Experimental Design Approach in the Optimization of Potentiometric

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Applied Chemistry

An experimental design approach in the optimization of potentiometric method for lansoprazole determination using lansoprazole-tungstate based ion-selective electrode Nafisur Rahman, and Sumaiya Khan Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.8b01281 • Publication Date (Web): 02 Jul 2018 Downloaded from http://pubs.acs.org on July 9, 2018

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Industrial & Engineering Chemistry Research

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An experimental design approach in the optimization of potentiometric method for lansoprazole determination using lansoprazole-tungstate based ion-selective electrode NafisurRahman* and Sumaiya Khan Department of Chemistry Aligarh Muslim University, Aligarh-202002 (UP), India Email: [email protected]

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Industrial & Engineering Chemistry Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract The PVC membrane immobilized with lansoprazole-tungstate and plasticized with dioctyl phthalate was characterized by FTIR, XRD and SEM. The effects of critical parameters such as response time, pH and temperature on the potential were analysed and these were optimised using central composite design (CCD) and desirability function. Under the optimised conditions, the plot of measured potential against concentration of lansoprazole exhibited linearity from 2×10-5 to 2×10-3 mol L-1 at pH 4.4. The slope of the plot and detection limit was -41.50 mV/decade and 1.57×10-5 molL-1, respectively. The response time of the proposed ion-selective electrode was ≤30s. The electrode exhibited good selectivity for lansoprazole over a number of ionic species, commonly found in commercial dosage forms. The response mechanism was also discussed. The proposed ion-selective electrode was successfully applied for potentiometric determination of lansoprazole. Keywords: Lansoprazole; Ion-selective electrode; Central composite design; Interaction mechanism; Potentiometry; Pharmaceuticals


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1. Introduction Lansoprazole is a proton pump inhibitor and its IUPAC name is 2-[[[3-methyl-4-(2, 2, 2trifluoroethoxy)-2-pyridinyl] methyl] sulfinyl]-1-H-benzimidazole (Scheme 1).1 It is generally administered as enteric coated tablets or capsules. Lansoprazole becomes protonated and produces the sulphenamide form of the drug which enables covalent binding with H+/K+ ATPase enzyme. This prevents the secretion of acid by proton pump. 2-4 Lansoprazole has been prescribed for the treatment of peptic ulcers, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Helicobacter pylori are bacteria which is responsible for causing ulcers in the stomach. 5 The use of lansoprazole with antibiotic helps to eradicate Helicobacter pylori. The quality and quantity of the pharmaceutical products are controlled by analytical techniques. The applications of various analytical techniques in pharmaceutical analysis have been reviewed.6-8 Several analytical approaches such as HPLC, 9-12 HPTLC,13,14 capillary electrophoresis,15,16 spectrophotometry,17-21 spectrofluorimetry22,23 and flow injection analysis24,25 were reported for estimation of lansoprazole in different matrices. In addition, electroanalytical methods have been developed for estimation of lansoprazole. The polarographic behaviour of lansoprazole was investigated at the dropping mercury electrode which has been exploited to develop methods for its assay in dosage forms. 26-28,30 Voltammetric techniques such as square-wave adsorptive stripping voltammetry, differential pulse voltammetry and anodic voltammetry have also been used for assay of lansoprazole.29,31,32

However,

analytical

methods

based

on

HPLC,

HPTLC,

spectrophotometry, capillary electrophoresis and flow analysis are either associated with multiple sample preparation steps and longer analysis time or very costly. The electrochemical methods using a mercury electrode for reduction of lansoprazole may be associated with the environmental pollution.



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Recently, the applications of membrane ion-selective electrodes have been extended for assay of drugs pharmaceutical formulations and biological samples due to good selectivity and accuracy with wide linear dynamic range. 33 The ion-pair complexes have been used as ionophores

for

fabrication

of

PVC

membrane

based

ion-selective

electrode.

