Flow injection determination of ketotifen fumarate using PVC membrane selective electrodes

Bioelectrochemistry 77 (2009) 53–59

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Bioelectrochemistry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b i o e l e c h e m

Flow injection determination of ketotifen fumarate using PVC membrane selective electrodes M.M. Khater, Y.M. Issa ⁎, Sabrein H. Mohammed Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt

a r t i c l e

i n f o

Article history: Received 4 March 2009 Received in revised form 15 June 2009 Accepted 25 June 2009 Available online 13 August 2009 Keywords: Ketotifen Flow injection analysis Ion-selective electrodes PVC membrane

a b s t r a c t In this study a PVC membrane electrode for determination of ketotifen fumarate is reported, where ketotifen tetraphenylborate (Keto-TPB) was used as ion exchanger. The electrode has linear range of 5.6 × 10− 6– 1.0 × 10− 2 and 1.0 × 10− 5–1.0 × 10− 2 mol/L, with detection limits 2.37 × 10− 6and 4.60 × 10− 6 mol/L in batch and flow injection analysis (FIA), respectively. The electrodes show a Nernstian slope value (58.40 and 61.50 mV/decade in batch and FIA, respectively), and the response time is very short (≤ 10 s). The potential is nearly stable over the pH range 2.0–8.0. Selectivity coefficient values towards different inorganic cations, sugars and amino acids reflect high selectivity of the prepared electrodes. These are used for determination of Ketotifen using potentiometric titration and standard addition methods in pure samples and its pharmaceutical preparations (Zaditen tablets and syrup). The average recovery values are 99.5 and 99.2% with RSD 1.4 and 1.2% for potentiometric titrations and standard addition methods, respectively. The electrode response at different temperatures was also studied. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Ketotifen fumarate, is named as 4-(1-methylpiperidin-4-ylidene)-4Hbenzo-4,9-dihydro-10H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10-one hydrogen (E)-butenedioate [1] while it has the nomenclature 4-(1methyl-4-piperidinylidene)-4H-benzo-[4,5]-cyclohepta-[1,2-b]thiophene-10(9H)-one hydrogen fumarate [2]. It is used as an antihistaminic drug, of white, odorless and crystalline powder. It is often degraded by fat-burners such as Albuterol and Clenbuterol, (Fig. 1). It can be used in combination with other drugs in order to keep feeling their fat-burning effects for longer periods of time without the need for periods of on and off cycling. Side effects can include drowsiness, irritability, nosebleeds and dry mouth. Ketotifen increases appetite; therefore another side effect is typically weight gain, and potentially improves insulin sensitivity within muscle tissue. Ketotifen was determined by several spectroscopic methods at 300 nm [3], using picric acid at 405 nm [4], ambrlyst 15 was used to clean up ketotifen [5], bromophenol blue, and bromothymol green, bromothymol blue or bromocresol purple [6]. Sastry [7] determined ketotifen spectrophotometrically using either diazotized sulphanilimide, N-bromosuccinimide (NBS), Folin-Ciocateau or Azocarmine G. He also [8] measured the fluorescence of the drug at 428.2 and 468 nm. El-Kousy used atomic absorption spectroscopy after precipitation of ketotifen as its [Co(SCN)4]2− ion pair [9]. Different chromatographic methods were reported [10–25]. Coulometric titra-

⁎ Corresponding author. E-mail address: [email protected] (Y.M. Issa). 1567-5394/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bioelechem.2009.06.017

tion method was used for determination of ketotifen based on oxidation with electrogenerated iodine [26]. It was determined using differential pulse polarography with a detection limit 2.5 nM [27]. Iontransfer voltammetry was used to study its reduction [28]. Carbon paste electrode including ketotifen fumarate and hexacyanoferrate was used for cyclic voltammetric determination of the drug [29]. Ion selective electrode for ketotifen fumarate was described based on its ion pair with potassium tetrakis[3,5-bis(trifluoromethyl)-phenyl] borate using PVC membrane plasticized with 2-nitrophenyloctyl ether, 2-nitrophenyldodecyl ether, bis-(2-ethylhexyl)sebacate or 1-isopropyl-4-nitrobenzene [30]. In the present work we used sodium tetraphenylborate (NaTPB) as ion pairing material for ketotifen fumarate. The proposed electrode was fully characterized according to the IUPAC recommendations [31] and was used for potentiometric determination of ketotifen fumarate in the pure form and in its pharmaceutical preparations applying batch and flow injection analysis techniques.

