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Kinetic spectrophotometric determination of gemifloxacin mesylate and moxifloxacin hydrochloride in pharmaceutical preparations using 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole.

1. Introduction

Gemifloxacin mesylate (GMF) is (R,S)-7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cydopropyl-6- fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid methanesulfonate, and moxifloxacin (MOX) is {1-cyclopropyl-7-[2,8-diazobicyclo (4.3.0) nonane]-6-fluoro-8-methoxy-1,4 dihydro-4-oxo-3-quinoline carboxylic acid} (Scheme 1) [1]. GMF and MOX are broad-spectrum fluoroquinolone antibiotics that are active against both Gram-positive and Gram-negative bacteria [2]. The bactericidal activity of the drug is mediated by the inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV, essential enzymes involved in bacterial DNA replication, transcription, repair, and recombination. GMF and MOX are antibiotics used to treat respiratory infections, including acute sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia, as well as dermatological infections, as a second-line agent in tuberculosis. Due to their clinical advantages, GMF and MOX are receiving a great interest and there was an increase in number of their pharmaceutical dosage forms in the market in recent past. For routine analysis of the studied drugs, a simple, rapid, and cost-effective analytical method was required.

No official (pharmacopoeia) method has been found for the assay of GMF and MOX in their pharmaceutical formulations. Several methods have been reported on the determination of fluoroquinolones either in pure forms, in dosage forms, or in biological fluids like chromatography [3-6], capillary zone electrophoresis [7, 8], electrochemistry [9-11], atomic absorption spectrometry [12,13], spectrofluorimetry [14-16], and spectrophotometric methods for GMF [17-28] or MOX [12, 29-36] (Tables 1 and 2). These methods were associated with some major drawbacks such as decreased selectivity due to measurement in ultraviolet region and/or decreased simplicity of the assay procedure (e.g., tedious precipitation or liquid-liquid extraction steps in the ionpair formation-based methods). For these reasons, it was worthwhile to develop a new simple and selective spectrophotometric method for the determination of the studied drugs in their pharmaceutical dosage forms.

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Kinetic methods have certain advantages in pharmaceutical analysis regarding selectivity and elimination of additive interferences, which affect direct spectrophotometric methods. The literature is still poor in analytical assay methods based on kinetics for the determination of GMF and MOX in dosage forms. Furthermore, some specific advantages that the kinetic methods possess are as follows [37]:

(i) simple and fast methods because some experimental steps such as filtration and extraction are avoided prior to absorbance measurements;

(ii) high selectivity since they involve the measurement of the absorbance as a function of reaction time instead of measuring the concrete absorbance value;

(iii) other active compounds present in the commercial dosage forms may not interfere if they are resisting the chemical reaction conditions established for the proposed kinetic method;

(iv) colored and/or turbid sample background may possibly not interfere with the determination process.

Therefore, there is a need for another kinetic approach to estimate the drug in commercial dosage forms. This paper describes a simple and sensitive kinetic spectrophotometric method for the determination of GMF and MOX in bulk and drugs formulations. 4-Chloro-7-nitrobenzo-2-oxa-1,3diazole (NBD-Cl) was selected as a derivatizing reagent because it forms chromogenic derivatives with primary or secondary amines requiring relatively mild reaction conditions. GMF and MOX contain primary and secondary amino groups, respectively, which are known to react with (NBDCl) in aqueous/acetone medium resulting in the formation of orange yellow color drug-NBD derivatives, which absorbs maximally at [[lambda].sub.max] 466 and 464 nm for GMF and MOX, respectively. The absorbance increases with time and therefore, two calibration procedures, that is, initial rate and fixed-time methods, are adopted for the determination of each drug in commercial dosage forms.

2. Materials and Methods

2.1. Apparatus. All absorption spectra were made using Kontron 930 (UV-Visible) spectrophotometer (German) with a scanning speed of 200 nm/min and a band width of 2.0 nm, equipped with 10 mm matched quartz cells.

2.2. Materials and Reagents. All chemicals were of analytical reagent grade and the solvents were of spectroscopic grade.

Pharmaceutical grade gemifloxacin mesylate (GMF) was supplied by Al-Obour Pharmaceutical & Chemical Industries Company, Egypt, and its potency was 99.99 [+ or -] 0.39%. Moxifloxacin hydrochloride (MOX) reference standard was provided by Sabaa, Kahira Company, Egypt, and its purity was 100.01 [+ or -] 0.707%.

Pharmaceutical Preparations. All the following tablets were purchased from the commercial source in the local market. Factive tablets were obtained from Oscient Pharmaceuticals Corporation, USA; Flobiotic tablets were obtained from Hikma Pharm. & Chem. Ind. Company, Egypt. GemiQue tablets were obtained from Obour Pharm. & Chem. Ind. Company, Egypt, labeled to contain 320 mg GMF per tablet. Avelox tables were obtained from Bayer, Germany, and Moxiflox tablets were obtained from EVA Pharm. & Chem. Ind. Company, Egypt. Moxifloxacin tablets were obtained from Sabaa International Company for Pharmaceuticals and Chemical Industries, Egypt, labeled to contain 400 mg MOX per tablet.