Phosphotungstate,34-36 tetra phenyl borate,37,38 phosphomolybdate,36 tungstophosphate,39 tetrakis (4-chlorophenyl) borate40 and silicotungstate41 were used as counter ions in the fabrication of PVC based ion-selective membranes. There is no report available for direct potentiometric determination of lansoprazole involving ion-selective electrode. There are many factors affecting the selectivity of ion selective electrodes such as temperature, time, pH etc. In order to achieve better performance of a proposed method, response surface methodology (RSM) is applied to screen and optimize the factors. RSM is a statistical method which explores a relationship between several important process parameters and response variables. Furthermore, RSM has distinct advantage over conventional optimization methods. It reduces the time required for experimentation as it minimizes the number of experiments to be performed. Central composite, Box-Behnken, and Doehlert designs are the most commonly used methodology for the optimization of analytical methods. Among these experimental designs, CCD is widely used for the estimation of variables and their interactions. The CCD statistical method was applied in the optimization of magnetic extraction for the determination of antidepressants in biological samples.42 Dispersive liquid-liquid microextraction coupled with UV-visible spectrophotometry was applied for the determination of quinine. 43 The critical factors were optimized using CCD and desirability function. Hantzsch condensation reaction was utilized in the development of spectrophotometric method for the determination of midodrine hydrochloride in oral samples. The process variables, such as pH, temperature, heating time and volume were screened and optimized using 2-level full factorial design and 24 full factorial designs, respectively.44


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Central composite design has been applied to optimize HPLC experimental parameters for the assay of captopril45 and for the determination of amphetamine and methamphetamine in urine samples.46 However, CCD and desirability function has not been utilized in the optimization of critical variables of potentiometric method using ion-selective electrode. Herein, we describe a lansoprazole selective PVC membrane electrode based on the use of lansoprazole-tungstate as the ion-exchanger and dioctylphthalate as plasticizer. The experimental factors were optimised using central composite design and desirability function. The performance of the proposed ion-selective electrode was investigated and its application was successfully demonstrated for the estimation of lansoprazole in commercial dosage forms. 2. Experimental 2.1. Apparatus A Shimadzu UV-1800 spectrophotometer and FTIR spectrophotometer (Interspec 2020, Spectrolab, UK) were employed for recording UV-VIS and IR spectra, respectively. Scanning electron microscope (JEOL JSM-6100, Japan) was used to examine the surface morphology of the membranes. Shimadzu X-ray diffractometer (XRD-6100) was employed to obtain X-ray diffraction data. A potentiometer (model 318, Systronics India Limited, Ahmedabad) and pH meter (model: Cyberscan pH 2100) were used to measure the potential and pH of the solutions, respectively. 2.2. Reagents and materials. The reagents used for the fabrication of the membrane were sodium tungstate, poly (vinyl chloride) (PVC) of high molecular weight, dioctyl phthalate (DOP) (Otto ChemikaPvt. Ltd, India), tetrahydrofuran (THF) (S.D. Fine Chem. Ltd, India) and lansoprazole (Cipla Limited,



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India). Pharmaceutical preparations of lansoprazole such as Junior Lanzol 30 tablets (30 mg/tablet; Cipla Ltd., Malpur, Dist. Solan, India) and Lanbow-30 capsules (30 mg/capsule; Skymap Pharmaceuticals, Roorkee, India) were obtained from local market. 2.3. Preparation of solutions. Lansoprazole (purity ≥ 98%) (1.0 × 10-2 mol L-1), as a stock solution, was prepared by dissolving 0.1847g pure drug in minimal volume of methanol and then completed to 50 mL with distilled water. Working solutions of lansoprazole of varying concentrations (1.0×10-6 to 1.0 × 10-2 mol L-1) were prepared by diluting the stock solution. Solution of sodium tungstate (1.0×10-2 mol L-1) was prepared in distilled water. 2.4. Preparation of electroactive material. Lansoprazole-tungstate (LAN-T) was obtained by mixing 50 mL of 1.0 × 10-2 mol L-1 lansoprazole solution with 50 mL of sodium tungstate (1.0×10-2 mol L-1). The resulting precipitate of LAN-T was kept overnight in the mother liquor. The precipitate was then filtered off on Whatman filter paper No1 with continuous washing with distilled water. Finally, it was dried at 40 oC. 2.5. Determination of composition of lansoprazole tungstate. 100 mg of powdered lansoprazole-tungstate was dissolved in 1M HCl. The concentration of lansoprazole and tungsten were determined spectrophotometrically21 and ICP-MS, respectively. 2.6. Adsorption of lansoprazole onto lansoprazole-tungstate. The adsorption experiment was carried out to determine the adsorption capacity of lansoprazole-tungstate by batch equilibrium method. A known amount of the electroactive