2. Experimental 2.1. Reagents All reagents used were of chemically pure grade. Doubly distilled water was used throughout all experiments. Ketotifen fumarate (ketofuma., M.wt = 425.5 g/mol), and its pharmaceutical preparations (Zaditen tablets, 1 mg/tablet and Syrup 1 mg/5 ml) were provided by Novartis PHARMA S.A.E. Cairo, Egypt. sodium tetraphenylborate (NaTPB) Na[C24H20B], dibutyl phthalate (DBP), dioctyl phthalate

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M.M. Khater et al. / Bioelectrochemistry 77 (2009) 53–59

Fig. 1. The structural formula of ketotifen fumarate.

(DOP), tricresyl phosphate (TCP), ethylhexyl adipate (EHA), poly vinyl chloride (PVC) of high relative molecular weight and tetrahydrofuran (THF) were obtained from Aldrich chemical company. In FIA measurements, the carrier and reagent solutions were degassed by means of vacuum-suction to remove air bubbles which may affect the potential response of the electrode or the flow of the carrier solution. Sample solutions used for injections were freshly prepared prior to measurements. The samples were initially diluted with distilled water. The pH and ionic strength were adjusted in the interior of the manifold. 2.2. Apparatus The potentiometric measurements in batch mode were carried out with a Jenway 3010 digital pH/mV meter. A techne circulator thermostat Model C-100 (Cambridge-England) was used to control the temperature of the test solution. A WTW packed saturated calomel electrode (SCE) or Ag/AgCl/KClsat. were used as an external reference electrode. FIA system is composed of a four channel peristaltic pump (Ismatei, ISM 827), (Zurich, Switzerland) and an injection valve model 5020 with exchangeable sample loop from Rheodyne (Cotati CA, USA). The electrodes were connected to a WTW micro-processor pH/ion-meter pMx 2000 (Weilheim, Germany) and interfaced to a strip chart recorder model BD 111 from Kipp and Zonn (Deflt, Netherlands). In this flow system, a wall-jet cell, providing low dead volume, fast response, good wash characteristics, ease of construction and compatibility with electrodes of various shapes and sizes, was used where a homemade teflon-cup with axially positioned inlet polypropylene tubing is mounted at the sensing surface of the electrode body. The optimized distance between nozzle and the sensing surface of the electrode was 5 mm; this provides the minimum thickness of the diffusion layer and consequently, a fast response.

dissolving the required amount of PVC in 5 ml THF. The calculated amount of ion-associate was dissolved in THF and mixed with the PVC solution in Petri-dish (5.0 cm diameter), then the calculated volume of DBP was added. The total weight of constituents in each batch is fixed at 0.2 g. The membranes were left to dry freely in air (not less than 24 h) to obtain homogenous and uniform thickness. Then, curing small disks (7.5 mm) were punched from the cast films and mounted in a homemade electrode body. The electrodes were filled with a solution that is 10− 2 mol/L with respect to KCl and 10− 3mol/L with respect to drug solution and preconditioned by soaking in 10− 3 mol/L of the drug solution. The electrochemical cell is represented as follows: Ag/AgCl//inner solution/membrane/test solution//Ag/AgCl/ KClsat.. 2.5. Calibration of the electrode For batch measurements, suitable increments of standard Ketofuma. solution were added to 50 ml doubly distilled water so as to cover the concentration range 1.0 × 10− 6–1.0 × 10− 2 mol/L. The sensor and the reference electrodes were immersed in the solution and, after each addition; the values were plotted versus pDrug, at 25 ± 1 °C. For FIA Measurements, a series of freshly prepared solutions of the drug covering the range 1.0 × 10− 6–1.0 × 10− 2 mol/L was injected to the flow stream and the corresponding peak heights were recorded and used to draw the calibration graphs. 2.6. Regeneration of the electrode For this purpose the exhausted electrode (electrode that posses slope deviating pronouncedly from the theoretical value) was soaked, at 25 ± 1 °C, for 1 day in 10− 2 mol/L NaTPB solution followed by soaking for similar periods in 10− 2 M solution of the investigated drug. Subsequently, the electrode activity was checked by performing calibration graphs at 25 ± 1 °C. 2.7. Effect of pH on the electrode potential In batch measurements, the effect of pH of the drug solution on the potential values of the electrode in concentrations of 1.0 × 10− 3, 1.0 × 10− 4 and 1.0 × 10− 5 mol/L was studied. Aliquots of 50 ml were transferred to 100 ml titration cell. The ion-selective-, Ag/AgCl/KClsat., and combined glass electrodes were used to simultaneously record the mV and pH values. The pH of the solution was varied over the range of 2.0–12.0 by the addition of very small volumes of 2.0 mol/L HCl and/or (0.1–1.0 mol/L) NaOH solution. The mV-readings were plotted against the pH-values for the different concentrations.

