Microsoft Word - 113-128 113 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Uni and Multivariate Optimization for the Spectrophotometric Determination of Cimetidine Drug via Charge-Transfer Complex Formation Sarmad B. Dikran Alaa K. Mohammed Ali Kh. Mahmood Dept. of Chemistry/ College of Education for Pure Science (Ibn- Al Haitham)/ University of Baghdad Received in: 7/May/2015, Accepted in:14/June/2015 Abstract Charge transfer complex formation method has been applied for the spectrophotometric determination of cimetidine, in bulk sample and dosage form. The method was accurate, simple, rapid, inexpensive and sensitive depending on the formed charge- transfer complex between cited drug and, 2,3-Dichloro-5,6-dicyano-p- benzoquinone (DDQ) as a chromogenic reagent. The formed complex shows absorbance maxima at 587 nm against reagent blank. The calibration graph is linear in the ranges of (5.0 - 50.0) µg.mL-1 with detection limit of 0.268µg.mL-1. The results show the absence of interferences from the excipients on the determination of the drug. Therefore the proposed method has been successfully applied for the determination of cimetidine in pharmaceutical preparations. Keywords: Simplex, Spectrophotometric, Cimetidine , Charge- transfer. 114 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Introduction Cimetidine, or N-Cyano-N-methyl-N-[2-[5-[[methylimidazol-4-yl] thio]ethyl] guanidine [1], is an H2-receptor antagonist drug which reduces the volume and hydrogen ion concentration of gastric juice, it is used for the treatment of duodenal ulcers, Zollinger-Ellison syndrome, and other gastric hypersecretory states [2]. It's also indicated for the relief heartburn and prevents rebleeding in patients of peptic and duodenal ulcers [2,3]. Cimetidine, due to its effects on the immune system and as an H2-receptor antagonist, can inhibit growth of carcinogen-induced colonic tumors in rats, as well as the in vitro human colon cancer cell lines[4]. The Chemical structure of cimetidine is given in (Scheme 1). Scheme (1) Several methods have been reported for determination of cimetidine in bulk and pharmaceutical dosage forms, these methods include titrimetry [5], high performance thin layer chromatography [6], high performance liquid chromatography[7-9], liquid-liquid extraction[10] and Potentiometry [11,12]. Spectrophotometry [13-18] are most convenient techniques because of their inherent simplicity, adequate sensitivity, low cost and wide availability in all quality control laboratories. In experimental chemistry, the optimization of technical system is the process of the adjusting of the control variables to find the levels that achieve the best optimization. Usually, many conflicting response must be optimized simultaneously. In lack of systematic approaches the optimization is done by trial and error, or by changing one control variable at a time while holding the rest constant, such methods requires a lot of experiments to be carried out. Simplex optimization of experimental parameters was first introduced by Spendley [19], and then modified by Nelder [20] and Aberg [21]. Simplex is a geometric figure in which there are n +1 vertices, where (n) represents the number of variables [22], the method found a lot of applications in field of analytical chemistry [23-25], because it offers the capability of optimizing several factors simultaneously depending on a statistical design search to find out the maxima or minima of response, by rejecting the point producing the worst response and a replacement of it by the new point which is obtained statistically. The present work describes the utility of 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ) reagent for spectrophotometric determination of cimetidine in pure form as well as in these dosage forms. In addition, the optimization of chemical dependent variables of affecting absorbance have been studied by using modified simplex method via computer program. N H NH3C S N H N H H3C N CN 115 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Apparatus A cintra 5 spectrophotometer with 1 cm quartz cells were used for absorbance measurements. PH-meter DW-9421 from Philips instrument, a Sartorius BL 210S balance, and a Pentium 4 computer (DELL) was used for data processing. Experimental Material and Reagents All chemicals used were of analytical reagent grad