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material (20 mg) was transferred to 25 mL of 1×10 -3 mol L-1 aqueous solution of lansoprazole, maintained at pH 4.4. The mixture was shaken at a constant temperature at a speed of 120 rpm for 3 h. The solution was filtered and the residual concentration of lansoprazole was determined by spectrophotometry. The adsorption capacity (Q) can be calculated from the following equation:47 Q = (Co-C) V/W

(1)

where, Q represents adsorption capacity (mg g-1), Co and C are the lansoprazole concentrations before and after adsorption (mg L -1), respectively, V is the initial volume of lansoprazole solution (L) and W is the mass of the electroactive material (g). 2.7. Preparation of membranes. PVC membrane containing LAN-T was prepared following the method developed in our laboratory.48,49 In order to prepare the membranes, the varying amounts of finely divided LAN-T (15 and 30 mg) and PVC (100, 150 and 200 mg) were mixed. The resulting mixture was dissolved in 5 mL of THF and then, plasticized with DOP (0.5 mL). The sensing membrane was obtained by pouring the resulting solution into a petri dish and left to dry freely in air. 2.8. Preparation of ion-selective electrode. The membrane containing LAN-T was attached to one end of the hollow glass cylinder (i.d. 2 cm) with the help of araldite. The assembly was allowed to dry in air and lansoprazole solution (1.0×10-3 mol L-1) was transferred into it. The electrode was dipped in lansoprazole solution for 2 h. A saturated calomel electrode (SCE) was used as internal reference electrode. 2.9. Potential measurement



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All potentials were measured at 37 ± 1 °C by immersing lansoprazole-selective electrode and SCE in the sample solution maintained at appropriate pH using sodium acetate-HCl buffer solution. The cell assembly is shown in Scheme 2. 2.10. Experimental design. The optimization of major factors for potentiometric determination using lansoprazoletungstate based ion-selective electrode was carried out using CCD under RSM. 50 The experimental design was performed by Design Expert ® version 10 (trial version). Response time, pH and temperature were selected as three independent variables in the CCD. Five levels, coded −α, −1, 0, 1, and α, were applied to each variable which are shown in Table S1. A total of 20 experiments have been carried out under three factor and five level design. Table 1 shows the actual experimental design matrix. RSM uses the data obtained from experimental design to optimize the variables of the potentiometric method. Fitting and analysis of data obtained from experimental design followed the second order polynomial model. The general form of second order polynomial model for response surface analysis is expressed as: 3

3

3

3

𝑦 = 𝛽° + ∑ 𝛽𝑖 𝑥𝑖+ + ∑ ∑ 𝛽𝑖𝑗 𝑥𝑖 𝑥𝑗 + ∑ 𝛽𝑖𝑖 𝑥𝑖2 + 𝜀 𝑖=1

𝑖=1 𝑗=1

(2)

𝑖=1

Where y is the response (mV), βo is the constant term or intercept, βi, βii and βij represents the coefficients of the first order, quadratic and interaction terms, respectively. xi and xj are the coded values of the three variables. 𝜀 is the random error. Statistical significance of the parameters was determined from analysis of variance (ANOVA) of the CCD model. 2.11. Desirability function.


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Derringer’s desirability function51 is useful in the optimization of all variables simultaneously during the optimization process of analytical methods. In this procedure, each predicted response is transformed to an individual desirability function (d i) using the fitted model. The score of desirability function varies from 0 to 1. The global desirability function (D) is obtained by combining individual desirability scores using geometrical mean which is expressed as: 𝑛

1⁄ 𝑛

𝐷 = (∏ 𝑑𝑖 )

(3)

𝑖=1

Where, n and di represents the number of responses and individual desirability function, respectively. 2.12. Determination of lansoprazole in pharmaceutical preparations. The contents of lansoprazole tablets (Junior Lanzol 30 and Lanbow-30) were grounded to a homogenous fine powder. The drug was extracted with 10-15 mL of acetonitrile, so as to remove all the possible excipients that may be present in the tablets, and filtered. The filtrate was then evaporated in air and the dried drug was dissolved in 100 mL distilled water. The amount of the drug in tablet was obtained by measuring the electrode potential for each solution. 3. Results and discussion Lansoprazole was found to react with sodium tungstate in aqueous medium to form water insoluble lansoprazole-tungstate ion-pair complex (LAN-T). The chemical analysis of the material provided a combining ratio of 2:1 between lansoprazole and tungstate ion. The adsorption capacity of lansoprazole-tungstate for lansoprazole was found to be 14.8 mg/g. The sorption of other proton pump inhibitors such as omeprazole, pantoprazole and rabeprazole on lansoprazole-tungstate was very low (less than 1 mg/g). A tentative formula



