostaglandin, they were created from arachidonate by the action of cyclooxygenase coenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory including those specific for limitation of cyclooxygenase-2 [20]. N-(4-nitro-2-phenoxyphenyl)methanesulfonamide, IUPAC name of NIM (C13H12N2O2S) (Fig. 1) is a decently recent non-steroidal anti-inflammatory drug (NSAID) with painrelieving and fever-lessening properties. Employed in the healing of intense pain, initial stages of dysmenorrhoea, the symptomatic remedy for osteoarthritis and rheumatoid arthritis [21,22]. It can lessen the rate of the arrangement of gastrointestinal ulcers. NIM, pKa estimation of 6.85 is significant for gastric acceptability, as it prevents the back diffusion of hydrogen ion in charge of tissue harm [23]. The half-life of NIM shifted from 1.8 - 4.7 hours. It is to a great extent eliminated by means of its metabolic form, 4-hydroxy derivative (M1), however minor metabolite type of NIM can be identified in urine and feces, essentially in conjugated form. The percentage of NIM (M1) discharged through urine and feces is observed to be 50.5 - 62.5% and 17.9 - 36.2% respectively for an orally administrated dose [22]. The metabolite may accumulate gradually in patients, which may cause renal or hepatic issues [24,25]. In this manner, its significance as bioactive molecules forces its examination, investigation in biological and clinical samples. NIM has been acknowledged by spectrometry [26,27], chromatography [28–30], electrochemical method [31,32], capillary zone electrophoresis [33,34], HPLC with monolithic column [35] and at glassy carbon electrode [36] as a detector and with tandem mass spectrometry [37]. For biofluid trials, a technique of thin-layer chromatographic was utilized for the assurance of moiety in plasma. There were two HPLC strategies to identify NIM in plasma and human urine samples. Additionally, a considerable lot of the techniques referenced above are tedious, control steps, modern instruments, and required special
Unadulterated NIM and pure XAD-4 resin bought from SigmaAldrich for the analysis and utilized as it is received. A standard true solution of NIM of 1.0 mM concentration was produced with the help of HPLC grade ethanol solution. The phosphate buffer solutions (PBS) comprising ionic strength of 0.2M has been set up as reported in the literature [47,48], extending the pH from 3.0 to 11.2, utilized as supporting electrolyte in which electrochemical estimations were conducted. Other reagents were employed in analytical quality and doubly purified water was used in the entire experiment. 2.2. Instrumentation Electrochemical analyzer, Model; D630 CHI company (USA) was employed in electrochemical measurement. 10.0 ml glass compartment was utilized for the voltammetric estimation, employing a three-electrode arrangement wherein saturated silver/silver chloride electrode used as a reference electrode, platinum filament acts as an auxiliary electrode and the self-constructed, XAD resin amended CPE utilized as the working electrode. LI120, Elico model pH meter used for the measurement of the pH of developed phosphate buffer solutions and AFM instrument used for the characterization of the modified electrode. 2.3. Preparation of working electrode To develop XAD modified CPE, the process was set up by the blending of graphite powder (1.0 g), amberlite XAD-4 resin (0.05 g) as a modifier and paraffin oil (0.5 mL) in a small agate mortar, to ger homogenized paste. A uniformly mixed paste filled in the empty space present in the polytetrafluoroethylene tube (PTFE) furnished with copper string for an outer electrical connection. The developed electrode used to be cleaned or smoothened to get a sparkly surface and was actuated in a phosphate buffer solution in the ideal pH worked in the range of 0.6 V to 1.2 V till a balanced voltammogram is accomplished, using this activated electrode the sample under the investigation was carried out. For new sample study, the calibrated paste was disposed-off and the new paste was refilled into PTFE. The derived electrode was employed as XAD/CPE. Likewise, pure CPE was set up without the addition of modifiers. 2.4. Analytical methodology The modified CPE was firstly actuated in PBS (0.2M, pH 7.0) by the 2
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cyclic voltammetric technique in the potential range of 0.0 V and 1.4 V until a reproducible voltammogram was acquired. Then electrode was moved into the cell containing PBS (10.0 mL) with an appropriate quantity of NIM. After that, the potential scan was started, and cyclic voltammograms were recorded between 0.6 and 1.2 V with a 50.0 mVs−1 of scan rate. All investigations were carried out at room temperature of 25.0 ( ± 0.1) °C. The experimental criteria for SWV were; final potential: 1.2 V, initial potential: 0.6 V, amplitude: 25.0 mV, frequency: 15.0 Hz, scan rate: 50.0 mVs−1 and sensitivity: 1.0 × 10−4A/V.
