Nortriptyline ECS

ECS Transactions, 13 (20) 21-46 (2008) 10.1149/1.
3010727 The Electrochemical Society
Cathodic Adsorptive Stripping Voltammetric Behavior and Determination of Tricyclic Antidepressant Drug Nortriptyline Hydrochloride in Bulk Form and Pharmaceutical Formulation Rajeev Jain* and Keisham Radhapyari School of Studies in Chemistry, Jiwaji University, Gwalior-474011, India rajeevjain54@yahoo.co.in, Tele. fax: +91-751-2346209, Tele. No.: +91-751-2442766 Abstract
Nortriptyline hydrochloride is second generation commonly administered tricyclic antidepressants used widely in endogenous depression and may also be effective in some cases of reactive depression. The electro reductive behavior of nortriptyline hydrochloride was investigated and a well-defined cathodic peak was observed. From the electrochemical response the main reduction step was found to be related to the reduction of C=C group. A versatile fully validated voltammetric method for quantitative determination of nortriptyline hydrochloride in commercial tablets has been proposed, where direct dissolution of tablets is carried out in 0.1 M tetraethylammoniumperchlorate (TEAP) containing dimethylformamide (DMF) solutions. Cyclic voltammetric (CV), differential pulse cathodic adsorptive stripping voltammetric (DPCAdSV) and squarewave cathodic adsorptive stripping voltammetric (SWCAdSV) techniques were applied to study nortriptyline hydrochloride at a HMDE, exhibiting a well defined irreversible reduction peak at -1.02 V vs. Ag/AgCl (3M KCl). The current versus concentration plot was linear over the range 0.1-4.5 g mL-1 and 0.1-5.5 g mL-1 using SWCAdSV and DPCAdSV modes respectively, with a minimum detectability of 0.05 g mL1
and 0.057 g mL-1 and with mean percentage recoveries of 99.7 and 99.4 respectively.
Keywords: Nortriptyline; Stripping voltammetric determination; CV; SWCAdSV; DPCAdSV; Pharmaceutical formulation.
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ECS Transactions, 13 (20) 21-46 (2008)
1. Introduction Tricyclic antidepressants (TCAs) [1] have been the cornerstones of antidepressive therapy for over three decades, and more than 1 million patients received TCAs in the US in 2000. Nortriptyline hydrochloride is second generation commonly administered tricyclic antidepressants used widely in endogenous depression and may also be effective in some cases of reactive depression [2,3]. It is used in the treatment of depression and childhood noctural enuresis (bedwetting). In addition it is sometimes used for chronic pain modification and labile effect in some neurological conditions. Nortriptyline hydrochloride inhibits the uptake of serotonin, and to a lesser extent, norepinephrine (noradrenalin). It is also used off-label for the treatment of panic disorder, irritable bowel diseases, prevention of migraine headaches and chronic pain or neuralgia modification particularly temporomandibular joint disorder [4]. It can also aid in quitting smoking with one study showing a six month abstinence rate of 14% for subjects receiving nortriptyline compared to 3% for subjects not undergoing pharmacological treatment [5]. Side effects include dry mouth, drowsiness, orthostatic hypotension, urinary retention, constipation, and rapid or irregular heartbeat. Some sexual side effects may be a problem as well. However, the incidence of side effects with nortriptyline hydrochloride is somewhat lower than with the first generation tricyclics (e.g. imipramine, amitriptyline). Nortriptyline hydrochloride designated chemically as 3-(10,11-dihydro-5H-bibenzo [a,d]cyclohept-5-ylidene) N-methyl propylamine hydrochloride [Scheme 1], is a tricyclic antidepressant.