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for lansoprazole-tungstate was assigned based on the chemical analysis and literature background as:52 (Lansoprazole)2(HWO4)(OH). nH2O The resulting ion-pair complex has been examined as ion-exchanger sensing material in PVC membrane based ion-selective electrode for the potentiometric determination of lansoprazole. In addition to critical role of the nature of ion-exchanger, amount of ion-exchanger, type of plasticizer and its ratio with PVC are also important features. Several membranes were prepared using different amounts of ion-exchange material and PVC with a known amount of DOP. Table S2 summarizes the composition of lansoprazole-tungstate membranes and dynamic linear range with correlation coefficient. The results showed that the response of electrode based on membrane M-2 was linear from 2.0 ×10-5 to 2.0× 10-3 mol L-1 with R2=0.9998. Thus, the final results showed that the electrode made up of the membrane containing 30 mg LAN-T and 150 mg PVC provided the best sensitivity with a slope of 41.50 mV/decade. The low orders of water content, thickness, swelling and porosity of membrane (M-2) (5.79 %, 0.179 mm, 0.218 mm and 0.027, respectively) suggested negligible interstices and occurrence of ion diffusion through exchange sites. 3.1. Characterization of the membrane. Figure 1 (a and b) shows the FTIR spectra of lansoprazole and lansoprazole-tungstate. The IR spectrum of lansoprazole (curve a) exhibited the characteristic absorption peaks at 3247, 2984, 1581, 1267, 1173, 1117 and 1039 cm-1 corresponding to the stretching vibrations associated with

N

H

, C-H, the aromatic ring, C-N on the pyridyl ring, -CF3, C-O-C and

S=O, respectively. In addition, asymmetric and symmetric deformation of –CF3 can be characterized by the peak appearing at 645 cm-1. The IR spectrum of lansoprazole-tungstate


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(curve b) shows the sharp peak at 749 cm-1 that confirms the presence of tungstate ion.53 The bands peaking at 3434 cm-1 and 1621 cm-1 characterize the water molecule. However, obvious changes occurred in the feature region of the IR spectrum of lansoprazole-tungstate. In the feature region, the 3247 cm-1

N

H

stretching vibration peak of lansoprazole

disappeared. It indicated that bond formation between

N H

and tungstate ion has taken

place.54 Figure 2 (a and b) shows the surface morphology of the prepared membranes. Figure 2a shows SEM image of PVC membrane only. It can be seen that pores of different sizes are present on the surface of the membrane. SEM image (Figure 2b) of PVC membrane immobilized with LAN-T shows small voids and cavities on the surface. Figure 3 shows the X-ray diffraction patterns of membrane containing lansoprazole-tungstate. It can be seen that one broad peak at 2θ of 24° with d-spacing of 3.7083 A° was observed which indicated the amorphous nature of the material. 3.2. Effect of pH. The influence of pH on the potential values was studied in the pH range of 2.5 to 5.3 by placing the electrodes in 5.0×10-5 mol L-1 and 5.0×10-4 mol L-1 solution of lansoprazole. The pH of the test solutions was maintained using sodium acetate-HCl buffer solution. The plots of potential (mV) versus pH (FigureS1) indicated that the emf values were independent with respect to pH variations in the range of 3.5-4.5. In this pH range, the electrode can be applied for the determination of lansoprazole. At pH less than 3.5, the potential began to increase due to the interference of hydronium ions. The considerable decrease in potential observed at pH levels higher than 4.5 may be due to the decreased concentration of protonated form of lansoprazole.



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3.3. Response time. Response time is considered as the time required for the electrode to reach a stable potential within ±1 mV of the final equilibrium potential. 55 The potential of the ion-selective electrode was measured as a function of time in the concentration range of 5.0×10-5 mol L-1 to 1.0×103

mol L-1 lansoprazole. A stable response of the sensor was obtained within 30 s for varying

concentrations of lansoprazole and remained stable for several hours (Figure S2). 3.4. Temperature effect. To study the effect of temperature, the electrode potential reading was observed as a function of temperature. The potential – temperature plots at two different concentrations of lansoprazole (1.0 × 10-4 and 1.0 × 10-3 mol/L) are shown in Figure S3. The isothermal temperature coefficient (dEo/dT) of the potential of electrode is defined by the equation: 56 dEo/dT = dE/dT – (2.302R/F) log[LAN+]