2.3. Preparation of the ion-pair 2.8. Effect of interfering ions Ketotifen tetraphenylborate (Keto-TPB) was prepared by addition of 100 ml of 10− 2 mol/L ketotifen fumarate (Keto-fuma) solution to 100 ml of 10− 2 mol/L of NaTPB. The resulting precipitate was left in contact with its mother liquor overnight to assure complete coagulation. The precipitate was then filtered and washed thoroughly with distilled water, dried at room temperature and ground to fine powders. Stoichiometry of the ion-pair was 1:1 as confirmed by elemental analysis using automatic CHN analyzer (Perkin-Elmer model 2400) in the Micro Analytical Center, Faculty of Science, Cairo University. The C, H & N percentages are 82.20, 6.20 & 2.24% and the corresponding calculated ones are 82.19, 6.20 & 2.23%. 2.4. Electrode preparation Different percentages of Keto-TPB were used to cover the ranges of 1–10%. The membrane of optimum composition was prepared by

In the batch conditions, the matched potential methods (MPM) [32,33] was applied. This method was recommended in 1995 by IUPAC as a method that gives analytically relevant practical selectivity Pot coefficient values. The selectivity values of K Drug, Jz+ are calculated using the following equation: Pot

KDrug;J z+ =

adrug aJ

ð1Þ

Where: adrug is the activity of the added drug and aJ is the activity of the added interfering ion producing the same increase in potential. In FIA conditions, the separate solutions method [34] was applied, since MPM and other mixed solution methods are time consuming due to the need to prepare many solutions and perform many steps.

M.M. Khater et al. / Bioelectrochemistry 77 (2009) 53–59 Pot The selectivity coefficient values − logK Drug, Jz+ are calculated using the following equation:

pot

log KDrug;J z+ =

h i E2 − E1 z+ 1 = z + log½Drug − log J S

ð2Þ

Where: E1 and E2 are the electrode potentials of 10− 3 M solution of each of the investigated drug and interfering cation, Jz+, respectively and S is the slope of the calibration graph. 2.9. Potentiometric determination of ketotifen fumarate In batch measurements, the standard addition technique was applied [34] by adding known volumes of standard drug solution to 50 ml solution containing different amounts of Keto-fuma. solution. The change in mV reading was recorded for each increment and used to calculate the concentration of the drug in sample solution, using the following equation:  Cx = Cs

VS VX + VS

 nðΔE = SÞ 10 −

VX VS + VX

−1

ð3Þ

Where, Cx is the concentration to be determined, Vx is the volume of the original sample solution, V s and C s are the volume and concentration of the standard solution added to the sample under test, respectively, ΔE is the change in potential caused by the addition, and S is the slope of the calibration graph. Potentiometric titrations of 2–10 ml 10− 2 mol/L Keto-fuma. after dilution to 50 ml by doubly distilled water were titrated against 10− 2 mol/L NaTPB using the corresponding electrode. The end points were determined from the conventional S-shaped curves by the first derivative plots. Similarly, 10− 3 mol/L Keto-fuma. was titrated against 10− 3 mol/L NaTPB solutions. For analysis of tablets, 20 tablets were weighed and ground to fine powder and an appropriate weight from this powder was taken and dissolved in 60% ethanol then, the solution was filtrated in a 50 ml measuring flask and completed to the mark by doubly distilled water, the effect of ethanol on the calibration curve were studied and it has no effect on the slope value but it increases the limit of detection by small value. In case of syrup, it was taken directly to the titration cell. In FIA, 4.7 × 10− 4 mol/L of Keto-fuma., Zaditen tablet and syrup solutions were prepared according to the manufacture claim for concentration. The peak heights were measured and then used for calculating the recovery percent in tablets and syrup. 3. Results and discussion 3.1. Effect of composition The membrane composition was varied to obtain the best performance characteristics, (slope of calibration graph, rectilinear concentration range, detection limit, and reproducibility of the results). The potentiometric response of the electrodes prepared with the optimum amounts of Keto-TPB were examined in the concentration range 1.0× 10− 6–1.0 × 10− 2 mol/L of drug solution. Table 1, illustrates the response characteristics of the electrodes according to their slopes, linear concentration range, limit of detection and the response time for 5 replicates. The lower limit of detection is defined as the concentration of the analyte corresponding to the intersection of the extrapolated linear segments of the calibration graph [30]. After several trials as described in Table 1, it was found that the membrane of the composition of 2.00, 49.00 and 49.00% Keto-TPB, PVC and DBP, respectively, exhibits slope near to the theoretical value (58.40 mV/decade) and low detection limit 2.37 × 10− 6 mol/L except in the case of using 2.00, 49.00 and 49.00% Keto-TPB, PVC and EHA, respectively, where the detection limit is 1.00 × 10− 6 mol/L but the slope was 50.00 mV/decade which is smaller than