Stock Solutions. Stock standard solutions of GMF and MOX (100 [micro]g [mL.sup.-1]) were prepared by dissolving an exact weight (10 mg) of the studied drugs in 2.0 mL 0.005 MHCl and further diluted to 100 mL with bidistilled water in a 100 mL measuring flask. These solutions also were found to be stable for at least one week without alteration when kept in the refrigerator.

Reagents. 4-Chloro-7-nitrobenzofurazan (NBD-Cl) (Fluka, Germany), a fresh solution (5.0 x [10.sup.-3] M) in acetone, was prepared daily. Buffer solution was prepared as follows: 0.620 g boric acid and 0.75 g potassium chloride were dissolved with 100 mL of water and pH of 8.5 and 9.0 is adjusted only with 0.1 M sodium hydroxide solution.

2.3. Recommended General Procedures

2.3.1. Rate Data Method. Aliquots of standard GMF (100 [micro]g [mL.sup.-1]) (0.05-1.0 mL) and MOX (100 [micro]g [mL.sup.-1]) (0.2-1.2 mL) solutions were transferred into a series of 10 mL volumetric flasks. Then 0.4 mL of borate buffer solution was added followed by addition of 1.0 and 0.8 mL of (5.0 x [10.sup.-3] M) NBD-Cl solution for GMF and MOX, respectively, and the volume was made up to the mark with 50% (v/v) aqueous acetone, mixed well, and heated on water bath at 70 [+ or -] 5[degrees]C. After mixing, the contents of each flask were completed to 10 mL with 50% (v/v) aqueous acetone and immediately transferred to the spectrophotometric cell and the increase in absorbance was recorded at 466 and 464 nm GMF and MOX, respectively, as a function of time between 2.5-30 min against reagent blank treated similarly. The rate of the reaction (v) at different concentrations was obtained from the slope of the tangent to the absorbance-time curve. The calibration curve was constructed by plotting the logarithm of the reaction rate (log v) versus the logarithm of the molar concentration of the drug (log C). The amount of the drug was obtained either from the calibration graphs or the regression equation.

2.3.2. Fixed-Time Method. Accurately measured aliquots (0.05-1.0 mL) of GMF (100 [micro]g [mL.sup.-1]) standard solution and (0.2-1.2mL) of MOX (100 [micro]g [mL.sup.-1]) standard solution were transferred into 10 mL calibrated volumetric flasks. Then 0.4 mL of borate buffer solution was added followed by 1.0 and 0.8 mL of NBD-Cl solution (5.0 x [10.sup.-3] M) for GMF and MOX, respectively, and the volume was completed to the markwith 50% (v/v) aqueous acetone, mixed well, and heated on water bath at 70 [+ or -] 5[degrees]C for a fixed time of 20 and 15 min for GMF and MOX, respectively. After mixing, the contents of each flaskwere completed to 10 mLwith 50% (v/v) aqueous acetone and immediatelytransferred to the spectrophotometric cell and the absorbance was recorded at 466 and 464 nm GMF and MOX, respectively, against reagent blank treated similarly. The calibration curve was constructed by plotting the absorbance against the final concentration of the drug. The amount of the drug in each sample was computed from the corresponding equation of the calibration graph for the fixed time method (A = slope C + intercept).

2.4. Procedure for Pharmaceutical Formulations. A total of 20 tablets of each drug were crushed and finely powdered. An accurately weighed quantity of the mixed contents of the tablets, equivalent to 100 mg of the drug, was extracted into 50 mL of 0.005 M hydrochloric acid solution, stirred for 15 minutes, and then filtered using Whatman no. 42 filter paper into a 100 mL volumetric flask to isolate the insoluble excipients. The residue was washed twice with 0.005 M hydrochloric acid solution and washings were added to the filtrate and diluted to volume with the same solvent. Aliquots of the tablet solutions were treated as under the above recommended procedures. Determine the nominal content of the tablets either from a previously plotted calibration graph or using the corresponding regression equation.

2.5. Determination of Molar Ratio of the Reaction. Job's method of continuous variation [38] was employed. Master equimolar solutions (5.0 x 10-4 M) of drugs and reagent were prepared. Series of 10 mL portions of the master solutions of the drugs and the analytical reagent were made up comprising different complementary ratios (0 : 10, 1:9, 9: 1, and 10 : 0, inclusive) in 10 mL calibrated flasks. The solutions were further manipulated as described under the general recommended procedure and data treatment.