3.2. Electrochemical behaviour of NIM The cyclic voltammetric method was utilized to study the electrochemical response of NIM at the electrodes at PBS (pH 7.0). We obtained the cyclic voltammograms, at scan rate 50.0 mVs−1 for NIM solution (1.0 mM) for both bare CPE and modified XAD/CPE. On comparing the voltammograms. We observed that there is a drastic change in the behaviour of the NIM at the electrodes, which indicates the effective modification of the electrode due to which sensing area of the revised electrode was increased and also there was a recognizable increase in the sensitivity and selectivity. From a voltammogram (Fig. 3). it is clearly observed that the modified electrode has enhanced anodic peak current, in comparison with the unmodified CPE. So modified electrode used for further investigations. There was no reduction peak perceived in the reverse scan, which suggests that the irreversible process of NIM at the electrode.
2.5. Preparation of sample Eight to ten bits of NIM tablets were blended in an agate mortar. A weight relating to a 0.1 mM standard solution was taken in a 100.0 ml standard graduated flask and made to the mark with doubly purified water. Complete dissolution is achieved by sonicating for ten minutes, then phosphate buffer solution (pH 7.0) was used to dilute the suitable aliquots of clear supernatant liquid to prepare appropriate solutions. Every prepared sample solution was moved to a voltammetric vessel and examined by a standard addition method. Square wave voltammograms were noted between the potentials of 0.6 V to 1.2 V with 0 second accumulation time, and the oxidation peak current of NIM was estimated. To consider the accuracy of the proposed approach, and to inspect the excipients interference which was implemented in the dosage forms and by using the standard addition method, recovery experiments were done. This study was executed by the inducing precise quantity of NIM to a known concentration of the tablets. The obtained mixture was examined as in pure NIM.
3.3. Accumulation time effect One of the factors which play a significant role in the electrochemical study is accumulation time (tacc), it is the time in which the transport of the molecule or adsorption of the molecule from the mother liquor is more to the active area of the electrode, this part has an affect on the sensor's sensitivity and selectivity. The cyclic voltammetric strategy was employed for the investigation. Voltammograms were obtained for NIM solution (1.0 mM) in the time range of 0–120 s on the oxidation of the NIM. From the plot of accumulation time (tacc) Vs. peak current (Ip) shown in Fig. 4. we noticed that the peak current was a progressively declined from 0 to 30 s, also peak current slightly increased at 45 s and slightly decreased at 60 s, beyond the 60 s peak current was slowly increased. From this plot, at XAD/CPE, the highest value of peak current was at 0 s of accumulation time and was optimum for further studies.
2.6. Human urine sample analysis
3.4. Effect of variation of pH
Biological samples gathered from healthy individuals, spiked with a known amount of NIM to the diluted form of these samples were subjected to investigation. For these spiked urine samples, a square wave voltammetry technique has been applied to determine the NIM content. Recovery values were in great concurrence with the concentration of NIM (0.1 mM) spiked, also recovery values at ambient temperature i.e., 25.0 ± 0.1 °C.