unless otherwise is mentioned, cimetidine standard powders (purity 99.8%) were kindly provided by the State Company for Drug Industries and Medical Appliances, Samara-Iraq (SDI). DDQ 0.1 %( w/v) solution, was prepared by dissolving 0.01 g of the DDQ in 5 mL of acetonitrile and then the solution was diluted to a final volume 10 mL with acetonitrile. Working solutions were freshly prepared by subsequent dilutions. This solution is prepared daily using red- glass volumetric flask because it is a light sensitive reagent. Standard Drugs Solutions Cimetidine stock solution (500 µg.mL-1 ), was prepared by dissolving 50 mg of Cimetidine in 5mL methanol and diluting to 100mL in a volumetric flask with acetonitrile. Working solutions were freshly prepared by subsequent dilutions. General Recommended Procedure Measured volumes of the standard stock solution of the drug containing (25-250 μg) were transferred into 5-mL calibrated flasks, 0.3 ml of 0.1% DDQ solution was added to each, and then diluted to volume with acetonitrile. Absorbance measurements of resulting solutions were done at the wavelength of maximum absorption (587nm) against reagent blank which prepared by the same manner, but without addition of cimetidine. Analysis of Cimetidine in Pharmaceutical Preparations The content of 10 tablets were mixed well and a certain amount of fine powder was accurately weighted to give an equivalent to 200 mg for tablets and dissolve in 50 mL of methanol, swirled, left to stand for 5 mints and diluted to 100mL in a volumetric flask with acetonitrile. The solution then was filtered by using Whatman filter paper No.41 to avoid any suspended or undisclosed material before use, and the first portion of the filtrate was rejected, Working solutions were freshly prepared by subsequent dilutions with acetonitrile and analyzed by the recommended procedure. Results and Discussion Spectrophtometric procedures are popular for their sensitivity in the assay of drugs and hence, charge-transfer complex formation has received considerable attention for the quantitative determination of many pharmaceutical compounds [26-28]. Cimetidine react with DDQ to give yellow color charge-transfer complex, which exhibits absorption maxima at 587 against their reagent blank (Figure1). The some bands may be attributed to the formation of DDQ radical anion, which probably resulted from the dissociation of the donor-acceptor complex in relatively high polar solvents like acetonitrile 116 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 [28]. Therefore, in order to avoid the maximum interference from the reagent blank, the absorbance measurements were carried out at 587 nm in the subsequent work. Optimization of experimental variables I. Univariable Method The experimental variables affecting the development and stabilities of charge-transfer complex formation were achieved through a number of preliminary experiments. Such factors include reagent volume, reaction time, temperature, and the type of organic solvent. For this reason, a variable was modified while maintaining the other variables at their constant values, then by maintaining that variable at its optimized value, another was modified; all variables were optimized via this method. Effect of Reagent Volume: The influence of amount of the used reagent on the absorbance of cimetidine–DDQ complex is illustrated in (Figure 2). 0.3mL of 0.1% solution of DDQ was found to be optimum to develop the maximum color intensity for formed charge-transfer complex, after which no more increase in absorbance values was obtained; therefore, the cited amount of DDQ solution was used. Effect of reaction time The optimum reaction time is determined by following the color development at ambient temperature (25 ± 2 °C). It was found that the reaction of cimetidine with DDQ, under the conditions of the study, is instantaneous, and the formed complex attained maximum absorbance immediately after mixing. The developed color remained strictly unaltered for at least 2 hours in dark place. Effect of Temperature The optimum reaction temperature was determined by following the color development at ambient temperature in the range from (25 - 50 ± 2°C). It was found that the reaction between cimetidine and DDQ is independent on the temperature of the medium up to 40 °C; hence the absorbance of the complex remains, approximately, constant. The value of the absorbance starts to decrease considerably when reaction temperature raised above 40 °C, this may be due to decomposition of the formed charge transfer complex. 