55

Table 1 Response characteristics of the Keto-TPB electrodes at 95% confidence intervals, average of 5 replicates at 25.0 ± 0.1 °C. Composition % w/w

Ion-associate Plasticizer PVC 1 49.50 49.50 (DBP) ⁎2 49.00 49.00 3 48.50 48.50 7 46.50 46.50 10 45.00 45.00 2 49.00 49.00 (DOP) 2 49.00 49.00 (EHA) 2 49.00 49.00 (TCP)

Slope Linear concentration (mV/ range (mol/L) decade)

LOD (mol/L)

Response time (s)

56.00

2.50×10− 6–1.0×10− 2 2.37×10− 6 ≤10

58.40 53.30 47.20 53.60 53.8

2.5×10− 6–1.0×10−2 2.5×10− 6–1.0×10− 2 2.5×10− 6–1.0×10− 2 6.3×10− 5–1.0×10− 2 5.6×10− 6–1.0×10− 2

2.37×10− 6 4.20×10−6 5.62×10−6 1.0×10− 5 8.51×10−6

≤10 ≤10 ≤10 ≤10 ≤10

57.0

1.0×10−5–1.0×10− 2

7.72×10− 6

≤10

50.0

1.0×10−6–1.0×10− 2

1.0×10− 6

≤10

the Nernastian value. The membrane of optimum composition (assigned by ⁎ in Table 1) was used to carry out all the subsequent studies. The response characteristics of the electrodes, in batch conditions, were systematically evaluated according to the IUPAC recommendations [31,35]. 3.2. Effect of soaking The effect of soaking on the performance characteristics of the Keto-TPB electrode was studied for variable intervals of time from 15 min. to 17 days. The life span of the electrode is closely related to the nature of ion-exchanger, and its rate of leaching to the bathing solution. Detailed results showing the effect of soaking Keto-TPB electrode in 10− 3 M keto-fuma. solution are listed in Table 2. After several trials, it was found that, the life span of an electrode prepared from 0.50, 2.00, 49.00 and 48.50; KTPB, Keto-TPB, PVC and DBP (calibration curves were constructed every day) increased from 8 to 14 days when it is soaked in the same solution. This can be attributed to common ion effect which decreases the solubility of Keto-TPB into the bathing solution. 3.3. Regeneration of the electrode After regeneration of the exhausted electrode characteristics (slope, linear concentration range and limit of detection 36.00 mV/ decade, 1.00 × 10− 5 to 1.00 × 10− 2 mol/L and 7.21 × 10− 6 mol/L, respectively) were changed to 54.00, 1.00 × 10− 5 to 1.00 × 10− 2 mol/ L and 3.70 × 10− 6 mol/L, respectively. This can be attributed to the formation of Keto-TPB after transferring the electrode from the drug to NaTPB solutions. 3.4. Effect of pH The effect of pH of the test solution on the potential readings of the developed electrodes was studied in batch conditions. As can be seen Table 2 Effect of soaking on Keto-TPB electrode at 25.0 ± 1.0 °C. Soaking time

Slope (mV/ decade)

Linear range (M)

Response time (tresp), (s)

15 min 3h 1d 3d 5d 8d 17 d 30 d

50.0 55.0 58.0 57.7 57.5 54.0 42.0 36.0

5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 5.60 × 10− 6–1.00 × 10− 2 1.00 × 10− 5–1.00 × 10− 2

≤10 ≤10 ≤10 ≤10 ≤15 ≤15 ≤15 ≤15

56

M.M. Khater et al. / Bioelectrochemistry 77 (2009) 53–59 Table 3 Selectivity coefficient values (−logKPot Keto, JZ+) for Keto-TPB electrode.