The reaction at the electrode surface may be influenced by the pH of the medium. Effect of variation of pH investigated between pH 3.0 to pH 11.2 using 0.2M PBS by cyclic voltammetry. Cyclic voltammograms were noted in the range of potential from 0.6 V to 1.2 V for the modified sensor. From the voltammograms (Fig. 5). it was observed that, as pH of PBS values increases, potential peaks are slightly moved towards the less positive values, this is due to the involvement of the H+ ion at electrode reaction. Ep = K- (0.059 y/n) pH, where ‘y’ value indicating a number of H+ ions involved and the number of electrons designated by ‘n’. pH-dependent potentials of organic compounds, during its oxidation they were undergoing for deprotonation reaction [49]. Up to pH 7.0, the peak potentials are moved towards the lesser value after pH 7.0 they became pH-independent (Fig. 5A). From (5A) we noticed that the pH-independent peak potential shows a slope of 7.5 mV/pH in the range of pH 7.0 to pH 11.2. The dependence of pH which were in between pH 3.0 to 7.0 has a slope of 57.8 mV/pH, implies the slope value i.e. 57.8 mV/pH being close to the Nernstian value of 59 mV/pH, indicating that same number of protons and electrons were get participated [50] in the oxidation reaction of the NIM at the electrode and we got the linear equation; Ep = 0.0564 pH + +1.3102; R² = =0.9806. Weak acid or weak base involved in the electrode process has potential-pH variation, it shows the change in slope at pH = =pKa, the point of intersection of lines at pH 6.8 refers to the pKa value of NIM, i.e. 6.86 [51]. We got the highest peak current at pH 7.0 (5B). For the determination of NIM and further investigation PBS (pH 7) was used.
3. Results and discussion 3.1. The surface area of the electrode By means of a cyclic voltammetric (CV) strategy, the area of the electrode was achieved by utilizing K3Fe(CN)6 solution (1.0 mM) in KCl solution (0.1M) by filing the current-potential curves at distinct sweep rates. For a reversible process, the sensing electrodes active area was studied at T = =298 K, peak current (Ip) using the Randles Sevcik equation.
Ip=(2.69 × 105)n3/2A0D01/2
1/2C0
(1)
In Eq. (1) for K3Fe (CN)6 solution (1.0 mM) and KCl (0.1 M) as supporting electrolyte, D0 = =7.6 × 10−6 cm2 s−1 and n = =1. And by the help of the slope of the plot, Ip vs. υ1/2, A0 (surface area of the electrode) calculated, and values were found to be 0.040 cm2 and 0.081 cm2 for bare carbon paste electrode and XAD modified carbon paste electrode respectively. The enhancement in the surface area of the modified electrode is evidence for the effectual amendment of the electrode. AFM was employed for the characterization of the base of the modified electrode. From the investigation of AFM, the coarseness of the electrode and the delta Z values were received. Visual of AFM of XAD/CPE has shown in Fig. 2.
3.5. Effect of scan rate variation Physiochemical properties such as transfer coefficient, a number of 3
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Fig 2. AFM image of XAD/CPE.
Fig 3. Voltammetric behaviour of 0.1 mM of NIM in pH 7.0 PBS (I = 0.2 M); υ = 0.05 Vs−1. (A) Variation of peak current (Ip/μA) at bare electrode (CPE), and amberlite XAD modified electrode (XAD/CPE).
from10.0 mVs−1–230.0 mVs−1, scan rate. We obtained the linear relationship between peak current and the square root of the scan rate (6A) with linear regression equation: Ipa = =63.631ν1/2–3.2722; R2 = =0.9737, and it suggests that the diffusion-controlled oxidation process of NIM at XAD/CPE. When the observation done on the graphical representation of log Ip Vs log ν; (6B) linear regression equation obtained as follows: log Ip = =0.5912 log ν + +1.8085; R2 = =0.9734. The theoretical value for an ideal reaction controlled by diffusion reported to be 0.5 and from this plot the slope value, 0.5912 was close to that of the theoretical value [52]. When we calibrate the plot of Ep Vs log ν (6C), we noted that peak potential value shifting towards positive value as the scan rate increases, indicating the electrode process was irreversible. A great linear relationship with regression equation was received for the peak current and log of scan rate; Ep = =0.047 log ν + +0.9892; R2 = =0.9927. Leviron's equation [53] for an irreversible reaction at electrode process given as follows:
Fig 4. Preconcentration time of 0.1 mM NIM at XAD/CPE.
