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Current Pharmaceutical Analysis, 2009, 5, 416-423
Electrochemical Behavior of Ornidazole and its Adsorptive Stripping Determination in Pharmaceuticals enol Turan, Zehra Durmu* and Esma Kiliç Department of Chemistry, Faculty of Science, Ankara University, 06100 Ankara, Turkey Abstract: The elecrochemical behavior of ornidazole was investigated using various voltammetric methods. The number of electrons transferred and diffusion coefficient were calculated by using cyclic voltammetry and bulk electrolysis techniques. It is determined that ornidazole is adsorbed on the hanging mercury drop electrode (HMDE) by using cyclic voltammetric data. Therefore, sensitive adsorptive stripping voltammetric methods for the determination of ornidazole at HMDE were developed. A systematic study of various experimental conditions was examined by using differential pulse adsorpive stripping voltammetry (DPAdsSV) and square wave adsorptive stripping voltammetry (SWAdsSV). This electroanalytical procedure enabled to determine ornidazole in the concentration range 8.010-71.010-5 molL-1 for both DPAdsSV and SWAdsSV. The detection and quantification limits were found to be 7.610-8 and 2.610-7 for DPAdsSV and 3.410-8 and 1.310-7 mol L-1 for SWAdsSV, respectively. The methods were applied to three different commercial pharmaceutical capsule preparations.The data obtained from commercial preparations were compared with those from a published spectrophotometric method. No difference was found statistically.
Keywords: Ornidazole, Square wave adsorptive stripping voltammetry, Differential pulse adsorptive stripping voltammetry, Hanging mercury drop electrode, Pharmaceutical dosage. 1. INTRODUCTION Nitroimidazole drugs have been used for over 20 years, not only as major antimicrobial drugs but also as sensitizers of hypoxic tumors in conjunction with radiotherapy, thus possessing a wider spectrum of useful clinical activity than any other antibiotics [1, 2]. Ornidazole (ORN) is a 5nitroimidazole derivative and is used in the treatment of susceptible protozoal infections and also in anearobic bacterial infections. It has been used for amebic liver obscesses, duodenal ulcers, giardiasis, intestinal lambliasis and vaginitis [3-5]. ORN has recently been used with success in patients with active Chron’s disease [6]. It is more effective against amebiasis than metronidazole, which is the most commonly used nitroimidazole derivative in theraphy [7, 8]. ORN is one of the most frequently used antibiotics for curing Helicobacter pylori infection. ORN has also been preferred for surgical prophylaxis because of its longer elimination half-life and excellent penetration into lipidic tissues versus other nitroimidazole derivatives [9, 10]. ORN can be assayed by various methods; high-pressure liquid chromotographic [11-13], chemiluminescence [14] and spectrophotometric [15, 16] methods have been used for the determination of ORN in pharmaceuticals or biological fluids. All these reported methods are either not sufficiently sensitive or tedious and require highly sophisticated instrumentation. The voltammetric and polarographic techniques, such as cyclic voltammetry, linear sweep voltammetry or differential
*Address correspondence to this author at the Department of Chemistry, Faculty of Science, Ankara University, 06100 Ankara, Turkey; Tel: +90 312 2126720/1269; Fax: +90 312 2232395; E-mail:
[email protected] 1573-4129/09 $55.00+.00
pulse polarography/voltammetry have been widely applied for the determination of ORN [17-26]. These methods are faster, easer and chepear than spectroscopic and HPLC methods. The sensitivity increases when the stripping voltammetry is employed. Adsorptive stripping analysis is an extremely sensitive electrochemical technique for measuring trace amount of compounds. Its remarkable sensitivity is attributed to the combination of an effective preconcentration step with advanced measurement procedures that generates an extremely favorable signal to back ground ratio. However, reviewing the literature revealed that, up to the present time, there is no adsorptive cathodic stripping voltammetric method using hanging mercury drop electrode for the determination of ORN from pharmaceutical dosage forms. The aim of this study was to establish the experimental conditions for the determination of ORN and to investigate the voltammetric behavior and possible reduction mechanism of ORN on HMDE using cyclic voltammetry and controlled potential electrolysis techniques. This work was also aimed to develop new, rapid, selective and simple square wave adsorption stripping voltammetry (SWAdsSV) and differential pulse stripping voltammetry (DPAdsSV) methods for the direct determination of ORN in raw materials, pharmaceutical dosage forms without timeconsuming extraction, separation, evapoartion steps prior to drug assay. On the other hand, there is no official method that has been adopted in the pharmacopoeias for the determination of ORN. For this reason, the results were compared with those from a published spectrofotometric method [15, 16]. These methods might be proposed as an alternative method to the HPLC techniques in therapeutic drug monitoring. © 2009 Bentham Science Publishers Ltd.