25°C was chosen to be optimum, because the product attained maximum and constant absorbance (Figure 3). Effect of Organic Solvent Several organic solvents, namely acetonitrile, dichloromethane, chloroform, methanol, benzene, 1,2-dichloroethane, in addition to water, were examined for their ability to solvate the reaction constituents and to results in maximum absorbance for cimetidine – DDQ charge transfer complex. Acetonitrile was found to be the most suitable solvent to achieve quantitative recovery of cimetidine complex (Table 1). II. Simplex Method Simplex method used to optimize the required reagent volume, reaction time and the reaction temperature. After choosing the convenient boundary conditions for each of the mentioned 117 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 control variables, four arbitrary experimental conditions should were carried out (Table 2) and the results were entered to the Multi-simplex program points (1 to 4) in Table 3. The Simplex program starts to reflect the worst point through the centroid of other points to obtain a new point 5. An experiment was then performed utilizing the variable setting as a reflected point; because this value was better than that at point 1, the latter was rejected and replaced by point 5. A measured absorption signal was feeding again to the program and the process is repeated successively until the optimum conditions are obtained and were similar to those obtained by the univariate method. Calibration Graph Employing the optimum experimental conditions, a linear calibration graph for the determination of cimetidine, by charge-transfer complex formation with DDQ, was obtained (Figure 4), which shows that Beer's law was obey in the concentration range of (5.0-50.0) µg.mL-1, with a correlation coefficient (R= 0.9997) and detection limit of 0.268 µg.mL-1. Spectral Characteristics of the Proposed Method Under optimum experimental conditions of the proposed method, the regression plot showed linear dependence of absorbance signals on the concentrations of the studied drug in the range given. The regression equations, correlation coefficients, molar absorptivities, detection limits and sandell sensitivity in addition to other parameters are given in Table 4. Stoichiometry of the Complex To propose a structure for the formed charge transfer complex between cimetidine and DDQ, two analytical procedures (Slope analysis and Job's of continuous variation method) were followed, Figures 5, 6 and 7 respectively. The results, in both studies, showed that the complex is composed from DDQ and cimetidine with a ratio of 1:1 (DDQ: cimetidine). Ratio = Slope R / Slope D = 4795 / 4793 = 1.00042 ≃ 1 The structure of the formed charge transfer complex can be represented as in Scheme 2. The mechanism of the reaction depends on the formation of an original donor-acceptor (DA) complex through the interaction between one of the nitrogen atoms of amine moieties in the cimetidine (as n-electron donor) and DDQ (as π-acceptor). Then, the dissociation of DA-complex may be promoted by the solvent, especially that with high ionizing power such as acetonitrile, where complete electron transfer from the donor to the acceptor moiety takes place. This is followed by formation of the DDQ radical anions as a predominant chromogen [29]. 118 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Scheme (2)  Accuracy and Precision The accuracy and precision of the proposed method was checked by analyzing three replicates of three different concentration levels of the drug (within Beer's law range). The accuracy was determined by calculating the relative error percentage, while the precision was tested by calculating the percentage relative standard deviation (%RSD). The results indicated good accuracy with resonable precision of the proposed method (Table 5). 