electrons involved in the mechanism and heterogeneous rate constant of a reaction at the electrode can be determined by varying the scan rate. In this, the peak current is proportional to the applied scan rate (Fig.6). The experiment was performed in the range of the scan rate
EP = E + 4
2.303 RT RTk log nF nF
+
2.303 RT logv. nF
(2)
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Fig 5. Cyclic voltammograms obtained for 0.1 mM NIM in buffer solution of different pH at XAD-CPE; υ = 0.05 Vs−1; tacc = 0s: (a) 3.0; (b) 4.2; (c) 5.0; (d) 6.0; (e) 7.0; (f) 8.0; (g) 9.2; (h) 10.4; (i) 11.2. (A) Influence of pH on the peak potential Ep/V of NIM. (B) Variation of peak currents Ip/µA of NIM with pH.
Fig 6. Cyclic voltammograms of 0.1 mM NIM in buffer solution of pH 7.0 (I = 0.2 M) at scan rate of : (a) blank; (b) 0.01; (c) 0.03; (d) 0.05; (e) 0.06; (f) 0.07; (g) 0.11; (h) 0.15; (i) 0.17; (j) 0.21; (k) 0.23 V s−1. (tacc = 0 s). (A) Dependence of peak current (Ip/µA) on the scan rate (υ/Vs−1). (B) Influence of logarithm of peak current (log Ip/µA) on the logarithm of scan rate (log υ/Vs−1). (C) Influence of peak potential (Ep / V) on the logarithm of scan rate (log υ/Vs−1).
where Ep is peak potential, n is a number of electrons transferred, k0 is the standard heterogeneous rate constant, α is the transfer coefficient, E0 is the formal redox potential, ν is the scan rate and other terms have their standard meanings.
The value of αn can be easily calculated by using the slope value of Ep versus log ν. For NIM at the modified electrode, the slope is 0.05, then αn determined to be 1.1828 by taking T = =298K, R = =8.314 JK−1 mol−1, and F = =96480 C mol−1. The value of ‘α’ 5
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found to be 0.56 by using the Bard and Faulkner [3,54] equation, as follows:
Ep = E p
Ep/2 = 47.7mV.
(3)
In (3), Ep/2 is the potential where the current is at exactly half of its peak value. There is a formula given for irreversible reaction; dEp/ dpH = =0.059X/αn, in which ‘X’ is the proton number involved during the reaction. And we obtained the solved equation as αn = =0.4595X and by substituting α and n values, X value found to be 2. The k0 value calculated as, 3.43 × 103 s−1. Therefore the number of protons and the number of electrons participated in the reaction mechanism of the NIM at XAD/CPE was found to be two. 3.6. Probable electrode mechanism of NIM While studying the effect of pH we noted that for all pH range we got one well defined anodic signal for the oxidation of NIM. The ionized and non-ionised form of NIM found to exist due to its pKa value of 6.85. we may predict, neat pH 7.0 the different forms of NIM to be obtained according to the equilibrium [38] shown in Scheme 1. The proton-dependent mechanism for NIM appears in acidic medium while the mechanism of proton independent reaction appears in the basic medium in the rate-determining steps or before. From the pH study, the number of electrons and protons that participated in the reaction was found to be two. In the acidic pH; as pH increases, peak current also increases and in case of basic medium peak current decreases as pH increases. From this the resolved oxidation peak could be ascribed most likely to the methyl sulphonamide group oxidation contained in the structure of NIM as similar to that of earlier reports [38,44]. On the basis of all these considerations, we proposed the probable mechanism as presented in Scheme 1.