(4)

The value of dE/dT was obtained from the slope of potential – temperature plots. The values of isothermal coefficient of the lansoprazole-tungstate electrode were calculated using equation (4) and the mean value of (dE o/dT) was found to be 1.48×10-4 VoC-1. This indicated that the thermal stability of the electrode is very high in the studied temperature range. 3.5. Optimization. The experimental data obtained from CCD were fitted to multivariate models to generate the regression equations. The suitability of models in describing the potentiometric method was judged by comparing the model statistics (Table S3). The quadratic model was selected on the basis of low standard deviation (0.1902) and high value of R2 for further studies. An


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empirical relationship between the predicted response (mV) and independent variables can be represented by the following quadratic model. R1 (Potential) = -52.55 + 0.5735A – 2.45B + 0.3454C - 0.0150AB + 0.0175AC + 0.1125BC - 0.1427A2 - 0.0889B2 + 0.2311C2

(5)

The statistical significance and fitness of the selected model were assessed by analysis of variance (ANOVA) (Table 2). The model terms are considered significant when values of Prob> F is less than 0.05. In this study (Table 2), the value of Prob>F for the model is ˂0.0001 which confirmed that the quadratic model is highly significant. The lack-of-fit term is non-significant which showed that the quadratic model is adequate to provide a good theoretical description of experimental data. Moreover, the model terms A, B, C, A2 and C2 had significant effects on the potential because the value of Prob>F for each term was less than 0.05. However, the interactions between the variables are considered insignificant because the values of Prob>F for interaction terms are greater than 0.100. The value of predicted R2 (0.9687) is in close agreement with that of adjusted R2 (0.9923) which demonstrated the good predictability of the quadratic model. The plot of measured values against the predicted response (Figure 4) exhibited a good agreement among them. The validity of ANOVA is further carried out from certain model diagnostic plots. Further the plot for normal probability (Figure S4) shows the residuals along the straight line, signifying normal distribution of errors. This ensures the adequacy of the selected model. 3.5.1. Effect of variables and response surface plots: The effect of each variable in the response model can be represented in terms of percent contribution (PC). The percent contribution can be calculated using the following equation: 57

PC =

SSi 100 SSm


(6)


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Where, SSi and SSm are the sum of squares for the individual variable and sum of squares for the model, respectively. The results are shown in Table 2, which revealed that the pH of the solution has shown maximum contribution (92.07%) whereas response time and temperature have exhibited low level of contribution with PC value of 4.78 and 1.83, respectively. The contribution of all interactive terms is minimum in response model. Therefore, the interaction terms AB, AC and BC were insignificant as per model which signifies that the effect of one factor on the potential is independent of the second factor. Figure 5 (a and a’) shows the effect of pH and time on the potential while keeping the third variable constant (T = 37°C). As can be seen in figure, the potential slowly increases with increase in pH. The potential changes from -53 mV to -55 mV when pH changes from 3.8 to 4.8. It is also observed that a constant potential was observed after 26 seconds. Figure 5 (b and b’) shows the interactive effects of time and temperature while keeping the other variable at its central value. The potential slightly changes with change in temperature from 37°C to 58°C and response time from 14 to 30 seconds. Figure 5 (c and c’) shows the interactive effects of pH and temperature on the potential. At 37°C, potential slightly changes with increase in pH. 3.5.2. Perturbation plot. A comparison of the effects of all variables at the optimum condition of potentiometric method is shown in the form of perturbation plot (Figure 6). As can be seen in the figure, the potential is strongly affected by pH whereas response time and temperature have affected the potential to a small extent only. 3.6. Desirability function and optimization.


