Anal Bioanal Chem (2004) 378 : 13511356

DOI 10.1007/s00216-003-2427-7

O R I G I N A L PA P E R

N. Erk

Voltammetric behaviour and determination of moxifloxacin

in pharmaceutical products and human plasma

Received: 18 August 2003 / Revised: 4 November 2003 / Accepted: 14 November 2003 / Published online: 28 January 2004
Springer-Verlag 2004

Abstract The oxidative behaviour of moxifloxacin was

studied at a glassy carbon electrode in different buffer systems using cyclic, differential pulse, and Osteryoung squarewave voltammetry. The oxidation process was shown to
be irreversible over the entire pH range studied (2.010.0)
and was diffusion-controlled. The methods were performed
in BrittonRobinson buffer and the corresponding calibration graphs were constructed and statistical data were evaluated. When the proposed methods were applied at pH 6.0
linearity was achieved from 4.4107 to 1.0105 mol L1.
Applicability to tablets and human plasma analysis was illustrated. Furthermore, a high-performance liquid chromatographic method with diode-array detection was developed. A calibration graph was established from 4.0
106 to 5.0105 mol L1 moxifloxacin. The described
methods were successfully employed with high precision
and accuracy for estimation of the total drug content of
human plasma and for pharmaceutical dosage forms of
moxifloxacin.
Keywords Moxifloxacin Cyclic voltammetry
Differential pulse voltammetry Osteryoung
square-wave voltammetry High-performance liquid
chromatography Human plasma

Introduction
Quinolones have evolved from antibacterial agents with a
limited gram-negative spectrum to a class of antibiotics
with a broad spectrum of activity and extensive indications for the treatment of infections. Moxifloxacin {1-cyclopropyl-7-(2,8-diazobicyclo[4.3.0]nonane)-6-fluoro-8methoxy-1,4-dihydro-4-oxo-3-quinolone carboxylic acid}
is a new fourth-generation quinolone with demonstrated

N. Erk ()
Department of Analytical Chemistry, Faculty of Pharmacy,
Ankara University, 06100 Ankara, Turkey
e-mail: erk@pharmacy.ankara.edu.tr

effectiveness against acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and communityacquired pneumonia [1, 2, 3, 4]. Moxifloxacin is rapidly
and essentially absorbed after oral administration, with peak
plasma concentration reached within 14 h after treatment
and a long half-life (1115 h); this makes it suitable for
once daily administration. Moxifloxacin appears promising for the treatment of respiratory tract infections caused
by common bacterial species [5].
The methods available for determination of the moxifloxacin in biological fluids or in pharmaceutical products
are based on high-performance liquid chromatography
(HPLC) [6, 7, 8, 9, 10]. In these studies linear dynamic
ranges were between 3.2 and 0.025, between 0.05 and 3.2,
between 5.8 and 8000 g mL1, and between 50 and
10,000 ng mL1, and limits of detection were 0.00652,
0.05, and 0.03 g mL1 and 1.00 ng mL1 [6, 7, 8, 9, 10],
respectively. Also recently, a spectrofluorimetric method
was reported for determination of moxifloxacin in biological media [11].
In recent years, modern electroanalytical techniques,
such as cyclic voltammetry, differential pulse voltammetry,
and Osteryoung square-wave voltammetry, are becoming
increasingly important in the determination of compounds
of pharmaceutical interest [12, 13, 14, 15, 16, 17, 18]. In
general, these methods are faster, easier, cheaper, and more
sensitive than spectrometric and HPLC methods and the
experimental methodology is less tedious. Moreover, they
can be successfully employed for the analysis of materials
in complicated systems (e.g. tablets, biological fluids, etc.).
No electroanalytical data for moxifloxacin are yet available in the scientific literature. As far as we are aware, use
of cyclic voltammetry, differential pulse voltammetry, or
Osteryoung square-wave voltammetry has not been described for determination of moxifloxacin in pharmaceutical products and in human plasma. Furthermore, an official method for the determination of this drug in pharmaceutical products and human plasma has not yet been described in any pharmacopoeia.
This work was performed to reconsider the electrochemical behaviour of the at a glassy carbon electrode drug

1352

in BrittonRobinson (BR) buffers, acetate buffers, and

phosphate buffers. It was also intended to optimize an
electrochemical procedure for direct determination of the
drug (without derivatisation) in pharmaceutical formulations and human plasma using cyclic voltammetry, differential pulse voltammetry, and Osteryoung square-wave
voltammetry. Data from use of the voltammetric techniques
were compared with those from the proposed high-performance liquid chromatographic method chosen as reference.