Fig. 2. Effect of pH on 10− 3 (a), 10− 4 (b), and 10− 5 mol/L (c) of Keto fuma. solution on the potential response of Keto-TPB electrode.

from Fig. 2, the potential variation ± 1 mV due to pH change is considered acceptable in the pH ranges 2.00–8.00. At pH values lower than the previously mentioned pH ranges, the potential readings slightly increase which can be related to interference of hydronium ion. While at pH values higher than pH 8.00, the potential readings decrease gradually due to the formation of free base of the drug and decrease of the protonated species in the test solutions. 3.5. Response time The response time [31] of each electrode was tested by measuring the time required to achieve a steady state potential (within ± 1 mV) after successive immersion of the electrode in a series of drug solution, each having a 10-fold increase in concentration from 1 × 10− 5 to 1.0 × 10− 2 mol/L. The electrode yielded steady potentials within 5– 10 s. The potential readings stay constant, within ± 1 mV, for at least 4 min. Typical potential-time plot for the response characteristics of keto-TPB electrode is shown in Fig. 3. When the electrode was transferred from 1.00 × 10− 4 to 1.00 × 10− 5 mol/L solutions, it was stabilized to a value higher than the calculated one, which may be due to its memory effect.

Interferent

Batch

FIA

Interferent

Batch

Na+ NH+ 4 K+ 2+ Ni Mg2+ Cr3+ Cu2+ Glucose Lactose Maltose

2.48 2.52 1.97 4.05 3.99 4.07 3.95 2.78 2.73 2.45

1.58 1.84 1.58 3.41 3.99 4.07 3.95 – – –

Fructose Sucrose DL-Threonine Glycine D-Alanine L-Arginine L-Cysteine HCl DL-Histidine DL-Asparagine –

3.05 2.79 3.02 3.37 3.16 1.79 1.69 3.42 3.20 –

cations do not interfere because of the difference in their mobility and permeability as compared to ketotifen cation. In the case of sugars and amino acids the high selectivity is related to the difference in polarity and lipophilic nature of their molecules relative to ketotifen cation. 3.7. Optimization of the electrode response in FIA conditions Flow injection analysis (FIA) becomes a wide spread of methods which are characterized by its versatility, high sampling frequency and minimum sample treatment prior to injection into the system, reduced time of analysis and low consumption of reagents compared to the manual procedure [37]. The FIA system was used to evaluate the working characteristics of the constructed electrodes, and to make the applicability of the developed system viable for the determination of the studied drug in different samples. Following this, the optimization of several physicochemical and hydrodynamic parameters of the system was conducted using a univariated method, namely, the dispersion coefficient, the carrier composition, the injection volume and the flow rate. The dispersion coefficient, D, defined as the ratio of concentration of sample material before and after the dispersion process has taken place, can either be limited (D = 1–3), medium (D = 3–10) or large (D N 10) [36], was 1.13. The influence of the injection volume on the performance of the detector response was assessed by proceeding to intercalation of volumes (20.00, 37.50, 75.00, 150.00, 340.00 and 500.00 µL) of the drug standard solution, fixing the flow rate at

3.6. Selectivity of the electrode The selectivity coefficients presented in Table 3 indicate that, KetoTPB electrode is highly selective to ketotifen cation. Most inorganic

Fig. 3. Potential-time plot for the response of Keto-fuma. electrode.

Fig. 4. The recordings obtained for sample volume of 20.0 (a), 37.5 (b), 75.0 (c), 150.0 (d), 340.0 (e) and 500.0 µl (f) of 10− 3 M Keto-fuma. solution.

M.M. Khater et al. / Bioelectrochemistry 77 (2009) 53–59

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studied at different flow rates (5.35, 7.50, 9.70, 12.50, 17.85, 23.25 and 25.00 mL/min.) using 10− 3 M Keto-fuma. solution. Using a constant injection volume, the residence time of the sample is inversely proportional to the flow rate [38]. Therefore, low flow rate would seem likely to produce a steady state signal but will also lead to increased response time due to increased residence time of the sample at the active membrane surface (thicker boundary layers). Fig. 5 represents the recordings obtained for the effect of flow rate variation on the peak heights. It was found that, as the flow rate increased, the peaks become higher until a value (optimum flow rate) the peaks obtained above which are nearly the same. The optimum flow rate (Fm, mL/min) value for the studied electrode is 12.50 mL/min. Under the above conditions, the system permitted analyses to be carried out using a low dispersion system and a carrier stream that is 0.033 mol/L Na2SO4 and 10− 7 mol/L drug. The optimized factors of the FIA along with the response characteristics of the electrode under these conditions were evaluated according to the IUPAC recommendations. The slope, linear concentration range and limit of detection were 64.84 mV/decade, 1.00 × 10− 5–1.00 × 10− 2 mol/L and 4.60 × 10− 6 mol/L, respectively. Fig. 6 represents the recording obtained by the studied electrode at optimum FIA and its corresponding calibration graph. Fig. 5. The recordings obtained for the effect of flow rate of 5.35 (a), 7.50 (b), 9.70 (c), 12.50 (d), 17.85 (e), 23.25 and 25.00 ml/min (g) on the peak height of 10− 3 M Ketofuma. solution.