3. Results and Discussion

3.1. Absorption Spectra. The reaction between the investigated drugs and NBD-Cl in slightly alkaline borate buffer produces an orange-yellow color with maximum absorbance at 466 and 464 nm for GMF and MOX, respectively (Figure 1). Different experimental parameters affecting the color development and its stability were carefully studied and optimized. Such factors were changed individually while keeping others constant. These factors include pH and volume of buffer, NBD-Cl concentration, temperature, and solvent.

3.2. Optimization of the Reaction Conditions

3.2.1. The Effect of pH and Volume of Buffer. The effect of pH change the absorbance was studied by using 0.1 M borate buffer in the pH range 7.5-10. Below pH 7.0, no color was formed. With increasing the pH, higher absorbance values were obtained with maximum absorbance at pH values 9.0 and 8.5 for GMF and MOX, respectively, (Figure 2). At higher pH values, the background absorbance of the reagent increased resulting in a net decrease in absorbance of the drug solutions. Other buffers having the same pH values such as phosphate buffer and citric acid phosphate (Mcllvaine's buffer) and weak bases such as 0.1 M sodium bicarbonate were tried and compared with the 0.1 M borate buffer. Borate buffer was found to be superior because it resulted in more stable highly colored solutions. The effect of the volume of borate buffer was studied and it was found that 0.4 mL was sufficient to get the highest color intensity.

3.2.2. The Effect of NBD-Cl Concentration. The most important factor affecting on the formation of reaction product was the concentration of NBD-Cl. The influence of the concentration of NBD-Cl was studied using different volumes of (5.0 x [10.sup.-3] M) NBD-Cl solution. Figure 3 shows that 1.0 and 0.8 mL of (5.0 x [10.sup.-3] M) NBD-Cl solution for GMF and MOX, respectively gave maximum sensitivity. Increasing the volume of NBD-Cl leads to the decrease in the absorbance; this may be due to the high background absorbance of the reagent.

3.2.3. The Effect of Temperature and Time. The effect of temperature was studied in the range of 30-90[degrees]C with constant heating time. Increasing the temperature of the water bath produced an increase in the reaction rate and consequently in absorbance of the reaction product up to 70 [+ or -] 5[degrees]C for the two drugs, above which almost constant absorbance values were obtained. Therefore, 70[degrees]C was selected as the optimum temperature for both drugs (Figure 4). Heating at temperatures higher than 70 [+ or -] 5[degrees]C resulted in slightly turbid solutions. In order to determine the optimum time required for the completion of the reaction, the derivatization reaction was carried in the range of 5.0-40 min. Complete color development was attained after 20 and 15 min for GMF and MOX, respectively, in water bath at 70 [+ or -] 5[degrees]C.

3.2.4. Effect of Solvent. Several diluting solvents were tested to determine the most appropriate solvent: methanol, acetone, dichloromethane, chloroform, and acetonitrile. Acetone was found to be the best solvent regarding sensitivity and the highest absorbance values. The effect of time on the stability of the drug-NBD-Cl derivative in acetone was studied at different time intervals. The color remains stable at least for 12 h, while methanol caused about 50% decrease in sensitivity. The situation was much worse when distilled water was used because turbid solutions were obtained. A summary for the optimization of the variables affecting the reaction of both drugs with NBD-Cl is given in Table 3.

3.3. Kinetics Study of the Reactions. The rate of reaction was found to be drug dependant. The rates were followed at 70 [+ or -] 5[degrees]C with various concentrations of the investigated drugs in the range 1.029 x [10.sup.-6] - 1.65 x [10.sup.-5]M (0.5-8.0 [micro]g [mL.sup.-1]) for GMF and the range 4.57 x [10.sup.-6]- 2.74 x [10.sup.-5] M (2.012 [micro]g [mL.sup.-1]) for MOX, keeping NBD-Cl at the concentration stated above. The graphs shown in Figures 5 and 6 clearly indicate that the reaction rates obey the following equation:

Rate of the reaction = [DELTA]A/[DELTA]t = K'[[C].sup.n]. (1)

The rate of reactions could be estimated as [DELTA]A/[DELTA]t [39], where A is the absorbance, t is the measuring time in seconds, K' is the pseudo-order rate constant, C is the concentration of the drug mol [L.sup.-1], and n is the order of reaction.

Taking logarithms of rates and concentrations, (1) is transformed into

log (rate) = Log = log [DELTA]A/[DELTA]t + log K' + n log [C]. (2)

A calibration curve was constructed by plotting the logarithm of the reaction rate log (rate) versus logarithm of drug concentration log [C] which showed a linear relationship (Figures 7 and 8). The logarithmic form of the above equation is written as follows:

log (rate) = log [DELTA]A/[DELTA]t = 2.1602 + 1.1449 log [GMF], r = 0.9995, (3)

log (rate) = log [DELTA]A/[DELTA]t = 0.9901 + 1.2901 log [MOX], r = 0.9999. (4)

Hence K' = 144.61 [sec.sup.-1] for GMF and 19.50 [sec.sup.-1] for MOX and the reaction is pseudo-first-order (n = 1) with respect to either of the two drugs.