Electrochemical Behavior of Ornidazole
2. EXPERIMENTAL 2.1. Apparatus All voltammetric measurements such as cyclic voltammetry, controlled potential coulometry, square wave adsorption stripping voltammetry and differential pulse adsorption stripping voltammetry were carried out using a 760 B CH-instrument electrochemical analyzer. A three electrode cell system incorporating the hanging mercury drop electrode as working electrode, platinum wire auxiliary electrode (BAS MW-1034) and an Ag/AgCl reference electrode (MF-2052 RE-5B) were used in all experiments. A three electrode combination system for bulk electrolysis was consisted of mercury pool (55.4 cm2) as working electrode, Ag/AgCl reference electrode (BAS MF2052 RE-5B) and coiled platinum wire auxiliary electrode (23 cm) (BAS MW-1033). The deionized water was supplied from Human Power I+, Ultra Pure Water System. All pH measurements were made with Thermo Orion Model 720A pH ion meter with an Orion combined glass pH electrode (912600) which had been calibrated with pH 4.13 and pH 8.20 stock buffer solutions before measurements. A PG instrument T-80+ model double beam UV-visible spectrophotometer with spectral width of 2 nm, wavelength accuracy of ± 0.3 nm and a pair of 10 mm matched quartz cells was used to measure absorbance of the ORN solutions. All the data were obtained at ambient temperature. 2.2. Reagents and Solutions ORN and its pharmaceutical dosage forms ornisid, ornidone and ornitop coated tablets containing ORN (250 mg per tablet) were supplied from different pharmaceutical company. Stock solutions of ornidazole (1.010-3M) were prepared in Britton-Robinson buffer (pH 5.0). Standard solutions were prepared by appropriate dilution of the stock solutions over the range of desired concentrations with Britton-Robinson buffer. All chemicals for preparation of Britton-Robinson buffer solution, such as, phosphoric acid (Riedel), boric acid (Riedel), acetic acid (Merck) and sodium hydroxide (Merck) were analytical reagent grade. Preparation of all the solutions were prepared with double-distilled deionized water. 2.3. Stripping Voltammetric Procedure A total volume of 5.0 mL supporting electrolyte (BrittonRobinson buffer) containing ornidazole was placed into the stripping cell for analysis. The solution was deoxygenated with prepurified argon (99.999 % purity) for 10 min. After deareation, a hanging mercury drop was formed. A selected accumulation potential was then applied to a mercury drop for a selected time period while the solution was strirred at 200 rpm. The strirring was then stopped, after 5s rest period, the voltammogram was recorded by applying a negativegoing scan. 2.4. Preparation of Pharmaceuticals The drug content of ten tablets was weighed, finely powered and mixed. The average mass per tablet was
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determined. A sample equivalent to one tablet was weighed and transferred in to a 100 mL calibrated flask and completed to the volume with BR buffer. The contents of the flask were sonicated for 20 min to achieve complete dissolution. The non-dissolved excipients were waited for setle down. The sample from the clear supernatant liquor was withdrawn and quatitatively diluted with BR buffer. This solution was then transferred to a voltammetric cell and the analysis was followed up as in the stripping voltammetric procedure at pH 5.0. 