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The optimum conditions for response were also determined by application of Derringer’s desirability function.58 In this numerical optimization, an appropriate value of the minimum, maximum and target of the three factors namely, response time, pH and temperature is selected and examined. A high desirability value (D = 1.000) was obtained for the three parameters and the response as well. Figure 7 represents the numerical optimization ramps for each factor and response, and the combined desirability is also mentioned. In accordance with the desirability ramp best potential (-53.3577) is attained at optimum conditions (A: time = 28 seconds, B: pH = 4.4 and C: temperature = 37 °C). 3.7. Calibration curve and statistical data. The potential values were measured by immersing the electrodes in varying concentrations of lansoprazole (1.0×10-6-1.0×10-2 mol L-1). A calibration curve was obtained by plotting the measured potential against the negative logarithm of lansoprazole concentration59 (Figure 8). As can be seen in figure, a linear dynamic range existed over the concentration range 2.0×105

to 2.0×10-3 mol L-1. The proposed ion-selective electrode showed a slope of -41.50 mV

decade-1. The detection limit of the electrode was found to be 1.57×10-5 mol L-1. Table 3 summarizes the regression parameters of the calibration plot. 3.8. Selectivity of the electrodes The selectivity coefficient of the electrode towards different cationic species was evaluated using the following equation:60 pot

𝑙𝑜𝑔 𝐾A,B =

pot

𝑙𝑜𝑔 𝐾A,B =

𝐸2 − 𝐸1 𝑍 + [1 − ( 𝐴⁄𝑍 )] log 𝑎𝐴 2.303𝑅𝑇⁄ 𝐵 𝑍𝐴 𝐹

(7)

𝐸2 − 𝐸1 𝑍 + [ 1 − ( 𝐴⁄𝑍 )] log 𝑎𝐴 𝐵 slope

(8)



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where E1 is the electrode potential in 1.0 × 10-3mol L-1 lansoprazole solution, E2 is the electrode potential in 1.0×10-3 mol L-1 solution of the interferent ion, aA is the activity of lansoprazole solution and ZA and ZB are the charges on lansoprazole and interferent ion, respectively. The performance of the lansoprazole electrode was examined by measuring the electrode potential of lansoprazole solution containing some interfering cations such as Na+, K+, NH4+, Ca2+, Mg2+, Ni2+, Co2+, Cr3+and Cu2+.The presence of sucrose in the solution did pot

not affect the electrode response. The calculated selectivity coefficient values (𝐾A,B ) are given in Table S4. The values of the selectivity coefficient in presence of most cations were found to be in the order of 10 -2 or smaller which pointed towards the reasonable selectivity for lansoprazole cation over the tested species. 3.9. Potentiometric responsive mechanism. In this study, lansoprazole-tungstate microparticles are embedded into PVC membrane which gives selective response to lansoprazole cation. This happens due to the exchange of lansoprazole cation with H+ present in lansoprazole-tungstate microparticles. In addition, the lansoprazole cations were also adsorbed on the surface of the microparticles (Figure 9). Therefore, a certain concentration of lansoprazole cation was formed in the membrane. The potential difference generated across the membrane was due to the difference in lansoprazole cation concentration on the two sides of the membrane. 3.10. Accuracy and precision. The accuracy and precision was demonstrated by carrying out five replicate determinations at three concentration levels of lansoprazole (7.39, 18.47, and 36.94 µg mL-1) during the same day and for five consecutive days. The results are reported in Table S5. The percentage relative standard deviation (% RSD) were found to be ≤ 0.77 % and ≤ 0.93 % for intra-day


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and interday precision, respectively. The results pointed towards the high precision. The accuracy was determined as percent relative error (% RE). The accuracy of the proposed method is high because the percent relative values were found to be in the range of -0.002 to 1.04. 4. Application The commercial tablets such as junior lanzol-30 and lanbow-30 containing lansoprazole were successfully analysed by potentiometric method using the newly fabricated ion-selective electrode and a reported spectrophotometric method. 21The results obtained by the proposed and reference methods were compared statistically using t- and F- tests (Table 4). Theoretical t-(n=8) and F- values (n=4, 4) at 95% confidence level are 2.306 and 6.39, respectively. As can be

seen in the table, the calculated values of t- and F- at 95% confidence level are 0.53 and 0.48 and 3.06 and 1.82, respectively. The results showed that the tabulated values of t- and F- are greater than the experimental values, confirming the accuracy and precision of the method. 5. Comparison with existing analytical methods The performance of the proposed potentiometric method using lansoprazole ion-selective electrode was compared with the existing analytical methods (Table S6). As can be seen in Table S6, that HPLC methods are more sensitive and determination can be done over wide concentration range. Methods based on HPTLC and capillary electrophoresis are applicable at lower concentrations. However, these methods require expensive instrumentation, mobile phase and supporting electrolytes. Spectrophotometric methods employ inexpensive instrumentation but some of the methods use organic solvents for extraction of lansoprazole and hence requiring longer time to complete the analysis. 61,62 Spectrofluorimetric methods are sensitive with narrow linear range. In addition, these methods are tedious and requiring more than 30 min to record the fluorescence spectra.23,63 Polarographic methods employ dropping