Fig 7. SWVs with increasing concentrations of NIM in pH 7.0 phosphate buffer solution at XAD-CPE. (tacc = 0 s): (a) blank; (b) 1.0; (c) 3.0; (d) 5.0; (e) 8.0; (f) 10.0; (g) 20.0; (h) 30.0; (i) 40.0; (j) 50.0 μM; (A): Plot of concentration (C/μM) versus peak current (Ip/µA). Table 1 Characteristics of NIM calibration plot using square wave voltammetry at XAD/ CPE. Linearity range (M) Slope of the calibration plot (μA M−1) Intercept (μA) Correlation coefficient (r) RSD of slope (%) RSD of intercept (%) Number of data points LOD (M) LOQ (M) Repeatability (RSD%) Reproducibility (RSD%)
4. Analytical applications 4.1. Effect of concentration variation Calibration curves were obtained by using a square wave voltammetric (SWV) technique by varying the concentration from 1.0 μM to 50.0 μM at pH 7.0. The SWV technique was restrained the immense capacitive current and provides enhanced resolution. We obtained the voltammograms as shown in Fig. 7. From the plot of peak current (Ip) versus Concentration (7A), we derive the linear regression equation and given as follows: Ip = =3.694C + +0.1646; R2 = =0.9941. For higher concentrated solutions, deflection in linearity was observed due to the adsorption of the NIM or its oxidative products on the modified electrode surface. By using the limit of detection (LOD) equation and limit of quantification (LOQ) equation, the values were calculated to be 1.28 × 10−8 M and 4.28 × 10−8 M respectively [42]
LOD=3S/M.
(4)
LOQ=10S/M.
(5)
5.0 × 10−7 to 1.0 × 10−4 36.941 1.6458 0.9941 0.0052 0.0096 09 1.28 × 10−8 4.28 × 10−8 0.1176 0.1547
Table 2 Comparison of detection limits of NIM by other sensors utilized. Comparison with reported methods Method and Sensors utilized Capillary zone electrophoresis Flow amperometry Reverse phase liquid chromatography Electroanalytical method using carbon black within dihexadecylphosphate film as a sensor Micellar electro kinetic chromatography Novel potentiometric sensor HPLC method using short monolithic column Multiwalled carbon nanotubes modified GCEa Spectrophotometric method Ultra HPLC with tandem mass spectroscopy Cysteic acid and carbon nanotubes modified GCEa Amberlite XAD-4 modified CPEb
where ‘S’ is the standard deviation of the peak current of the blank (five replicates) and ‘m’ is the slope of the calibration curve. Table 1 gives information regarding the calibration plot characters at XAD/CPE and comparison with the pre-reported methods have been presented in Table 2.
LOD 2.00 3.10 2.30 1.60
(M) × 10−5 × 10−6 × 10−6 × 10−8
9.00 3.20 1.62 1.60 1.47 6.49 5.00 1.28
× × × × × × × ×
10−7 10−7 10−7 10−7 10−7 10−8 10−8 10−8
References [34] [40] [30] [44] [29] [46] [35] [32] [45] [37] [31] Present work
a = Glassy Carbon Electrode, b = Carbon Paste Electrode
4.2. Analysis of tablet sample
voltammetric technique was used for the tablet analysis by using the standard addition method. Recovery investigations were performed after the addition of the known amount of the drug to various preanalysed formulations of NIM. The outcome had great concurrency with the content on the label. The recoveries found to be in the range of 1.0 × 10−6 M to 8.0 × 10−6 M lies between 96.0 to 98.63% with RSD of 1.56% (Table 3).
The solution to be investigated was set up by dissolving a suitable measure of the powdered tablet (Nicip plus, 100.0 mg per tablet) with respect to the true solution in 100.0 mL graduated flask by using ethanol. The tablet solution was diluted by using a pH 7.0 buffer solution to prepare the required concentration of the sample. Square wave 6
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4.4. Investigation of spiked human urine samples
Table 3 Application of SWV technique for the determination of NIM in tablet samples at XAD-CPE and recovery test. Labelled claim (mg) Amount found (mg)* RSD (%) Added (mg) Found (mg)* Recovered (%) RSD (%) * Average of five determination
We employed square wave voltammetry for the detection of NIM in spiked urine samples. We collected the urine samples from healthy volunteers. These drug-free urine samples are screened through a filter paper and store in frosty conditions until the assay. We added a known measure of NIM to drug-free urine sample for the estimation of the recovery. A known quantity of drug-spiked into the urine sample diluted a hundred folds with the PBS before investigation without further pre-treatments. NIM in the urine sample was determined from the calibration graph. The detection result of three urine specimens obtained and recorded in Table 5. The recovery values were found within the interval of 90.0 to 97.4% and RSD was 4.33%. Good recoveries of NIM were achieved, which indicates the applicability of the proposed approach to the analysis of NIM in biological samples like plasma and urine samples.