2.5. Recovery Experiments Recovery of ORN from the matrix effects was used as a measure of the accuracy or the bias of the method. The concentrations in the same range as utilized in the linearity studies is used. To investigate the accuracy and reproducibility of the proposed methods, recovery experiments were carried out using the standard addition method. In order to know whether the excipients show any interference with the analysis, a known of milligrams of pure ornidazole were added to the pharmaceutical solutions and these solutions were analyzed by proposed method. The recovery results were determined based on four paralel analyses. A spectrofotometric method [16] was applied to compare with developed methods. 2.6. Spectrofotometric Procedure Stock solution of ORN (1.010-3 M) was prepared in Brittton-Robinson buffer ( pH: 5.0). Standard solutions in the concentrations range from 1.010-6 M to 1.010-5 M were prepared by appropriate dilution of the stock solutions with Britton-Robinson buffer. Working standard solutions were scanned in the UV range of 200-800 nm to determine ORN. The absorbance of ORN solutions was measured at 320 nm. 3. RESULTS AND DISCUSSION 3.1. Electrochemical Behavior of ORN Electrochemical behavior of ORN was investigated by using voltammetric techniques [17-26]. However, no previous cathodic determination of ORN was reported using adsorptive stripping voltammetry. To demonstrate the usefulness of adsorptive stripping voltammetry for determination of ORN, which may allows very rapid, sensitive determinations and remarkable increase in the peak currents, the determination of ORN on a HMDE were investigated by using SWAdsSV and DPAdsSV techniques. As a first step, the detailed electrochemical behavior of ORN and its adsorption properties was studied by using cyclic voltammetry, controlled-potential electrolysis. Therefore, the electrochemical behavior of ORN was investigated at pH 5.0. In cylic voltammetric studies, a single well-defined reduction peak of ORN was observed in BR buffer ( pH 5.0) (Fig. 1). A reduction peak was obtained at a potential of 0.40 V that was not accompanied by an anodic peak indicating the irreversible nature of ORN electrode reaction. In addition, cyclic voltametric measurements showed an
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When the scan rate varied from 0.15 to 1.0 Vs-1 in 1.010-4 M solution of ORN, a linear dependence of the peak intensity ip (A) upon the scan rate (Vs-1) was found, confirmed an adsorptional behaviour. This equation is noted below in BR buffer solution (pH 5.0). ip(A) = 5.010-6 (Vs-1) +1.010-6, r = 0.991 ( N = 12) A plot of logarithm of peak current versus logarithm of scan rate gave a straight line with a slope of 0.60 for ORN, close to the theoretical value of 1.0, which expressed the adsorption controlled electrode process for an ideal reaction (Fig. 3) [28].
Fig. (1). Cylic voltammograms of (a) blank solution (b) 1.010-4 M ORN in BR buffer solution at pH 5.0, scan rate: 0.1 Vs-1.
Using a 1.010-4 M ORN solution, the adsorptive saturation of the drug onto the mercury electrode surface was achived after preconcentration for 15 s. The surface excess value was determined by the use of Q-t1/2 graphs. The extrapolation of the Q-t1/2 graph of the supporting electrolyte and the solution containing ORN to t1/2=0 point gives us the Qdl and Qt=0 values respectively. The Q ads value is calculated from Qads = Qt =0 Qdl The surface excess value is obtained from Qads = nFA [29]. The amount of reactant
Fig. (2). Cylic voltammograms of 1.010-4 M ORN in BR buffer solution at pH 5.0 at different scan rates including: (a) 0.01, (b) 0.025, (c) 0.05, (d) 0.10, (e) 0.20, (f) 0.40, (g ) 0.80 and (h) 1.0 Vs-1.