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mercury electrode which is associated with environmental pollution. The fabrication of lansoprazole ion-selective electrode is very simple which provides reproducible results. The electrode can be used satisfactorily upto 2 months. The limit of detection of the proposed method is poor as compared to other existing methods. The proposed method is fast, pollution free and not requiring multiple steps for sample preparation. Therefore, it is concluded that the proposed method can be employed for rapid determination of lansoprazole in commercial dosage forms. 6. Conclusion A new lansoprazole ion-selective electrode was prepared based on PVC membrane immobilized with lansoprazole tungstate as an electroactive material. The variables were optimized using response surface methodology. Under the optimal conditions, the electrode showed a linear response in the concentration range of 2.0×10 -5 to 2.0×10-3 mol L-1 with the detection limit of 1.57×10-5 mol L-1.The life span of the electrode was about 2 months. The proposed method can be used as an alternate method for analysis of lansoprazole in commercial dosage forms. Supporting information Tables S1,S2,S3,S4,S5 and S6 ; Figures S1,S2,S3 and S4 ORCID N.Rahman: 0000-0002-8324-5067 Acknowledgement UGC (DRS-II) and DST (FIST and PURSE) are acknowledged for providing necessary supports to carry out this work. One of the authors (Sumaiya Khan) is also thankful to UGC,


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New Delhi, for awarding the Maulana Azad National Fellowship [F1-17.1/MANF-2012-13MUS-UTT-15041/(SA-III-Website)] to carry out this work. Department of Applied Physics and USIF, A.M.U., Aligarh, is gratefully acknowledged for recording XRD and SEM, respectively. References (1) Spencer, C. M.; Faulds, D. Lansoprazole- A reappraisal of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficiency in acid-related disorders. Drugs 1994, 48 (3), 404-430. (2) Vanderhoff, B. T.; Tahboub, R. M. Proton pump inhibitors: an update. Am. Fam. Physician 2002, 66 (2), 273-280. (3) Welgae, L. S.; Berardi, R. R. Evaluation of omeprazole, lansoprazole, pantoprazole and rabeprazole in the treatment of acid-related diseases. J. Am. Pharm. Assoc. 2000, 40 (1), 52-62. (4) Langtry, H. D.; Wilde, M. I. Lansoprazole, update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs 1997, 54 (3), 473-500. (5) Smith, H. A review of proton pump inhibitors. S. Afr. Pharm. J. 2014, 81 (5), 13-16. (6) Alothman, Z. A.; Rahman, N.; Siddiqui, M. R. Review on pharmaceutical impurities, stability studies and degradation products: an analytical approach. Rev. Adv. Sci. Eng. 2013, 2 (2), 155-166. (7) Siddiqui, M. R.; Alothman, Z. A.; Rahman, N. Analytical techniques in pharmaceutical analysis: a review. Arabian J. Chem. 2013, 10 (1), S1409-S1421. (8) Rahman, N.; Azmi, S. N. H.; Wu, H. F. The importance of impurity analysis in pharmaceutical products: an integrated approach. Accred. Qual. Assur., 2006, 11 (1), 69-74.



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27

O

N S

N

N H

O

F

F F

Scheme 1. The chemical structure of Lansoprazole

Scheme 2. Cell assembly



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Figure 1. FTIR spectra of (a) lansoprazole and (b) lansoprazole-tungstate

Figure 2. SEM images for (a) PVC membrane (b) PVC membrane incorporating lansoprazole tungstate.


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29

100

80

60

intensity (count)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


40

20

0

20

30

40

50

60

70

80

2

Figure 3. X-ray diffraction pattern of lansoprazole-tungstate membrane.

Figure 4. Plot of measured values vs. predicted value



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30

Figure 5. Contour and 3D response surface plots showing the effect of response time and pH (a and a’), response time and temperature (b and b’) and temperature and pH (c and c’) on the potential.


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31

Figure 6. Perturbation plot (A: response time; B: pH; C: temperature)

Figure 7. Desirability ramp of electrode potential



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32

Figure 8. Plot of potential vs. –log [lansoprazole].

Figure 9. Interaction of lansoprazole cation with LAN-T that produces membrane potential.