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N H
Scheme 1
CH 3
Tricyclic antidepressants (TCAs) are a group of compounds that are used for the treatment of psychiatric patients suffering from clinical depression. [6]. The monitoring of such compounds is important for quality assurance in preparations and for obtaining optimum therapeutic concentrations, while minimizing the risk of toxicity. The therapeutic concentration range for most TCAs is approximately 100 to 300 g L-1, while toxic effects can occur when plasma concentrations exceed 500 g L-1 [7]. Trialkylamines and related compounds are difficult to detect as they are not easy to derivatise and they do not absorb very well in the UV-visible region, since they have low molar absorptivities. Also many methods require time-consuming sample preparation techniques, particularly gas chromatography [8]. A variety of methods have been reported for the determination of the drug including Spectrophoptometry [9-16], Fluorimetry [10,17,18], Titrimetry [19,20], colorimetric [21], Rapid radioisotopic [22], Radioimmunoassay [23], Thin layer chromatography [24,25], Gas chromatography [26-28], Capillary gas-liquid chromatography [29], Micellar liquid chromatography [30] and High Performance Liquid Chromatography [14,31-35]. Further, electrogenerated chemiluminescence and potentiometric titration [36-38] have been developed for the determination of nortriptyline hydrochloride. However, although the selectivity and the detection limit have been improved in these methods, these are rather
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time consuming methods and require large number of complicated steps to follow on for analysis. For this purpose the desirable technique for the analysis of drugs should be rapid, simple, low cost and of high sensitivity in analysis. Moreover, nortriptyline hydrochloride molecule has electroactive groups but its electrochemical behaviour has never been investigated. The electrochemical investigation of nortriptyline hydrochloride has been undertaken to have some insight into its redox process, which is important for our understanding of its property as well as its metabolism in biological system. Furthermore, there appears to be no electroanalytical method for the determination of nortriptyline hydrochloride in pharmaceutical formulation and bulk form. A survey of literature reveals that electrochemical techniques have demonstrated a large applicability in studies of electrodic reactional mechanisms of pharmaceutical compounds [39,40]. Electrochemical methods [41-48], such as differential pulse polarography (DPP), stripping voltammetry (SV) and differential pulse voltammetry (DPV), squarewave voltammetry (SWV) have been widely applied for the determination of pharmaceuticals. In general these methods offer high sensitivity, low limit of detection, easy operation and sometimes the use of simple instrumentation. In all these available electrochemical methods stripping analysis is an extremely sensitive technique that utilizes a bulk electrolyte step to pre-concentrate the analyte from the sample solution into or onto the working electrode. Most stripping measurements involve pre-concentration into or onto mercury electrode. In this case, the pre-concentration step can be viewed as an effective electrochemical extraction in which the analyte is preconcentrated into or onto the mercury phase to a much higher level than it exists in solution. The pre-concentrated step is followed by an electrochemical measurement of the
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concentrated analyte. This combination of a pre-concentration step with advanced measurement procedures generates the extremely favourable signal-to-background ratio that characterizes stripping analysis. Adsorptive stripping analysis greatly enhances the scope of stripping measurements towards various organic compounds. The high sensitivity and low cost of stripping analysis have led to its application in a large number of analytical problems [49]. This technique did not require sample pre-treatment or time-consuming extraction or evaporation steps prior to the drug assays. The purpose of the present work is to study the voltammetric behavior of nortriptyline chloride by employing different voltammetric techniques and to establish the methodology for their trace determination using cyclic voltammetry (CV), differential pulse cathodic adsorptive stripping voltammetry (DPCAdSV) and squarewave cathodic adsorptive stripping voltammetry (SWCAdSV) in pharmaceutical formulation. 2. Experimental 2.1 Reagents and materials Nortriptyline hydrochloride (99% purity) was obtained from Reliance Formulation Pvt. Ltd., Ahmedabad, India and was used as received. Tablets containing Nortriptyline hydrochloride (Sensival) labeled 25 mg Nortriptyline hydrochloride were obtained from commercial sources. Tetraethylammoniumperchlorate (TEAP) (0.1 M) solution was prepared in dimethylformamide (DMF) and used as supporting electrolyte. A stock solution of nortriptyline hydrochloride 1mg mL-1 was prepared in DMF. The solutions for recording voltammograms were prepared by mixing appropriate volume of stock solution and 0.1 M