Nicip plus 100.00 98.20 1.43 1.00 0.96 96.41 1.56
Table 4 Influence of potential interferents on the voltammetric response of 0.1 mM NIM. Interferent
Concentration (M)
Signal change (%)
Tartaric acid Citric Acid Ascorbic acid Lactose Sucrose Dextrose Starch Gum Acacia Glycine Urea
0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01
−0.76 −0.8 −0.67 −0.72 −0.56 −0.72 −0.73 −0.76 −0.77 −0.81
4.5. Analyzing repeatability and reproducibility of the constructed electrode Repeatability of the XAD/CPE was examined to evaluate the efficiency and quality of steadiness. The electrode was conserved in an airtight container for about 10 days. We noticed that the electrode retained 95.7 to 97.8% of its original peak response for 0.1 mM NIM concentration. The results indicating the stability of the constructed electrode. To examine the electrode reproducibility of the modified electrode preparation methodology, a 0.1 mM NIM solution was estimated at amberlite XAD-4 resin amended carbon paste electrode (restored each time as in Section 2.3) with regular intervals within a day [55]. The RSD of the peak current was 2.58% (five replicates) recommending great reproducibility of NIM determination. The reproducibility of the electrode between days is the same as within a day if the temperature was kept practically steady. Due to the deposition of oxidative products on the peripheral area of the modified electrode, after the progressive usage of the electrode, the current response was diminished. For this reason, we have to refill the electrode as said in Section 2.3.
4.3. Excipients interference study For eventual systematic utilization of the proposed strategy, the interference of some common excipients utilized in the pharmaceutical formulation was inspected. The study of excipients was carried out by using a SWV method at the constructed electrode using NIM (0.1 mM) and the excipients of 0.01 M concentration. Thus to perceive the interruption on peak current and peak potential of NIM was conducted. From Table 4 it is observed that even 100 folds of excipients like tartaric acid, ascorbic acid, citric acid, lactose, dextrose, sucrose, starch, gum acacia, glycerine, and urea did not disturb the voltammetric signals of NIM and percentage signal change was below 0.1% (Fig. 8). In this manner, the methodology can be utilized for the detection of the NIM even though the excipients were present, and consequently, it was considered to be selective.
5. Conclusion The determination of NIM was examined at a bare CPE and XAD/ CPE surface by using a cyclic voltammetric method and square wave voltammetric techniques. From the voltammograms, we concluded that easy transfer of electrons and enhanced sensitivity took place at the modified electrode in comparison with bare carbon paste electrode. The study of pH revealed that the procedure increasingly reasonable at pH
Fig 8. Influence of potential interferents on the voltammetric response of 0.1 mM NIM at XAD-CPE. 7
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Scheme 1. Possible electrode reaction mechanism of NIM. Table 5 Application of SWV technique for the determination of NIM in spiked human urine samples at XAD/CPE. Urine Samples
Spiked (10−4 M)
Sample 1 Sample 2 Sample 3 Recovery (%)
0.1 0.0968 96.8 0.5 0.450 90.0 0.8 0.779 97.375 = =90.0–97.4; *Average five readings.
Detected* (10−4 M)
% age of Recovery
RSD
% RSD
0.04238 0.04558 0.04213
4.42376 4.55784 4.21264
[6] [7] [8]
[9]
7.0. The electro-oxidation of NIM was observed to be irreversible reaction involving an equal number of electrons and protons with a diffusion-controlled process. Physiochemical parameters were determined by studying the effect of scan rate. The detection limit (LOD) was found to be 1.28×10−8 M with good sensitivity and selectivity. Investigation of the excipients demonstrated that no interference of typically utilized additive and excipients in the formulation of medicines. Apart from this, the result acquired in the investigation of NIM in spiked urine samples and tablet analysis indicates the applicability of the technique for analysis of NIM in pharmaceutical and real biological fluids like plasma and urine samples.
[10]
[11]
[12]
[13]
Declaration of competing interests [14]
The authors of this manuscript declare no conflicts of interest.
[15]
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