Materials and methods

Materials
Bulk moxifloxacin drug was a gift from Bayer Pharmaceutical Division (West Haven, USA). Moxifloxacin tablets labelled as containing 400 mg/tablet, were purchased locally in Turkey.
Reagents and solutions
BrittonRobinson buffers (acetic acidboric acidphosphoric acid;
0.04 mol L1), acetate buffer (sodium acetateacetic acid; 0.2 mol L1)
pH 3.25.2, and phosphate buffer solution (disodium hydrogen
phosphate anhydrous salt; 0.05 mol L1) were used for voltammetric experiments. The desired pH was adjusted with concentrate solutions of NaOH or HCl.
Moxifloxacin (10.0 mg) was dissolved and diluted to 100 mL
with methanol, to obtain a final concentration of 2.49104 mol L1
moxifloxacin. The stock solution was stored in brown bottles at
+4 C. More dilute solutions (4.41071.0105) were prepared daily
by accurate dilution just before use. The moxifloxacin solutions
were stable and their concentrations did not change with time.
Working solutions ranging between 4.0106 and 5.0105 mol L1
were prepared by diluting the moxifloxacin stock solution with
mobile phase. The solutions were injected and chromatographed
according to the working conditions previously given.
The working solutions for voltammetric investigations were prepared by dilution of the stock solution with selected 0.04 mol L1
BrittonRobinson buffer pH 2.010.0, 0.2 mol L1, acetate buffer
pH 3.25.2, and 0.2 mol L1 phosphate buffer pH 5.38.3. Working
solutions for high-performance liquid chromatographic investigations were prepared by appropriate dilution of the stock standard
with mobile phase.
The proposed methods were used to determine moxifloxacin in
pharmaceutical dosage forms. Ten Avelox tablets (declared amount
of moxifloxacin per tablet 400.0 mg) were placed in an agate mortar, ground and finally the correct amount of powder was dissolved
in 9:1 (v/v) methanolwater by stirring for 30 min. Excipients were
separated by filtration and the residue washed three times with
same solvent. The solution was transferred quantitatively into a
calibrated flask and diluted to a final volume of 100 mL with same
solvent, furnishing a stock solution of 1.0104 mol L1. All the test
solutions were obtained by diluting this stock solution with the selected supporting electrolyte.
Voltammograms were recorded by following the voltammetric
procedure. The high-performance liquid chromatographic determination of moxifloxacin was performed by adding an aliquot of the
above mentioned solution to mobile phase then filtering the solution obtained through 0.45 m membrane filters. Triplicate 20 L
injections were made for each solution.
Human plasma samples were obtained from healthy volunteers
and stored frozen until the assay. Trichloroacetic acid, perchloric
acid, sulfuric acid, ethanol, and acetonitrile were investigated for
precipitating human plasma proteins. Acetonitrile was found to be the
optimum precipitant because this substance can be added in small
volumes to successfully bring about precipitation. First, 0.5 mL of
human plasma was mixed with acetonitrile (1.0 mL) and with stan-