irreversible nature of the reduction process for HMDE. The influence of the potential scan rate on ip and Ep at HMDE was investigated for 1.010-4 M ORN in the 0.05-10 Vs-1 range. The peak potential shifted to more negative values as tha scan rate increased (0.011.00 Vs-1) (Fig. 2). This phenomenon is consistent with an irreversible electrochemical process. Linear plots of ip vs v1/2 should be obtained for diffusing electroactive species, where as species adsorbe on the electrode surface should result in linear plots of ip vs. v [27].
adsorbed on the mercury surface ( mol.cm–2) was obtained as 2.0 10-10 mole cm-2 at pH 5.0. According to controlled potential coulometry, the number of transferred electrons was found to be as 4. This result shows that hydroxylamine is generated for the reduction peak of ORN. The following equation which expresses adsorption phenomena validated by Garrido [30] was used to calculate the diffusion coefficient of ORN : ip = 1.06x106 n2 A C v D1/2 tp1/2
Electrochemical Behavior of Ornidazole
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by means of DPAdsSV and SWAdsSV techniques were found to be following. The pH of a solution is a critical factor affecting both the rate and equilibrium state of the accumulation process and the rate of the electrode reaction. The influence of the pH on the DPAdsSV and SWAdsSV response was studied at HMDE of 1.010-5 M ORN between pH 2.0 to 8.0. It can be observed from Fig. (4) that the peak currents were nearly same between pH 4.0 and 6.0 for DPAdsSV and SWAdsSV techniques. The working pH was chosen as 5.0.
Fig. (3). log ipc-log v plot of 1.010-4 M ORN in BR buffer solution at pH 5.0.
The mean of the diffusion coefficient calculated from this equation was obtained as 2.19 ± 0.65 10-6 cm2s-1. 3.2. Proposed Mechanism The nitro group is one of the strongest of the common electron-withdrawing groups. The cyclic voltammogram was recorded at HMDE and only a cathodic peak is observed at about 0.40V at the pH values between 2.0 and 9.0. But, the oxidative peak is not found in between 0.05 Vs-1 and 10 Vs-1 scan rates. It was reported that a single cathodic peak of ORN splits into two peaks in more concentrated solutions and /or different media or electrodes [18]. This splitting may be attributed to formation of radical species. However, this phenomenon could not be observed with ORN at HMDE in this condition. As contolled potential coulometry indicated that ORN is 4e, 4H+ transfer process, the nitro group can be reduced to a hydroxylamine derivative. The total reaction is described as following: N
N Cl +
4e-
+
4H+
N+ O-
The influence of the accumulation potential (from 0.2 V to 0.6 V) on the DPAdsSV and SWAdsSV signal was studied at HMDE for 1.010-4 M ORN solution. Fig. (5) displays the variation of the peak current (ip) values versus accumulation potential for 1.010-5 M ORN. The dependence of the peak current on the accumulation potential showed a decrease at more negative potentials. The maximum peak current in the deposition step was observed
CH3 N
O
Fig. (4). Effect of the pH on a 1.010-5 M ORN solution at HMDE: () SWAdsSV and () DPAdsSV (accumulation time 15 s; accumulation potential 0.0 V ; rest time 5s; stirring rate 200 rpm) .
Our findings are in accordance with the accepted mechanism for the electroreduction of aromatic and heteroaromatic nitro compounds in protic media [17, 24, 25]. 3.3. Determination of ORN Due to adsorption of ORN on the elecrode surface, the electrochemical determination of ORN was established on adsorptive pulse techniques. Adsorptive pulse techniques are effective and rapid electroanalytical techniques with wellestablished advantages, including good discrimination aganist backround currents and low detection limits [31]. Especially, adsorptive stripping analysis greatly enhances the scope of stripping measurements toward numerous low amount organic compounds. Short adsorption times (1-5 min) result in a very effective interfacial accumulation [31]. Optimal conditions such as pH, accumulation potential and accumulation time for voltammetric determination of ORN
Cl + H2O
N HO
OH
CH3
N H
OH
for the accumulation potential of -0.0V for DPAdsSV and SWAdsSV techniques. The maximum peak current at an accumulation potential of 0.0 V for pH 5.0 is because of an increase accumulation rate, due to the more favorable alignment of the molecules by the electric field at the electrode solution interface. The observed gradual decrease in peak currents may be attributed to the consequence of desorption of the ORN. The results are in accordance with the findings similarly structured nitroimidazole [26]. The dependence of the peak current on the the accumulation time was studied at different times (060 s) both DPAdsSV and SWAdsSV signals. Maximum peak currents were obtained at 15s for both DPAdsSV and SWAdsSV. For longer times above 15 s, the peak current tended to reach a plateau, indicating that gradual saturation of ORN occured following a typical adsorption isotherm
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Fig. (5). Effect of the accumulation potential on SWAdsSV () and DPAdsSV () responses of ORN at HMDE in pH 5.0, (accumulation time 15 s; rest time 5s; stirring rate 200 rpm) .