3.4. Evaluation of the Kinetic Methods. The determination of MOX and GMF under the optimized experimental conditions mentioned above, in which the NBD-Cl concentration was at least 30 times the concentration of GMF or at least 18 times the concentration of MOX, would result in pseudozero-order conditions with respect to NBD-Cl concentration and the rate of reaction will be directly proportional to the concentration of the drug in a pseudo-first-order rate equation as follows:

Rate = K' [C], (5)

where K' is the pseudo-first-order rate constant.

Equation (5) was the basis for several experiments, which were performed to obtain the drug concentration using the rate data. Initial rate, rate constant, fixed-concentration, and fixed-time methods [40] were tried and the most suitable analytical method was selected taking into account the applicability, sensitivity (i.e., the slope of the calibration graph), correlation coefficient (r), and intercept (a).

3.4.1. Initial-Rate Method. In this method, graphs of the rate (at the beginning of the reaction) versus drug concentration were not easy to obtain, because the first step of the reaction was too fast to follow, so tangents of the curve at zero-time were not easy to draw. Therefore, this method could not be applied.

3.4.2. Rate-Constant Method. The best way to obtain an average K value for the reaction is to plot the logarithm of the concentration or the logarithm of any related property versus time. The slope of the line is -K7/2.303, from which the rate constant is obtained. If a straight line is obtained, it indicates that the reaction is first order. Graphs of log (absorbance) versus time over the concentration ranges 1.03 x [10.sup.-6] -1.65 x [10.sup.-5] M (0.5-8.0 [micro]g [mL.sup.-1]) for GMF and 4.57 x [10.sup.-6] -2.74 x [10.sup.-5] M (2.0-12 [micro]g [mL.sup.-1]) for MOX were plotted and all appeared to be rectilinear. Pseudo-first-order rate constants (K7) corresponding to different concentrations of the investigated drugs [C] were calculated from the slopes multiplied by -2.303 (Table 4). Regression of K' versus [C] gave the following equations:

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (6)

The values of (r) indicate poor linearity which is probably due to inconsistency of K' as a result of the inevitable slight changes in temperature of the reaction.

3.4.3. Fixed-Concentration Method. Reaction rates were determined for different concentrations of the investigated drugs. A preselected absorbance value was fixed (0.3 for both MOX and GMF) for different concentrations of the two drugs, in the range 8.24 x [10.sup.-6] - 1.65 x [10.sup.-5] M (4.0-8.0 [micro]g [mL.sup.-1]) for GMF and the range 9.14 x [10.sup.-6]-2.74 x [10.sup.-5] M (4.0-12^g[mL.sup.-1]) for MOX, and the time required for each concentration to reach the preselected absorbance value was measured in seconds (Table 5). The reciprocal of time (1/f) was plotted versus the initial concentrations of the drug and the following equations were obtained by linear regression:

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (7)

Although the correlation coefficient values are acceptable (>0.999), the method still suffers from the narrow linearity ranges.

3.4.4. Fixed-Time Method. Reaction rates were determined for different concentrations of the studied drugs. At a pre-selected fixed time, which was accurately determined, the reaction was quenched by cooling and absorbance was measured. Calibration graphs of the absorbance (A) versus initial concentration [C] were established at different fixed-time intervals of 2.5-30 min. (Figures 6 and 7). At each fixed time, regression equation parameters were calculated and it was found that the slopes increase with time and the most acceptable values for the intercept and the correlation coefficient (r)wereobtainedatafixed time of 20 min for GMF and 15 min for MOX, which were therefore chosen as the most suitable time intervals for measurements. Calibration graphs were linear over the concentration ranges mentioned in Table 6.

3.5. Stoichiometric Ratio. The stoichiometry of the reaction was studied by adopting Job's method of continuous variation [38] for fixed-time method. Job's method plot reached maximum absorbance at a mole fraction of 0.5 which indicated a reaction ratio of 1: 1 (drug: NBD-Cl). The reaction mechanism can be explained by the formation of a Meisenheimer complex which is produced through a nucleophilic substitution reaction type. As presented in the following scheme, one molecule of NBD-Cl condenses with one molecule of the drug through its secondary aliphatic amino group (Figure 9).

3.6. Mechanism of the Color Reaction. N-Alkyl substituted tertiary amine fluoroquinolones such as ofloxacin and pefloxacin were found inactive towards NBD-Cl. Even aalkyl substituted secondary fluoroquinolone such as lomefloxacin gave weakly colored unstable products with NBDCl, possibly due to steric hindrance. Hence, NBD-Cl can be considered a selective reagent for the two studied drugs (GMF or MOX) among other fluoroquinolones of similar structure (Scheme 2).