5 ml/min. An obtained progressive increase in the intensity of the analytical signals was verified [38]. Fig. 4 is a typical representation chart for recordings obtained for the effect of sample volume variation on the peak heights of 10− 3 M of the drug, using the investigated electrode. The volume of the sample loop (Vinj,µl) used was 75 µl as the peak height reaches its maximum value at this volume then remains constant. The dependence of the peak height and time to return to the base line, on the flow rate was studied. The response of the electrode was

3.8. Potentiometric determination of ketotifen fumarate The electrode was used as a sensor for determination of 0.212 mg of Keto-fuma. in pure solutions, zaditen tablet and zaditen syrup applying the standard addition method with recovery% and RSD% of 98.0–99.2% and 1.02–1.5%, respectively. The potentiometric titrations were carried out on 2.13–42.55 mg of the pure drug (Fig. 7), similarly for 2.13 mg zaditen tablet and 2.00 mg zaditen syrup. The recovery% and RSD% are 97.3–102.0 and 0.19–0.72, respectively. Table 4 shows the results obtained, which are in good agreement with those obtained by the official method [1]. The present method has the advantage that it does not need any extraction or separation. In order to decide whether the difference between the results; obtained by the official and the suggested method can be accounted

Fig. 6. The recordings (a) and their corresponding calibration graph (b) obtained for Keto-TPB conventional type electrode at optimum FIA conditions.

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M.M. Khater et al. / Bioelectrochemistry 77 (2009) 53–59

Fig. 7. Potentiometric titrations of 8.51 (a), 12.76 (b), 21.27 (c), and 42.55 mg (d) of Ketotifen fumarate solution against 10− 2 mol/L NaTPB solution using Keto-TPB electrode.

not only by random errors but also by paired t-test and F-test (Table 5). Comparing the F- and t-test values with the tabulated ones, it is clear that the obtained values were lower than the 5% critical values, (95% confidence level) for 5 replicate measurements, i. e., showed near values to that obtained by the official method.

Table 4 Determination of Ketotifen fumarate in pure solutions and pharmaceutical preparations applying the standard additions method and potentiometric titrations in batch condition. Standard addition method

Potentiometric titration

Sample

Taken (mg)

Recovery%

RSD%

Taken (mg)

Recovery%

RSD%

Pure solution

0.212

99.2

1.20

100.0 100.0 100.0 97.3 101.4 98.6 102.0

0.72 0.51 0.27 0.52 0.41 0.19 0.73

100.0

0.71

Zaditen tablet (1 mg/tablet) Zaditen syrup (1 mg/5 ml)

0.212

98.0

1.50

2.13 4.26 8.51 12.76 21.27 42.55 2.13

0.212

98.0

1.02

2.00

Table 5 Statistical treatment of data obtained for the determination of Ketotifen fumarate applying the standard addition method and potentiometric titration using keto-TPB conventional electrode in comparison with official methods. Official

X ± st.d. RSD% t-test F-test

100.2 ± 0.96 0.95

Standard addition method

Potentiometric titration

Pure solution

Zaditen tablet

Zaditen syrup

Pure solution

Zaditen tablet

Zaditen syrup

99.3 ± 0.53 1.20 0.91 1.55

98.0 ± 0.71 1.50 2.60 2.73

97.4 ± 0.55 1.00 2.90 1.34

98.7 ± 0.10 0.19 2.40 1.30

102.0 ± 0.41 0.80 3.10 1.37

101 ± 0.41 0.80 3.00 1.37

X ± st.d.: recovery % ± standard deviation. F-tabulated is 9.82 at 95.0% confidence limit. t-tabulated is 3.14 at 99.0% confidence limit and 6 degrees of freedom.

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