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TEAP supporting electrolyte. All chemicals used were of analytical reagent grade quality (Merck and Sigma) and were employed without further purification. 2.2 Apparatus Electrochemical measurements were performed using a AUTOLAB TYPE III (Eco-Chemie B.V., Utrecht, The Netherlands) potentiostat-galvanostat with 757VA computrace software. The utilized electrodes were hanging mercury drop electrode (HMDE) as working electrode, Ag/AgCl (3M KCl) as reference electrode and a graphite rod as auxiliary electrode. The electrochemical cell was Metrohm 663 VA stand. Controlled potential coulometric experiments were carried out using Autolab Potentiostat/Galvanostat PGSTAT Metrohm 663 VA stand as electrochemical cell, fitted with a PC provided the appropriate GPES 4.2 (General Purpose Electrochemical Software) Software. Coulometric experiments were performed in the potentiostatic mode using Pt foil with large surface area as working electrode and a Pt wire, counter electrode. All the solutions examined by electrochemical technique were purged for 10min with purified nitrogen gas after which a continuous stream of nitrogen was passed over the solutions during the measurements. Ready made precoated TLC silica gel coated plates from E Merck, Germany were used for TLC separation. The IR spectrum of solid complex was recorded using KBr pellets on a Shimadzu, Japan, and model Prestige IR 20, IR spectrophotometer. 2.3 Procedure Nortriptyline hydrochloride determination was performed on commercially available tablet dosage form Sensival. The amount of nortriptyline hydrochloride present in each tablet was 25 mg. Excipients such as colloidal silicon dioxide, corn starch, gelatin,
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glacial acetic acid, glycerin, methylparaben, propylparaben, silicone fluid, sodium lauryl sulfate, and titanium dioxide were added to dosage form. Five tablets were weighted accurately and crushed to a fine powder. A sufficient amount of powder for preparing a stock solution of 1.0 mg mL-1 was weighed and transferred into 25 mL volumetric flask and completed to volume with dimethylformamide (DMF). The content of the flask was sonicated for 30min to provide complete dissolution and then completed to volume with same solvent and centrifuged. An aliquot of the supernatant liquid was then transferred into a calibrated flask and a series of dilutions (0.1 to 5.5 g mL-1) were prepared with 0.1 M TEAP containing DMF and then transferred to a volumetric cell and desire waveform was recorded in the range (-0.8 V to -1.2 V). The drug content in per tablet was determined referring to the related regression equations. 3. Results and Discussion The electrochemical behavior of nortriptyline hydrochloride on HMDE was studied by using cyclic voltammetry (CV), differential pulse cathodic adsorptive stripping voltammetry (DPCAdSV) and squarewave cathodic adsorptive stripping voltammetry (SWCAdSV). In all electrochemical methods nortriptyline hydrochloride gave one well defined reduction peak in 0.1 M TEAP containing DMF which is attributed to the reduction of unsaturated C=C- bond at mercury electrode. 3.1 Cyclic Voltammetric Behavior The reversibility of the reduction process was investigated by using cyclic voltammetry. The cyclic voltammogram of nortriptyline hydrochloride 2.5 g mL-1 in 0.1 M TEAP contaning DMF at hanging mercury drop electrode (HMDE) exhibits a single well
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defined peak in the potential range -0.8 V to -1.2 V, at all concentrations due to the reduction of the C=C- groups. The interfacial accumulation of nortriptyline hydrochloride can be observed in cyclic voltammograms in Figure 1a, without preconcentration, and after a preconcentration step (-0.1V, 200s, 2000rpm) Figure 1b.The peaks obtained without accumulation after a preconcentration step; thus indicates that nortriptyline hydrochloride adsorbs readily at the electrode surface, and a considerable increase in sensitivity can be gained by adsorptive accumulation prior to the voltammetric determination. The cathodic wave is not accompanied by a corresponding anodic one, which indicates the nonreversibility of this process. According to the Randles-Sevick equation in a linear diffusion-controlled process, ip 1/2, for the adsorptive process, ip . The peak currents of nortriptyline hydrochloride are plotted against the scanrate. The peak currents ip increases linearly with increasing scan rate ; the ip versus 1/2 curve shows an upward incline. This points out to the adsorptive nature of the peak. The plots of log ip against log for 2.5 g mL-1 nortriptyline hydrochloride are straight lines which can be expressed by the equation: log ip(A) = 0.418 + 0.983 log (Vs-1); r2 = 0.998; n = 6 with slope of 0.98. These calculated results agree with the theoretical value of 1.0, indicating the adsorptive nature of the reduction species [50-52]. The peak potential shifts to more negative values on increasing the scan rate, which confirms the irreversibility of the reduction process [53]. The relationship between the current function and the scan rate may be simply indicated by the curve of ip/1/2 versus scan rate, which decides the various electrode processes. If an electrode is diffusion controlled, the current function will be independent of
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scan rate. In the case of adsorption, ip versus 1/2 increases with increasing scan rate. As the system studied belongs to those where reactant is strongly adsorbed, and the electrode reaction is irreversible, we may use Lavirons equation [54,55]: Ep = E' + (2.303RT/na F) log (RTKf / naF) (2.303 RTnaF) log According to above eq., the plot of Ep versus log should be linear. From its slope, the n value can be determined and from the intercept Kf can be calculated. A set of cyclic voltammograms for 2.5 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF at different scan rate were recorded.