3.7. Validation of the Method

3.7.1. Linearity. In the proposed method, linear plots with good correlation coefficients were obtained in the concentration ranges of 0.5-8.0 and 2.0-12 [micro]g [mL.sup.-1] for GMF and MOX, respectively. Table 3 presents the performance data for the proposed spectrophotometric method, including molar absorptivities, Sandell's sensitivities, linearity ranges, and regression equations calculated from calibration graphs. Other statistical parameters such as the intercept (a), the slope (fc), and the relative standard deviation are also given in Table 3. The high values of the correlation coefficients of the regression equations indicate good linearity over the working concentration ranges.

3.7.2. Detection and Quantitation Limits. In accordance with the recommendations of ICH [41], the limit of detection, LOD, is 3.3 [sigma]/s, where a is the standard deviation of replicate determinations of the blank and s is the slope of the calibration graph. On the other hand, the limit of quantitation, LOQ, is defined as 10 [sigma]/s. The detection and quantitation limits of the two fluoroquinolones using the proposed spectrophotometric procedures are presented in Table 3. Obviously, the LOD and LOQ values as well as the concentration ranges are lower due to the higher sensitivity which is offered by this technique.

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3.7.3. Accuracy and Precision. The accuracy and precision of the proposed methods were carried out by six replicate determinations at four different concentrations. Percentage relative standard deviation (RSD%) as precision and percentage relative error (RE%) as accuracy of the suggested method were calculated. Table 7 shows the values of relative standard deviations for different concentrations of the drugs determined from the calibration curves. These results of accuracy and precision show that the proposed methods have good repeatability and reproducibility. The proposed methods were found to be selective for the estimation of GMF and MOX in the presence of various tablet excipients. For this purpose, a powder blend using typical tablet excipients was prepared along with the drug and then analyzed. The recoveries were not affected by the excipients and the excipients blend did not show any absorption in the range of analysis.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

http://dx.doi.org/10.1155/2014/917234

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[36] L. M. Abdellaziz and M. M. Hosny, "Development and validation of spectrophotometric, atomic absorption and kinetic methods for determination of moxifloxacin hydrochloride," Analytical Chemistry Insights, vol. 6, no. 1, pp. 67-78, 2011.

[37] D. P?rez-Bendito, A. G?mez-Hens, and M. Silva, "Advances in drug analysis by kinetic methods," Journal of Pharmaceutical and Biomedical Analysis, vol. 14, no. 8-10, pp. 917-930,1996.

[38] P Job, Spectrochemical Methods of Analysis, Wiley Intersience, New York, NY, USA, 1971.

[39] F. Wilkinson and V. Nostrand, Chemical Kinetics and Reaction Mechanism, Rheihold Company, New York, NY, USA, 1980.

[40] D. Perez-Bendito and M. Silva, Kinetic Methods in Analytical Chemistry, John Wiley and Sons, New York, NY, USA, 1988.

[41] International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Validation of Analytical Procedures: Text and Methodology, Q2(R 1), Complementary Guideline on Methodology dated 06 November 1996, ICH, London, UK, 2005.

[42] J. N. Miller and J. C. Miller, Statistics and Chemometrics for Analytical Chemistry, Prentice Hall, England, UK, 5th edition, 2005.

Mohammed G. Abdel Wahed, Ragaa El Sheikh, Ayman A. Gouda, and Sayed Abou Taleb

Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt

Correspondence should be addressed to Ayman A. Gouda; aymangouda77@gmail.com

Received 4 September 2013; Accepted 3 December 2013; Published 3 February 2014

Academic Editor: Adam F. Lee

TABLE 1: Comparison between the reported spectrophotometric methods
for determination of GMF.

Reagent                         [[lambda].sub.max]    Concentration
                                        nm           range ([micro]g
                                                      [mL.sup.-1])

UV spectrophotometry                   272                8-40
UV spectrophotometry                   267                10-70
Iodine                                 290               6.0-30
2, 3-Dichloro-5,                       470               2.0-10
  6-dicyano-p-
  benzoquinone (DDQ)
7,7,8,8-                               840              2.5-12.5
  Tetracyanoquinodimethane
  (TCNQ)
Tetracyanoethylene (TCNE)              420               1.0-5.0
Safranin O                             525               3.0-15
Methylene blue                         650               4.0-20
Naphthol blue 12BR                     620               2.0-10
Azocarmine G                           540               2.0-10
Folin-Cio calteu/N aOH                 685                10-50
3-Methyl-2-benzothiazolinone           617               10-100
  hydrazone Fe[Cl.sub.3]
Fe[Cl.sub.3]/1,10-                     466               40-200
  phenanthroline
Ninhydrine (DMF)                       590               4.0-32
Ascorbic acid (DMF)                    530               8.0-40
p-benzoquinone (PBQ)                   400               9.0-72
Palladium/zero order                   430               2.0-14
Palladium/1st derivative               480               1.0-10
Palladium/2nd derivative               500               1.0-15
NBD-Cl                                 466               0.5-8.0