119 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 The proposed method was advantageous when compared statistically with other methods found in the literature in having good sensitivity and the results are shown in Table 6. Interferences Study The results showed that no interferences were found in the presence of up to 500 µg.mL-1 of the studied excipients (lactose, sucrose, starch, glucose, magnesium stearate and sodium citrate) in the determination of cimetidine (Table 7). Analysis of Dosage Forms The applicability of the proposed method for the determination of cimetidine in commercial dosage form was examined by analyzing of their content of the active ingredient by the proposed method (charge-transfer complex formation). The results given in Table 8, reveal that the recoveries were in the range of, reflecting high accuracy and precision of the proposed method as indicated by low percentage relative standard deviation value. The recommended method was statistically compared with official, standard and other methods, no significant differences were found between the calculated and theoretical values of t and F- test at 95% confidence limit (Table 9). Conclusions The utility of DDQ reagent for the spectrophotometric determination of cimetidine was established. The method based charge-transfer complex formation between the cited drug and DDQ as a chromogenic reagent. The proposed method was found to be accurate, simple and sensitive. It was satisfactorily applied to the determination of cimetidine in pharmaceutical product samples. References 1. Budavari, S. (2001) The Merck index”, New Jersy, Merck Company, Inc 2. Alwan, Ala,dine, A. S. and Abou, Yousif, Z. (1990) Iraqi Drug Guide, 1st edition, NBSD, Iraq, 40-41. 3. British pharmacopeia (2012) CD. Rom, Co. UK. 4. Rendic ,S. (1999) Drug Interactions of H2-Receptor Antagonists Involving Cytochrome P450 (CYPs) Enzymes from the Laboratory to the Clinic, Croat Med J., 40(3):357-367. 5. Kumar, KG. and Karpaselvi, L. (1994) Determination of cimetidine in pure form and in dosage forms using N,N-dibromo, dimethylhydantoin, The Analyst, 119(6) :1375-1376. 6. Kelani, Km.; Aziz, Am.; Hegazy, Ma. and Farrah, La. (2002) Determination of cimetidine, famotidine, and ranitidine hydrochloride in the presence of their sulfoxide derivatives in pure and dosageforms by high-performance thin-layer chromatography and scanning densitometry, J. AOAC Int. Sep-Oct, 85(5):1015-1020. 7. 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Table (1): Effect of different solvents on the determination of 20µg.mL-1cimetidine; 0.1% DDQ.     Solvent Absorbance Acetonitrile 0.432 Dichloromethane 0.259 Chloroform 0.158 Methanol 0.128 Benzene 0.057 1,2-Dichloroethane 0.119 Water 0.028 122 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Table (2): Boundary of Simplex indeprndent variables for determination of cimetidine. Table (3): Multivariate experiments (Simplex) for the determination of 20 µg.mL-1 cimetidine. Variable Range Step size Reagent volume (mL) 0.1-0.5 0.1 Reaction Time (min.) 0-20 5.0 Temperature (°C) 25-45 5.0 Exp. No. Reagent volume (mL) Reaction time (min.) Temperatur e (°C) Abs. Operation 1 0.1 0 25 0.256 2 0.4 20 25 0.328 3 0.2 20 45 0.322 4 0.5 10 35 0.354 5 0.5 20 45 0.317 R 6 0.3 5 30 0.427 C 7 0.5 0 25 0.404 R 8 0.4 0 35 0.408 R 10 0.2 0 25 0.410 R 11 0.1 5 35 0.233 R 12 0.4 0 25 0.416 R 13 0.2 5 25 0.392 C 14 0.4 0 30 0.411 R 15(13) 0.2 5 25 0.392 R 16 0.5 5 35 0.382 C 17 0.3 0 25 0.432 C 18 0.3 0 30 0.430 C 19(10) 0.2 0 25 0.410 C 123 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Table (4): Spectral characteristics and statistical data of the regression equation for determination of cimetidine via charge transfer formation. Parameter Value λmax (nm) 587 Color yellow Linearity range (µg.mL-1) 5.0-70.0 Molar absorptivity (L.mol-1.cm-1) 4794.441 Regression equation A = 0.0190 [Cim. µg.mL-1] + 0.0564 Calibration Sensitivity 0.0190 Sandell's Sensitivity (µg.cm-2) 52.632 Correlation of Linearity (R2) 0.9994 Correlation coefficient (R) 0.9997 Detection limit (µg.mL-1) 0.268 Table (5): Evaluation of accuracy and precision for the determination of cimetidine by proposed procedure. Conc. ((µg.mL-1) Relative Error % R.S.D.