Fig 1. Cyclic voltammograms for conc. 2.5 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF at scan rate of 100 mVs-1 ; (a) without accumulation; (b) after a preconcentration step, tacc 200 s, Eacc 0.1 V and stirring speed 2000 rpm.
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3.2 Controlled potential coulometric behavior By using controlled potential coulometry, the number of electrons transferred, n values were calculated from the charge consumed by 4.5 g mL-1 concentration of nortriptyline hydrochloride. The charge consumed was determined in 0.1M TEAP containing DMF. For this purpose 2mL of 4.5 g mL-1 solution of the electro active species was placed in the cell and electrolysis was carried out at a potential -1.1 V to -1.3 V against Ag/AgCl reference electrode. During the electrolysis, solutions were continuously stirred and purged with nitrogen. Number of electrons n was calculated using the equation Q = nFN, where Q is charge in coulombs, F is Faradays constant and N is number of moles of the substrate The value is found to be two for cathodic peak of nortriptyline hydrochloride in 0.1M TEAP containing DMF. Cyclic voltammograms of nortriptyline hydrochloride just before (Fig. 2b) and after electrolysis (Fig. 2a) were taken and compared. Disappearance of cathodic peak at -1.0 0.3 V confirms reduction of C=C- bond. Before and after the electrolysis the products were also analyzed by IR spectrometry. The absence of sharp peaks in the range of 1654.92 1670.35 cm-1 in the product confirmed the reduction of C=C- group. Voltammetric studies in conjunction with coulometry and TLC results confirm the formation of only one product. In the electrolyzed product only one product having Rf different from nortriptyline hydrocloride was observed indicating the formation of only one new product.
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On the basis of CV, DPCAdSV, SWCAdSV, Cpe, coulometry, chromatographic and spectral studies following mechanism [56] may be postulated for the reduction of nortriptyline hydrochloride [Scheme 2].
+ 2e - + 2H
N H CH3
N H
Scheme 2
CH 3
Fig. 2. Cyclic voltammograms for conc. 4.5 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF at scan rate of 100 mVs-1 (a) Before electrolysis (b) After electrolysis.