dard solution of moxifloxacin to give drug concentrations of

4.4107, 5.7106, and 1.0105 mol L1 for voltammetric techniques and 4.0106, 1.0105, and 5.0105 mol L1 for HPLC analysis. Addition of acetonitrile prevents moxifloxacin from binding to
proteins and coagulating plasma proteins. The mixtures were vortex mixed for 10 min. After deproteination and centrifugation of
sample for 15 min at 6000 rpm the supernatant (1 mL) was separated. Appropriate volumes of this solution were added to appropriate supporting electrolyte and the voltammograms were then
recorded. HPLC analysis of the prepared solutions was performed
on 20-L samples. No anticoagulant was used in these methods.
Excipients (cornstarch, magnesium stearate, lactose, sodium
lauryl sulfate, poly(ethylene glycol) 6000, titanium dioxide, carboxymethylcellulose, hydroxypropylmethylcellulose, and talc) were
added to the drug for recovery studies, according to manufacturers batch formulas for 400.0 mg moxifloxacin per tablet.
Instrumentation
The voltammetry experiments were performed using a BAS 100 W/B
electrochemical analyser. A three-electrode system was completed
by means of a glassy carbon working electrode (BAS MF 2012
type), silver/silver chloride electrode (BAS MF 1063 type) as reference electrode and platinum (BAS MV 1032 type) as auxiliary
electrode. The potentials in the text were measured relative to the
silver/silver chloride electrode.
To provide a reproducible active surface and improve the sensitivity and resolution of the voltammetric peaks, the working electrode was polished with 0.5-m alumina powder on a polishing
cloth before each electrochemical measurement. The electrode
cleaning procedures require only 2 min. The electrode was then
thoroughly rinsed with methanol and double-distilled water, and
gently dried with tissue paper.
The HPLC system consisted of a membrane degasser, binary
solvent-delivery system, a Rheodyne injector equipped with a
20-L sample loop, and diode array and multiple wavelength
UVvisible detectors (1100 Series, Agilent Technologies, USA).
The detection wavelength was at 270 nm, and peak areas were integrated automatically with Windows NT-based LC ChemStation
Software.
Chromatographic conditions
Reversed-phase chromatography was used, with mobile phases
which included of methanolacetonitrile, 50:50 (v/v). The analytical column was a Supelcosil C18 column (150 mm4.6 mm i.d.,
5 m particle size). All analysis was performed under isocratic
conditions at a flow rate of 1.0 mL min1 and at room temperature.
A diode-array detector was fixed at 270.0 nm.
Before use all solvents were filtered through a 0.45-m Millipore filter and degassed in an ultrasonic bath.

Results and discussion

Voltammetric methods
Several supporting electrolytes such as BrittonRobinson
buffer, acetate buffer, and phosphate buffer were tested by
cyclic voltammetry, and BrittonRobinson buffer was
found to be best, the voltammogram of moxifloxacin being well defined and sensitivity reasonably high. The effect of the concentration of BrittonRobinson buffer as the
supporting electrolyte (0.01, 0.04, and 0.05 mol L1) and
the influence of pH 2.010.0 were tested. The highest peak
current was obtained with 0.04 mol L1 BrittonRobinson
buffer at pH 6.0. Accordingly BrittonRobinson buffer,
pH 6.0, was chosen as the best supporting electrolyte. Phos-

1353

Fig. 2 Peak potential, Ep, of 5.7106 mol L1 moxifloxacin solution in BrittonRobinson buffer (pH 2.010.0) scan rate 20 mV s1,
pulse amplitude 50 mV)

Fig. 1 Successive cyclic voltammograms of moxifloxacin (5.7

106 mol L1): (a) first cycle and (b) second cycle in Britton
Robinson Buffer, pH 6.0, containing 10% methanol, at a scan rate
of 100 mV s1

phate and acetate buffers yielded results approximately

the same as those obtained in BrittonRobinson buffer.
Successive cyclic voltammograms obtained from moxifloxacin in BrittonRobinson buffer, pH 6.0, containing
10% methanol, at scan rate of 100 mV s1 are shown in
Fig. 1. In cyclic voltammograms one well-defined anodic
peak was observed. The fact that no peak was observed in
the reverse scan suggests that the oxidation process is irreversible. As can seen in Fig. 1. in the second cycle peak
currents of all the oxidation peaks decreased. Similar
cyclic voltammograms were obtained in phosphate and
acetate buffers. The anodic peak might be because of the
nature and position of the electrophilic substituents on the
aromatic ring. A mechanism can be proposed that the redox process of moxifloxacin occurs to yield dimeric compounds which bond via the radical cations formed by the
oxidation of the amine group.
Study of the influence of scan rate showed that the
peak current changed linearly with scan rate (v) according
to the equation Ip=Avx. The x values 1.0 and 0.5 are expected for adsorption-controlled and diffusion-controlled
reactions [19]. The regression of log Ip versus log v gave a
slope value of 0.47, indicating that the oxidation current is
diffusional in nature and has no important surface reaction
effect under the conditions used. A linear relationship between peak current and square root of the scan rate, with
a slope of 1.05, showed that the oxidation process is predominantly diffusion-controlled in the whole scan rate
range studied. As the scan rate was increased from 10 to