Reagent                         Molar absorptivity     Reference
                                  L [mol.sup.-1]
                                    [cm.sup.-1]

UV spectrophotometry                                      [17]
UV spectrophotometry                                      [19]
Iodine                           1.46 x [10.sup.4]
2, 3-Dichloro-5,                 4.17 x [10.sup.4]        [23]
  6-dicyano-p-
  benzoquinone (DDQ)
7,7,8,8-                         3.42 x [10.sup.4]
  Tetracyanoquinodimethane
  (TCNQ)
Tetracyanoethylene (TCNE)        8.41 x [10.sup.4]
Safranin O                       2.81 x [10.sup.4]
Methylene blue                   2.20 x [10.sup.4]        [24]
Naphthol blue 12BR               4.02 x [10.sup.4]
Azocarmine G                     4.15 x [10.sup.4]
Folin-Cio calteu/N aOH                                    [25]
3-Methyl-2-benzothiazolinone
  hydrazone Fe[Cl.sub.3]
Fe[Cl.sub.3]/1,10-
  phenanthroline
Ninhydrine (DMF)                 9.68 x [10.sup.3]
Ascorbic acid (DMF)              5.58 x [10.sup.3]        [26]
p-benzoquinone (PBQ)             4.98 x [10.sup.3]
Palladium/zero order            1.365 x [10.sup.4]
Palladium/1st derivative         9.37 x [10.sup.4]        [28]
Palladium/2nd derivative         1.59 x [10.sup.4]
NBD-Cl                          4.0892 x [10.sup.4]   Present work

TABLE 2: Comparison between the previously mentioned spectrophotometric
methods for determination of MOX.

Reagent                      [[lambda].sub.max]    Concentration
                                    (nm)          range ([micro]g
                                                   [mL.sup.-1])

Ammonium reineckate                 525              100-1100
UV spectrophotometry                295               2.0-25
  HCl (0.1 N)
UV spectrophotometry                290               1.0-12
Crotonaldehyde/dichlone             648               3.0-48
Folin-Ciocalteu's/                  750               5.0-40
  [Na.sub.2]C[O.sub.3]
UV spectrophotometry
HCl (0.1 N) (pH 1.2)                296               1.0-12
Phosphate buffer (pH 7.4)           289               1.0-14
2,3,5,6-Tetrachloro-
  1,4-benzoquinone/
  acetaldehyde
  Initial rate                      652               5.0-100
  Fixed time                        652               15-150
Bromocresol green (BCG)            415.8              2.0-20
[Fe.sup.3+]/1,10-                   510               0.8-6.0
  phenanthroline
[Fe.sup.3+]/2,2; bipyridyl          520               0.8-4.0
Bismuth (III) tetraiodide           462                16-96
NBD-Cl                              464               2.0-12

Reagent                             Molar            Reference
                                absorptivity L
                                 [mol.sup.-1]
                                 [cm.sup.-1]

Ammonium reineckate           1.075 x [10.sup.3]        [12]
UV spectrophotometry                                    [30]
  HCl (0.1 N)
UV spectrophotometry                                    [31]
Crotonaldehyde/dichlone
Folin-Ciocalteu's/
  [Na.sub.2]C[O.sub.3]
UV spectrophotometry
HCl (0.1 N) (pH 1.2)          4.63 x [10.sup.4]         [33]
Phosphate buffer (pH 7.4)     4.08 x [10.sup.4]
2,3,5,6-Tetrachloro-
  1,4-benzoquinone/
  acetaldehyde
  Initial rate                                          [34]
  Fixed time
Bromocresol green (BCG)                                 [35]
[Fe.sup.3+]/1,10-             6.61 x [10.sup.4]
  phenanthroline
[Fe.sup.3+]/2,2; bipyridyl     8.5 x [10.sup.4]         [36]
Bismuth (III) tetraiodide      4.5 x [10.sup.3]
NBD-Cl                       3.48535 x [10.sup.4]   Present work

TABLE 3: Experimental and analytical parameters for the kinetic
spectrophotometric determination of GMF and MOX.