behavior. For further analytical studies, an accumulation time of 15 s was chosen at HMDE. Using these optimised preconcentration conditions, DPAdsSV and SWAdsSV voltammograms for solutions with various concentrations of ORN were shown in different concentrations as an example in Fig. (6).
(b)
The two calibration curves obtained from both techniques for ORN determination were established applying the developed procedures. A linear relation in the concentration range between 8.010-7 and 2.010-5 M was found. The characteristics of the calibration plots are summarized in Table 1. Validation of the procedures for the quantitative assay of ORN was examined by evaluation of the limit of detection (LOD), limit of quantification (LOQ), repeatability (withinday). reproducibility (between-day), specifity, recovery, precision and accuracy. The precision around the mean value should not exceed 15 % of the RSD [32]. The low values of standard error (SE) of slope and intercept and close to unit correlation coefficient, established the precision of the proposed methods. These results demostrate good precision, accuracy and sensitivity. In this study LOD and LOQ values for ORN were calculated (Table 1) using LOD=3s/m and LOQ= 10s/m [33]. The abbreviation of s is the standard deviation of the signal from 1.110-6 M ORN aliquots (seven runs) and m is the slope of the related calibration curve. Both LOD and LOQ values confirmed the sensitivity of the proposed methods. 3.4. Ornidazole Assay in Tablets In order to evaluate the applicablitiy of the method to pharmaceutical preparations, ORN was determined in three pharmaceutical preparations (ornisid, ornidone and ornitop) under the same conditions as employed for the pure ORN by using standard addition method. Table 2 summarizes the results obtained for ORN in the corresponding pharmaceuticals to gether with DPAdsSV and SWAdsSV analysis. The recoveries are in good agreement with the RSD values are less than 1 %. Thus, the precision is
Fig. (6). Voltammograms of ORN using (a) DPAdsSV and (b) SWAdsSV at different concentrations including: 1: Blank; 2: 1.010-6; 3: 4.010-6; 4: 6.010-6 and 5: 8.010-6M (pH 5.0, accumulation potential: 0.0V, accumulation time:15s, stirring rate: 200 rpm).
very satisfactory for the analysis of pharmaceutical preparations as well as bulk drug. These results indicate that the content of ORN in the pharmaceuticals can be safely determined by using this method without interference from other substances in the preparations. The recovery studies of standard additions to commercial pharmaceuticals were carried out in order to provide further evidence of validity of the methods. The results related to these studies are presented in Table 2. It can be seen from this table that the mean recoveries and RSD values for DPAdsSV and SWAdsSV are in the range of 99.45 – 101.70 %, which is good evidence of validity of method. As can be seen in Table 2, both DPAdsSV and SWAdsSV methods were applied to pharmaceuticals after a simple dilution step with direct measurements. To indicate the the accuracy of the method, the SWAdsV results from the proposed methods were evaluated statistically as compared with UV-spectrophotometry (Table 3).