Fig. 3 Influence of pH on peak current for moxifloxacin (5.7

106 mol L1) in differential pulse voltammetry at scan rate 20 mV s1,
pulse amplitude 50 mV

500 mV s1, the peak potential shifted toward more positive potential, as expected for an irreversible oxidation
process [20]. The reversibility of the process was studied
at the glassy carbon electrode by use of cyclic voltammetry.
A Tafel plot was obtained with a scan rate of 5 mV s1
beginning from a steady-state potential in BrittonRobinson buffer pH 6.0 and from the slope of the linear part n
was found to be 0.32. The n value obtained (0.32) shows
the total irreversibility of the electron-transfer process.
In general, pH is one variable that commonly and strongly
influences the shapes of voltammograms, and therefore it
is important to investigate the effects of pH on electrochemical systems. Figure 2 illustrates the peak potential
obtained from 5.7106 mol L1 moxifloxacin over the pH
range 2.010.0 in BrittonRobinson buffer when differential pulse voltammetry was used. The potential of anodic
peak of moxifloxacin is shifted linearly towards less positive values with increasing the pH between 2 and 6. The
slope of the plot of Ep against pH is 57.0 mV per pH unit,
indicating the consumption of an ideal number of electrons. At pH>6 Ep is pH-independent. The intersection
point observed at pH 6 can be attributed to the acidbase
constant (pKa) of moxifloxacin. At pH<pKa the anodic oxidation process involves deprotonation of the cation radical formed. This result is in accordance with the plot of Ep
vs pH (Fig. 2). Figure 3 also shows the influence of pH on
peak height. The absolute value of the peak current (Ip)
passes through a maximum at pH 6.
The differential pulse voltammetric behaviour of moxifloxacin at a glassy carbon electrode was examined by

1354

varying pH over a wide range of values from acidic to alkaline media (between 2.0 and 10.0), by use of Britton
Robinson buffer solutions, and differential pulse voltammograms were acquired. The best results were obtained
for the solution of pH 6.0. To improve the sensitivity of
the determination differential pulse voltammetric conditions such as pulse amplitude, scan rate, and pulse width
were investigated. It was found that peak currents increased significantly with increasing pulse amplitude from
10 to 60 mV, then improved slightly from 60 mV to 100 mV.
The pulse amplitude chosen for practical determination
was 50 mV. In these experiments faster scan rates resulted
in higher peak currents but background currents also increased. Taking peak current and background current into
consideration the scan rate chosen was 20 mV s1. The effect of moxifloxacin concentration on peak current at
1004 mV was investigated. Differential pulse voltammetry optimum conditions were found to be pH 6.0 Britton
Robinson buffer, 9:1 (v/v) methanolwater, 20 mV s1 scan
rate, 50 mV pulse amplitude, 17 ms sample width, 50 ms
pulse width, 200 ms pulse period.
The Osteryoung square-wave voltammetric behaviour
of moxifloxacin at a glassy carbon electrode was investigated at different pH over a wide range of values from
acidic to alkaline media (between 2.0 and 10.0). The best results were obtained in BrittonRobinson buffer of pH 6.0,
although phosphate and acetate buffers yielded approximately the same results. Square-wave voltammetry conditions were pulse amplitude 25 mV, frequency 15 Hz, potential step 4 mV. The methods were successfully applied
to the pharmaceutical products and human plasma.
High-performance liquid chromatography
The reversed-phase HPLC method was developed to provide a specific procedure suitable for rapid quality control
analysis of moxifloxacin and as reference method for the
developed voltammetric methods. The mobile phase was
investigated after several trials with methanolacetonitrile
in different proportions. Selection of the mobile phase
(methanolacetonitrile, 50:50 (v/v)) and flow rate was