Parameter                                     GMF

pH and volume of borate buffer            pH 9.0/0.4mL
Volume of 5.0 x [10.sup.-3]                   1.0
  M NBD-Cl (mL)
Temperature ([degrees]C)                       70
Reaction time (min.)                           20
Solvent                            50% (v/v) aqueous acetone
Amax(nm)                                      466
Concentration range (M)              1.029 x [10.sup.-6] -
                                       1.65 x [10.sup.-5]
Concentration range ([micro]g               0.5-8.0
  [mL.sup.-1])
Molar absorptivity ([epsilon])        4.0892 x [10.sup.4]
  (L [mol.sup.-1] [cm.sup.-1])
Sandell's sensitivity (ng                    11.87
  [cm.sup.-2])
Regression equation (a)
  Slope                                      0.0972
  Intercept                                  0.0068
Correlation coefficient (r)                  0.9999
LOD (M), ([micro]g [mL.sup.-1])    2.47 x [10.sup.-7], (0.12)
LOQ (M), ([micro]g [mL.sup.-1])    8.24 x [10.sup.-7], (0.4)
Recovery % [+ or -] SD                100.03 [+ or -] 0.87
RSD%                                          0.87
RE%                                           0.91
t-value (b)                               0.21 (2.57)
F-value (b)                               2.03 (5.05)

Parameter                                     MOX

pH and volume of borate buffer            pH 8.5/0.4mL
Volume of 5.0 x [10.sup.-3]                   0.8
  M NBD-Cl (mL)
Temperature ([degrees]C)                       70
Reaction time (min.)                           15
Solvent                            50% (v/v) aqueous acetone
Amax(nm)                                      464
Concentration range (M)               4.57 x [10.sup.-6] -
                                       2.74 x [10.sup.-5]
Concentration range ([micro]g                2.0-12
  [mL.sup.-1])
Molar absorptivity ([epsilon])        3.48535 x [10.sup.4]
  (L [mol.sup.-1] [cm.sup.-1])
Sandell's sensitivity (ng                    12.56
  [cm.sup.-2])
Regression equation (a)
  Slope                                      0.0802
  Intercept                                 -0.0039
Correlation coefficient (r)                  0.9998
LOD (M), ([micro]g [mL.sup.-1])    8.22 x [10.sup.-7], (0.36)
LOQ (M), ([micro]g [mL.sup.-1])    2.74 x [10.sup.-6], (1.2)
Recovery % [+ or -] SD                99.99 [+ or -] 1.24
RSD%                                          1.24
RE%                                           1.30
t-value (b)                               0.38 (2.78)
F-value (b)                               2.07 (5.19)

(a) A = a + bC, where C is the concentration in [micro]g
[mL.sup.-1].

(b) Theoretical value for t and F at 95% confidence level at
P = 0.05.

TABLE 4: Values of rate constant K'.

[GMF] M                 K' ([S.sup.-1])

2.06 x [10.sup.-6]   -6.909 x [10.sup.-4]
4.12 x [10.sup.-6]   -9.212 x [10.sup.-4]
8.24 x [10.sup.-6]   -11.515 x [10.sup.-4]
1.24 x [10.sup.-5]   -13.818 x [10.sup.-4]
1.65 x [10.sup.-5]   -16.121 x [10.sup.-4]

[MOX] M                 K' ([S.sup.-1])

4.57 x [10.sup.-6]   -2.303 x [10.sup.-4]
9.14 x [10.sup.-6]   -4.606 x [10.sup.-4]
1.37 x [10.sup.-5]   -6.909 x [10.sup.-4]
1.83 x [10.sup.-5]   -9.212 x [10.sup.-4]
2.28 x [10.sup.-5]   -11.515 x [10.sup.-4]
2.74 x [10.sup.-5]   -13.818 x [10.sup.-4]

TABLE 5: Values of reciprocal time taken at fixed
absorbance for the different rates of variable
concentration of drugs at constant concentrations
of NBD-Cl.

[GMF] M               1/f ([S.sup.-1])         [MOX] M

8.24 x [10.sup.-6]   2.02 x [10.sup.-3]   9.14 x [10.sup.-6]
1.24 x [10.sup.-5]   3.70 x [10.sup.-3]   1.37 x [10.sup.-5]
1.65 x [10.sup.-5]   5.13 x [10.sup.-3]   1.83 x [10.sup.-5]
                                          2.28 x [10.sup.-5]
                                          2.74 x [10.sup.-5]

[GMF] M               1/f ([S.sup.-1])

8.24 x [10.sup.-6]   1.19 x [10.sup.-3]
1.24 x [10.sup.-5]   4.76 x [10.sup.-3]
1.65 x [10.sup.-5]   8.33 x [10.sup.-3]
                     1.11 x [10.sup.-2]
                     1.38 x [10.sup.-2]

TABLE 6: Regression equations for GMF and
MOX at fixed time and 70 [+ or -] 5[degrees]C.