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33

Table 1. Design matrix and responses for the CCD Factor 1

Factor 2

Std

Run

A: Time B: pH (seconds)

15 8 14 18 3 16 12 17 4 20 13 19 6 9 10 7 2 1 5 11

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

21.5 35.0 21.5 21.5 8.0 21.5 21.5 21.5 35.0 21.5 21.5 21.5 35.0 1.2 44.2 8.0 35.0 8.0 8.0 21.5

3.9 5.3 3.9 3.9 5.3 3.9 6.3 3.9 5.3 3.9 3.9 3.9 2.5 3.9 3.9 5.3 2.5 2.5 2.5 1.5

Factor 3

Response R1: C: Temp Actual potential (degree (mV) celcius) 47.5 -52.55 58.0 -53.77 65.2 -51.30 47.5 -52.55 37.0 -55.90 47.5 -52.55 47.5 -57.20 47.5 -52.55 37.0 -54.67 47.5 -52.55 29.8 -52.63 47.5 -52.55 58.0 -49.26 47.5 -53.58 47.5 -52.25 58.0 -55.11 37.0 -49.67 37.0 -51.00 58.0 -50.62 47.5 -48.54


Predicted potential (mV)

Residual

-52.55 -53.97 -51.31 -52.55 -56.00 -52.55 -56.92 -52.55 -54.92 -52.55 -52.48 -52.55 -49.26 -53.73 -51.99 -55.12 -49.76 -50.90 -50.47 -48.68

0.00 0.20 0.01 0.00 0.10 0.00 -0.28 0.00 0.25 0.00 -0.15 0.00 0.00 0.15 -0.26 0.01 0.09 -0.10 -0.15 0.14


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34

Table 2. Results of ANOVA and percent contributions of the components for response surface quadratic model Source

Sum of Squares

df

Mean Square

F value

p-value Prob>F

Remark

PC

Model

89.06

9

9.90

273.56

< 0.0001

Significant

A-A: Time

4.26

1

4.26

117.88

< 0.0001

Significant

4.78

B-B: pH C-C: Temperature

82.00

1

82.00

2266.80

< 0.0001

Significant

92.07

1.63

1

1.63

45.03

< 0.0001

Significant

1.83

AB

1.80×10-3

1

1.80×10-3

0.05

0.83

2.09×10-3

AC

2.40×10-3

1

2.40×10-3

0.07

0.80

2.69×10-3

BC

0.10

1

0.10

2.80

0.12

0.11

A2

0.25

1

0.25

6.92

0.02

B2

0.11

1

0.11

3.16

0.11

C2

0.77

0.77

21.36

0.9×10-3

Residual

0.36

1 1 0

Significant

0.28 0.13

Significant

0.87

0.04

Lack of Fit

0.36

5

0.07

Pure Error

0.00

0.00

Cor Total

89.43

5 1 9

Insignificant

Std. Dev.

0.19

R-Squared

0.9960

Mean

-52.54

Adj R-Squared

0.9923

C.V. %

0.36

Pred R-Squared

0.9687

PRESS

2.80

Adeq Precision

61.28

df = degrees of freedom, F-value = test for comparing model variance with residual variance, p-value = probability of seeing the F-value observed if the null hypothesis is supported, Cor total = totals of all information corrected for the mean, PC = percent contribution.


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35

Table 3. Critical response characteristics of lansoprazole sensor Parameters Linear range (mol L-1)

2.0×10-5-2.0×10-3

Correlation coefficient (r)

0.9999

Working pH range

3.5-4.5

Response time (s)

≤30

Slope (mV/decade)

-41.50

Sba

0.17

±t Sbb

0.41

Intercept

126.81

Sa c

0.62

±t Sad

1.52

LOD (mol L-1)

1.57×10-5

a= standard deviation of slope; b= confidence interval of the slope at 95% confidence level; c= standard deviation of intercept; d= confidence interval of the intercept at 95% confidence level. Table 4. Comparison of the proposed method with the reference method at 95% confidence level Proposed method Junior Lanzol 30 Recovery (%) 100.67 RSD (%) 1.01 t-value 0.53 F-value 3.06 Lanbow-30 Recovery (%) 100.22 RSD (%) 1.25 t-value 0.48 F-value 1.82 Theoretical t-(n=8) and F-values (n=4,4) at 95% respectively.

Reference method 101.52 1.76

100.67 1.67

confidence level are 2.306 and 6.39,




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Experimental Design Approach in the Optimization of Potentiometric

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