based on peak properties (height, asymmetry, tailing), baseline drift, run time, and ease of preparation of mobile phase.
Diode-array detection was fixed at 270 nm. An internal
standard was not used, because no extraction was involved in estimation of moxifloxacin in pharmaceutical
products. The system seems to be quite robust.
Analytical applications
On the basis of the voltammetric behaviour of moxifloxacin
a quantitative method was developed. To select the best
electrochemical methods I compared the anodic peak obtained by differential pulse and Osteryoung square-wave
voltammetry and the best ratio of peak to background currents was obtained with differential pulse and Osteryoung
square-wave voltammetry. Using the optimum conditions
described in the experimental section, the relationship between the current and the concentration was found to be
linear over the range 4.4107 to 1.0105 mol L1 for voltammetric methods (differential pulse voltammetry and
Osteryoung square-wave voltammetry) and from 4.0106
and 5.0105 for high-performance liquid chromatography. Analytical data for the calibration graphs are summarized in Table 1.
The detection limits (LOD; calculated as 3s/m, where s
represents the standard deviation of the peak current of
the sample (n=5) and m represents the slope of the calibration curve) were 2.4108 mol L1 for differential pulse
voltammetry, 4.3108 mol L1 for Osteryoung squarewave voltammetry, and 3.3107 mol L1 for high-performance liquid chromatography. On the basis of a signal-tonoise ratio of 10 the quantitation limit was estimated to be
6.5108 mol L1 for differential pulse voltammetry, 8.9
108 mol L1 for Osteryoung square-wave voltammetry, and
5.0107 mol L1 for high-performance liquid chromatography. Repeatability and recovery were examined by performing five replicate measurements of 5.7106 mol L1
moxifloxacin (for differential pulse and Osteryoung squarewave voltammetry) and 1.0105 mol L1 (for high-performance liquid chromatography). Mean recoveries of 99.87
1.08% (differential pulse voltammetry), 98.921.29%

Table 1 Data from statistical analysis of calibration curves in the determination of moxifloxacin by differential pulse voltammetry
(DPV), Osteryoung square-wave voltammetry (SWV), and high-performance liquid chromatography (HPLC)
Term
(mol L1)

Range
Regression equation (Y)a
Slope (b)
Std. dev. of slope (Sb)
Intercept (a)
Std. dev. of intercept (Sa)b
Std. error of estimation (Se)
Correlation coefficient (r)
aY=a+bC,

DPV

SWV

HPLC

4.41071.0105

4.41071.0105

4.01065.0105

6.24105
9.71106
0.48
3.33106
6.04106
0.9995

2.68105
7.51106
6.25102
6.62106
4.47107
0.9991

2.82104
1.73106
8.13102
5.15106
4.28107
0.9996

where C is the concentration (mol L1) and Y is the peak current and peak area for voltammetric methods and high performance
liquid chromatography, respectively
bFive replicate analyses

1355

(Osteryoung square-wave voltammetry), and 101.00.98%

(high-performance liquid chromatography) were achieved,
indicating the high +precision of the proposed procedures.
Robustness is the capacity of a method to remain unaffected by small, but deliberate, variations in method conditions [21]. The robustness of the proposed methods were
examined by varying the pH, the concentration of supporting electrolyte, temperature, and the stability of sample solution. The results showed that none of these variables significantly affected the recovery of moxifloxacin.
This provided an indication of the reliability of the proposed procedures for assay of the drug, which could be
considered robust.
The specificity of the optimized procedures for assay
of moxifloxacin was examined in presence of some common excipients (corn starch, magnesium stearate, lactose,
sodium lauryl sulfate, poly(ethylene glycol) 6000, titanium
dioxide, carboxymethylcellulose, hydroxypropylmethylcellulose, and talc) in the ratios usually used in pharmaceutical products. The mean percentage recovery of 5.7
106 mol L1 moxifloxacin showed there was no significant interference from excipients; the procedures were
therefore able to assay moxifloxacin in the presence of excipients and could thus be considered specific. The specificity of the proposed analytical methods was also checked
be measuring the ability to measure specifically only the
analyte, not other components that might also be expected
in human plasma. In accordance with this, blank human
plasma was scanned before and after the addition of moxifloxacin. Because no response was obtained on analysis
of pure human plasma sample at the working potential, it
might be concluded there was no interference of the components of the human plasma matrix. This means again
that the proposed method is selective.