Time   Regression equation    Correlation
(min)      for GMF (a)        coefficient

2.5    A = 0.0279C + 0.0419      0.980
5      A = 0.0723C + 0.0456     0.9956
10     A = 0.0707C + 0.0552     0.9990
15     A = 0.0911C + 0.0368     0.9993
20     A = 0.0972C + 0.0068     0.9999
25     A = 0.0958C + 0.0329     0.9986
30     A = 0.0979C + 0.0318     0.9990

Time   Regression equation    Correlation
(min)      for MOX (a)        coefficient

2.5    A = 0.0552C - 0.053      0.9967
5      A = 0.0662C - 0.0309     0.9989
10     A = 0.0775C - 0.0236     0.9992
15     A = 0.0802C - 0.0039     0.9998
20     A = 0.0814C - 0.0083     0.9994
25     A = 0.0815C - 0.0109     0.9983
30

(a) A: absorbance; C: concentration.

TABLE 7: Interday and intraday accuracy and precision for
the determination of GMF and MOX in bulk powders by the
proposed method (fixed time).

Drug               Taken [micro]g   Found [micro]g   RSD% (a)
                     [mL.sup.1]       [mL.sup.1]

                                       Interday

                        1.0             1.002          0.37
GMF                     3.0              2.99          0.25
                        5.0              4.96          0.31
                        7.0              7.04          0.52
Mean [+ or -] SD
                        3.0              2.98          0.23
MOX                     6.0              6.02          0.40
                        9.0              8.98          0.42
                         12             11.97          0.39
Mean [+ or -] SD
                                       Intraday

                        1.0             0.997          0.18
GMF                     3.0              2.97          0.11
                        5.0              4.98          0.27
                        7.0              6.96          0.30
Mean [+ or -] SD
                        3.0              3.04          0.21
MOX                     6.0              5.95          0.35
                        9.0              9.04          0.29
                         12             12.07          0.27
Mean [+ or -] SD

Drug               RE% (a)   Recovery%b [+ or -] SD

                   Interday

                    0.20      100.20 [+ or -] 0.37
GMF                 -0.33     99.67 [+ or -] 0.25
                    -0.80     99.20 [+ or -] 0.31
                    0.57      100.57 [+ or -] 0.52
Mean [+ or -] SD              99.91 [+ or -] 0.60
                    -0.67     99.33 [+ or -] 0.23
MOX                 0.33      100.33 [+ or -] 0.40
                    -0.22     99.78 [+ or -] 0.42
                    -0.25     99.75 [+ or -] 0.39
Mean [+ or -] SD              99.80 [+ or -] 0.41
                   Intraday

                    -0.30     99.70 [+ or -] 0.18
GMF                 -1.0      99.00 [+ or -] 0.11
                    -0.40     99.60 [+ or -] 0.27
                    -0.57     99.43 [+ or -] 0.30
Mean [+ or -] SD              99.43 [+ or -] 0.31
                    1.33      101.33 [+ or -] 0.21
MOX                 -0.83     99.17 [+ or -] 0.35
                    0.44      100.44 [+ or -] 0.29
                    0.58      100.58 [+ or -] 0.27
Mean [+ or -] SD              100.38 [+ or -] 0.90

(a) RSD%: percentage relative standard deviation;
RE%: percentage relative error. (b) Average of six
determinations.

TABLE 8: Application of the proposed methods
for the determination of GMF and MOX in their
pharmaceutical preparations.

Sample                   Proposed method      Reference methods (c)

Factive tablets
  X [+ or -] SD (a)     99.95 [+ or -]0.69     100.08 [+ or -]0.56
  t-value (b)                  0.33
  F-value (b)                  1.52
Flobiotic tablets
  X [+ or -] SD (a)    100.05 [+ or -] 0.74    99.94 [+ or -] 0.68
  t-value (b)                  0.24
  F-value (b)                  1.18
GemiQue tablets
  X [+ or -] SD (a)    99.90 [+ or -] 0.72     99.85 [+ or -] 0.49
  t-value (b)                  0.13
  F-value (b)                  2.16
Avelox tablets
  X [+ or -] SD (a)    99.47 [+ or -] 1.12     99.03 [+ or -]0.97
  t-value (b)                  0.66
  F-value (b)                  1.33
Moxiflox tablets
  X [+ or -] SD (a)     99.68 [+ or -]0.58     99.34 [+ or -]0.34
  t-value (b)                  1.13
  F-value (b)                  2.91
Moxifloxacin tablets
  X [+ or -] SD (a)    99.80 [+ or -] 0.87     99.94 [+ or -] 0.92
  t-value (b)                  0.25
  F-value (b)                  1.12

(a) Mean for six independent analyses.

(b) Theoretical values for t- and F-values at five
degrees of freedom and 95% confidence limit are
(t = 2.57) and (F = 5.05).

(c) Reference methods for GMF [26] and MOX 36].
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Title Annotation:Research Article
Author:Wahed, Mohammed G. Abdel; Sheikh, Ragaa El; Gouda, Ayman A.; Taleb, Sayed Abou
Publication:Journal of Spectroscopy
Article Type:Report
Geographic Code:7EGYP
Date:Jan 1, 2014
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