* % Taken Found* 10 9.920 -0.800 2.016 20 19.69 -1.550 2.792 40 39.436 -1.410 1.805 Average of three determinations* Table (6): Analytical parameters for the analysis of cimetidine by the proposed and others methods. Ref. No. methods Linear range µg.mL-1 ε L.mo-l. cm-1 Correlation Coefficient ( R) Recovery RSD% 18 Spectrophotometric 8.0-30.0 6710 99.8-100.2 0.810-0.840 5 H.P.TL.C. 5-50 - - 100.39 ± 1.33 6 H.P.L.C 0.25-83.0 0.998 99.2 - 100.8 17 Spectrophotometric 1s derivative 25.0-150.0 - - 100.27±0.679 - Spectrophotometric Complex formation 10.0-60.0 - - 99.84±0.858 - - Proposed method 5.0-70.0 4794.441 0.9997 98.485- 99.200 1.805-2.792 124 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Table (7): Percent recovery for 20 µg.mL-1of cimetidine in the presence of 500 µg.mL-1of excipients. Excipients Cimetidine Conc. Taken (20 µg.mL-1) Conc. Found (µg.mL-1) %Recovery Lactose 20.155 100.775 Sucrose 20.199 100.995 Starch 19.845 99.225 Glucose 19,888 99.440 Magnesium Stearate 19.929 99.645 Sodium Citrate 19.869 99.345 *Average of three determinations. Table (8): Spectrophotometric determination of cimetidine in pharmaceutical preparations via charge-transferee complex formation with DDQ. Sample Labeled amount (mg) Found amount (mg) Conc. taken (µg.mL-1) Conc. Found* (µg.mL-1) Relative Error % Rec. % R.S.D* % CIMETIDINE (Cimetidine) 200 mg Tablet UK. 200 202.26 10 10.113 1.130 101.13 1.331 202.04 20 20.204 1.020 101.02 2.214 Tagadine (Cimetidine) 200mg/ tablet SDI Iraq 200 203.46 10 10.173 1.730 101.73 2.860 202.25 20 20.225 1.125 101.13 1.510 CimedneR (Cimetidine) 200mg/ tablet DAD Jordaan 200 186.84 10 9.342 -6.580 93.420 2.419 186.83 20 18.683 -6.585 93.415 1.584 *Average of three determinations. 125 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Table (9): t- and F-values for analysis of cimetidine in pharmaceutical compounds for proposed (S.D.I.), and others methods. Proposed Method T-Valuesa F-valuesb Other Methods(N=5) µ S.D Ref. No. N=3 S.D = 0.286 µ = 10.173 Tc =1.048 0.706 5.000 Official 9.890 0.640 18 0.393 10.550 Other 9.950 0.930 30 0.979 14.643 Stander 10.020 0.167 31 a- Theoretical values for T-test at 95% confidence limit were N=6 (2.447). b- Theoretical values for F-test at 95% (19.247) confidence limit, were N=(4,2), (4,2) and 99% ( 18.000) were N=(2,4) respectively, c- Theoretical values for T at 95% confidence limit were N=2(4.303). Fig. (1): Absorption spectra (A) of 20µg.mL-1 cimetidine-DDQ charge-transfer complex, (B) of the blank solution under the recommended procedure Fig. (2): Effect of reaction time on the absorbance of 20 µg.mL-1 cimetidine; 0.1% DDQ. 126 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Fig. (3): Effect of temperature on the absorbance of 20 µg.mL-1 cimetidine; 0.1% DDQ. Fig. (4): Calibration graph of cimetidine under optimum experimental conditions. Fig. (5): Results obtained for the slop ratio method, with variable concentrations of cimetidine; (2.643x10-4M DDQ). 0.4 0.42 0.44 20 25 30 35 40 45 50 55 A b so rb a n ce Temperature (°C) 0 0.2 0.4 0.6 0.8 1 1.2 0 10 20 30 40 50 60 A b so rb a n ce Concentration of the Drug (μg.mL-1) y = 4793.1x + 0.0564 R² = 0.9994 0 0.2 0.4 0.6 0.8 1 1.2 0.0000 0.0001 0.0002 A b so rb a n ce Concentration of the Drug (mole.L-1) 127 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 Fig. (6): Results obtained for the slop ratio method, with variable concentrations of DDQ; (1.590x10-4M) cimetidine. Fig. (7): Continuous variation of 9.907 x10-4 M cimetidine, 9.907 x10-4 M DDQ. y = 4795.4x - 0.4032 R² = 0.9945 0 0.4 0.8 1.2 1.6 0.0001 0.0002 0.0003 A b so rb a n ce Concentration of DDQ (mole.L-1) 0 0.1 0.2 0.3 0.4 0 0.2 0.4 0.6 0.8 1 A b so rb a n ce (VD/VD+VR) 128 | Chemistry 2015) عام 3العدد ( 28مجلة إبن الھيثم للعلوم الصرفة و التطبيقية المجلد Ibn Al-Haitham Jour. for Pure & Appl. Sci. Vol. 28 (3) 2015 لتقدير دواء ايجاد الظروف الفضلى بدراسة المتغيرات االحادية والمتعددة السميتيدين بتكوين معقد االزدواج االيوني سرمد بهجت ديكران عالء كريم محمد علي خليل محمود / جامعة بغداد )ابن الهيثم (كلية التربية للعلوم الصرفة /قسم الكيمياء 2015/حزيران/14، قبل البحث في:2015/أيار/7استلم البحث في: الخالصة طريقة طيفية لتقدير السميتيدين في عينات نقية وفي المستحضرات الصيدالنية. كانت الطريقة دقيقة، بسيطة، استعمالتم ثنائي 2،3سريعة، غير مكلفة وحساسة تعتمد باالساس على تكوين معقد انتقال الشحنة بين العقار قيد الدراسة مع الكاشف 587المعقد المتكون اعظم امتصاص له عند الطول الموجي ) ككاشف لوني. اظھر DDQبارا بنزوكيونون( 5،6كلورو ) مايكروغرام / 50 – 5.0مقابل محلول الخلب، فقد اظھر منحني المعايرة عالقة خطية ضمن المدى من التراكيز (اً نانومتر الت مايكروغرام/ مل. أظھرت الدراسة أيضآ أن الطريقة المقترحة خالية من تأثير المتداخ 0.268مل وبحد كشف المتعارف على وجودھا في المستحضرات الصيدالنية، فقد أمكن تطبيق الطريقة بنجاح لتقدير السميتيدين في بعض تلك المستحضرات. : سمبلكس، طيفيي، سميتيدين، انتقال الشحنة.الكلمات المفتاحية