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3.3 Optimization of operational parameters Variation of the stripping voltammetric peak current of nortriptyline hydrochloride in 0.1 M TEAP containing DMF at HMDE was investigated using squarewave and differential pulse modes. Both the techniques gave comparable results but squarewave cathodic adsorptive stripping volatmmetry has been chosen for optimizing the operational parameters. The important instrumental variables such as accumulation time (tacc), accumulation potential (Eacc), pulse amplitude (Esw), scan increment (s) and frequency (f) were examined using the selected waveforms. The effect of accumulation time for 1.5 g mL-1 nortriptyline hydrochloride was investigated from 0 to 300s. As shown in Figure 3, a rectilinear relationship is observed in an accumulation time range from 0 to 200 s, following the equation: ip = 22.154 + 3.811 tacc, r2 = 0.998. Above 200s, saturation coverage of the electrode occurs and curvature of the graph is observed. Further, different SW voltammograms with increasing accumulation times were recorded for solutions containing nortriptyline hydrochloride at two concentrations 1.5 g mL-1 and 0.1 g mL-1 using the selected conditions. For 0.1 g mL-1 nortriptyline hydrochloride solution, the peak current increased linearly with the accumulation times tested (Fig. 4B), while for 1.5 g mL-1 solution, a rectilinear relation upto accumulation of 200s was obtained (Fig. 4A). Above this time, saturation of the mercury drop was observed. Hence, the choice of the accumulation time depends on the range of the analyte concentration being determined. The influence of accumulation potential (Eacc) on the cathodic peak current (ip) of nortriptyline hydrochloride was also examined over the potential range -0.1V to 1.0 V
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(Fig. 5). Maximum development of the peak current was achieved at -0.1V. Hence, an accumulation potential of -0.1V was used throughout the present study. At more cathodic values a decrease in peak current was observed indicating that the drug is no longer strongly adsorbed at potentials where the mercury is negatively charged with respect to the point of zero charge potential. The other dependences were therefore measured at a potential of accumulation of -0.1V.
plot of tacc vs ip
1000 i p (nA) 500 0 0 100 200 tacc 300 400
Fig. 3. Effect of accumulation time on the stripping peak current for 1.5 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF following accumulation at Eacc = -0.1V, Insert is the current/time plot.
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plot tacc vs ip
1000 800 i p (nA) 600 400 200 0 0 100 200 tacc 300 400
A B
Fig. 4. Effect of the accumulation time (tacc) on the SWCAdS peak current response for (A) 1.5 g mL-1 & (B) 0.1 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF; Eacc = -0.1V, frequency f = 50Hz, pulse amplitude Esw = 50 mV and scan increment s = 10 mV.
plot of Eacc vs ip
1000 800 600 400 200 0 0 0.5 Eacc 1 1.5
Fig. 5. Effect of the accumulation potential (Eacc) on the squarewave peak current (ip) for 1.5 g mL-1 nortriptyline hydrochloride in 0.1 M TEAP containing DMF; tacc = 200s; equilibrium time = 10s; frequency f = 50 Hz; s = 10 and pulse amplitude Esw = 50 mV.
Frequency was varied from 5 to 100Hz using a scan increment of 10mV, pulse amplitude of 50mV and 200s accumulation time. A linear relationship was obtained between the peak current and frequency of the signal upto 50Hz. It was chosen to improve the sensitivity without any distortion of the peak or the baseline.
i p (nA)
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Study of the effect of scan increment on adsorptive cathodic peak current of the drug in 0.1 M TEAP containing DMF revealed that the peak current enhanced upon the increase of scan increment (2-10mV). A scan increment of 10mV was preferable in the present study. At pulse amplitude 50 mV, the peak current was found to be much more sharp and defined. All the optimized experimental conditions are summarized in Table 1. 4. Validation of the Procedure 4.1 Linearity The applicability of the proposed squarewave cathodic adsorptive stripping (SWCAdS) voltammetric and differential pulse cathodic adsorptive stripping (DPCAdS) voltammetric procedures as an analytical method for the determination of nortriptyline hydrochloride was examined by measuring the stripping peak current as function of concentration of the bulk drug for at least three times under the optimized operational parameters. Three calibration graphs were constructed. The dependency existed between stripping peak current and the concentration of the drug was rectilinear with the range 0.1 4.5 g mL-1 for (SWCAdS) voltammetry and 0.15.5 g mL-1 for (DPCAdS) voltammetry. The calibration graph was represented by the following equation: DPCAdSV: ip (A) = (0.2100.005)C(g mL-1) + (0.2480.005); r = 0.9990.004; n = 7 SWCAdSV: ip (A) = (0.2260.004)C(g mL-1) (0.470.005); r = 0.9990.003; n = 7 The regression plots showed that there was a linear dependence of the current intensity on the concentration in both DPCAdSV and SWCAdSV modes over the range is given in Table 2. The table also shows the detection limits and the results of the statistical analysis of the experimental data such as slopes, intercept, the correlation coefficients
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obtained by the linear least squares treatment of the results along with standard deviation (S.D.) of the slope (Sb) and intercept (Sa) on the ordinate and the S.D. of the residuals (Sy/x). The good linearity of the calibration graphs and the negligible scatter of the experimental points are clearly evident by the values of the correlation coefficient and S.D. The specificity of the method was investigated by observing any interference encountered from the excipients of the tablets mass. It was shown that the proposed method co-administered drugs did not interfere. 4.2 Specificity Specificity is the ability of the method to measure the analyte response in the presence of all the potential impurities. The specificity of the optimized procedure for
Table 1. The optimized experimental conditions of the proposed procedure for the determination of nortriptyline hydrochloride.