Electrochemical Behavior of Ornidazole
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Table 1. Regression Data of the Calibration Lines for Quantitative Determination of ORN Using DPAdsSV and SWAdsSV in Standard Solution DPAdsSV Measured potential (V)
SWAdsSV
0.24
0.30
-7
-5
-7
Linearity range (M)
8.010 1.010
8.010 1.010-5
Slope (A M-1)
2.010-2
2.610-2
Intercept (μA)
-0.310-2
-0.810-2
Correl. Coeff.
0.9998
0.9997
SE of slope
0.05
0.03
SE of intercept
6.310
-4
1.810-3
LOD
7.610-8
3.410-8
LOQ
2.610-7
Repeatability of peak current (R.S.D. %)
1.0
Repeatability of peak potential (R.S.D. %)
1.0
Reproducibility of peak current (R.S.D. %)
1.3
Reproducibility of peak potential (R.S.D. %)
1.310-7
1.2
1.1
1.4
1.2
1.0
SE: Standard Error
Table 2. Results of the Assay from Dosage forms and the Recovery Analysis of ORN in Different Tablets DPAdsSV
SWAdsSV
Amount Found/mg
Amount Found/mg
Sample no.
Brand A
Brand B
Brand C
Brand A
Brand B
Brand C
1
249.1
252.0
249.1
251.7
249.4
251.1
2
248.3
254.8
250.2
249.3
251.1
251.4
3
250.6
255.1
247.4
251.4
251.1
250.5
4
247.0
255.1
252.0
250.6
249.2
248.5
Labelled amount
250.0
250.0
250.0
250.0
250.0
250.0
X
249.0
254.3
249.7
250.7
250.2
250.4
s
1.7
1.5
1.9
1.2
1.0
1.3
RSD %
0.7
0.6
0.9
0.4
0.4
0.5
95 % confidence limit
246.3251.7
251.9256.7
246.7252.7
249.1252.9
248.6251.8
248.3252.5
Mean recoveries %
99.5
101.7
99.8
100.2
100.2
100.2
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Table 3. Statistical Analysis of the Results Obtained by the SWAdsSV and Spectrophotometric Method for ORN in Tablets Method
Mean Recoveries %
SWAdsSV
100.3 ± 0.8
RSD %
N
4 0.5
UV-spectrometry
99.7 ± 1.7
F-Test significance
1.1 F(tabulated) = 4.88
t-Test significance
0.2 t (tabulated) = 2.23
According to the results of t- and F-tests, the variances between two methods were found to be insignificant at 95 % probablitiy level indicating that no significant differences exist between the performances of the two methods regarding their accuracy and precision. The described method is a direct method for the determination of ornidazole and does not include any extraction process. Voltammetry is a considerable time saver when compared with HPLC and the overall cost of analysis is lower than that of a chromatographic method. Most spectrophotometric methods include complex reactions which cause contamination and loss of substance and all of them have a lower sensitivity than the proposed SWAdsSV and DPAdsSV methods.
[3]
[4]
[5] [6]
[7] [8]
4. CONCLUSIONS Two adsorptive stripping voltammetric techniques have been developed for the determination of ornidazole in tablet dosage forms. The proposed methods are sensitive, precise, accurate and rapid enough tobe used in the routine analysis of ornidazole in pharmaceutical tests. Moreover, it can be used to selectively determine ornidazole in pharmaceuticals after suitable dilution of the sample without interference from the ingredients of tablet matrix. There is no official method in any pharmacopoeias related to dtermination of pharmaceutical dosage forms of ornidazole. The detection limit for ornidazole in tablet obtained in DPAdsSV and SWAdsSV techniques is lower than that obtained in classic voltammetric techniques [17-24] and other methods [10-12, 15, 16] The proposed procedure could be recommended for analysis of ornidazole in quality control and clinical laboratories and preferred to published chromatographic and spectrophotometric methods.
[9]
[10]
[11]
[12]
[13]
[14]
ACKNOWLEDGEMENTS We gratefully acknowledge the financial support of Ankara University Research Fund (Project No: 2005-07-05094).
[15]
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Accepted: 25 March, 2009