Fig. 4 Differential pulse voltammograms obtained for the determination of moxifloxacin in spiked human plasma: (a) background, (b) 4.4107 mol L1, (c) 5.7106 mol L1, and (d) 1.0
105 mol L1

Determination of moxifloxacin in human plasma samples

The optimized differential pulse voltammetry and Osteryoung square-wave voltammetry procedures were also successfully used for determination of moxifloxacin in protein-free spiked human plasma (Figs. 4 and 5). The generally poor selectivity of voltammetric techniques can expose difficulties in the analysis of biological fluids which
contain oxidizable substances (glutathione, ascorbate, ureate, tryptophan, cysteine, etc.). As can be seen from the
figures, no oxidation of compounds present in human
plasma occurs where the analytical peak appears. The determination of moxifloxacin in spiked human plasma samples was performed at three different concentration levels:
4.4107 mol L1, 5.7106 mol L1, and 1.0105 mol L1
by differential pulse and Osteryoung square-wave voltammetry and 4.0106, 1.0105, and 5.0105 mol L1 for
high-performance liquid chromatography. The recoveries
obtained are shown in Table 2. Good recovery of moxifloxacin was achieved from biological endogenous components in human plasma.

Fig. 5 Osteryoung square-wave voltammograms obtained from

the determination of moxifloxacin in spiked human plasma:
(a) background, (b) 4.4107 mol L1, (c) 5.7106 mol L1, and
(d) 1.0105 mol L1

1356
Table 2 Recoveries of moxifloxacin from spiked human plasma
by voltammetric techniques and by high-performance liquid chromatography
Amount Recovery (xSE, RSD, %)a
(mol L1)
DPV
SWV

HPLC

4.4107 101.31.20, 0.60% 99.21.11, 0.96%

5.7106 97.50.95, 0.64% 100.50.85, 0.99% 100.11.26, 0.98%

1.0105 99.11.32, 0.72% 99.10.94, 1.03% 99.41.08, 0.96%
ax,

Conclusions
Because electrochemical methods for pharmaceutical
products and spiked human plasma proved to be fast, precise, simple to perform, and produce low-cost results with
minimum interference from drug excipients and the biological endogenous matrix, these methods can be suggested as simple means of determination of moxifloxacin.

mean; RSD, relative standard deviation; SE, standard error

References
(meanaRSDb)

Table 3 Results
moxifloxacin tablets

from comparative analysis of

Drugc

DPV

SWV

HPLC

Batch no. 1
Batch no. 2
Batch no. 3
t-test of significanced

397.90.85
400.50.82
401.00.67
0.89

400.30.62
399.50.83
389.90.87

400.30.42
401.10.43
399.50.45

aEach

value is the mean from ten experiments

standard deviation
cAvelox tablets were labeled as containing 400.0 mg moxifloxacin
per tablet
dTheoretical value for 0.95% confidence limits, t=2.26
bRelative

Assay of moxifloxacin in tablets

The proposed procedures were successfully applied to the
determination of moxifloxacin in three batches of commercial formulations. The results presented in Table 3 are
in good agreement with the labelled content. All data are
averages from ten determinations.
The HPLC method was chosen as the analytical reference method. The proposed voltammetric techniques were
compared with the HPLC method. The results obtained
are summarized in Table 3. No significant differences were
found between the results obtained by HPLC and voltammetric techniques for same batch at the 95% confidence
level (Students t-test).

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