Variable Solvent type Purge time (s) Accumulation potential (V) Pre-concentration time (s) Rest period (s) Mercury drop size (cm2) Stirring rate (rpm) Frequency (Hz) Scan increment (mV) Pulse amplitude (mV)
Optimized value 0.1 M TEAP containing DMF 300 -0.1 200 10 4 2000 50 10 50
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Table 2. Analytical parameters for voltammetric determination of nortriptyline hydrochloride using SWCAdSV and DPCAdSV modes.
Parameter Conc. Range (g mL-1) LOD (g mL-1) LOQ (g mL-1) Mean found(%) Correlation coefficient(r2) Slope(A/g mL-1) Intercept(A) Sy/x Sa Sb % Error Applications
SWCAdSV 0.1 4.5 0.05 0.1 99.5 0.999 2.26 x 10-7 4.7 x 10-7 1.4 x 10-8 4 x 10-9 5 x10-9 0.94 Tablets
DPCAdSV 0.1 - 5.5 0.057 0.1 100.1 0.999 2.1 x 10-7 2.48 x 10-7 8 x 10-7 4 x 10-9 3 x10-9 0.67 Tablets
Sy/x , is the standard deviation of the residuals; Sa, standard deviation of the intercept of regression line ; Sb, standard deviation of the slope of regression line; % error, R.S.D.%/n.
estimation of nortriptyline hydrochloride was examined in presence of excipients such as colloidal silicon dioxide, corn starch, gelatin, glacial acetic acid, glycerin, methylparaben, propylparaben, silicone fluid, sodium lauryl sulfate, and titanium dioxide were added to dosage form. Samples containing 0.1 g mL-1 bulk nortriptyline hydrochloride and different concentrations of the excipient under evaluation were analyzed by means of the proposed procedure. The obtained mean percentage recoveries (%R) and the relative standard deviations (%RSD) based on the average of five replicate measurements (99.0 0.8 to 100.5 1.2) for SWCAdSV and (99.2 1.4 to 100 1.2) for DPCAdSV showed that no significant interference from excipients. Thus the proposed procedure can be considered specific.
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4.3 Repeatability The repeatability was examined by performing five replicate measurements for 0.1 g mL-1 bulk drug followed pre-concentration for 60s under the same operational conditions. Percentage recoveries (%R) of 99.1, 99.3, 99, 99.8 and 100.5 were achieved with a mean value of 99.54 and (%R.S.D.) of 0.6, which indicates repeatability and high precision of the proposed procedure. 4.4 Robustness The robustness was examined by evaluating the influence of small variation of some of the most important procedure variables including pre-concentration potential (Eacc) and pre-concentration time (tacc). The obtained result provided an indication of the reliability of the proposed procedure for the assay of nortriptyline hydrochloride and hence it can be considered robust. The obtained mean percentage recoveries based on the average of five replicate measurements were not significantly affected within the studied range of variations of some operational parameters, and consequently the proposed procedure can be considered robust. 4.5 Precision and stability The intra-day and inter-day precision of the proposed procedure was estimated by analyzing 0.1 g (100 ng) bulk nortriptyline hydrochloride solutions for four times in four successive days using SWCAdSV and DPCAdSV. The percentage recoveries based on the average of four separate determinations are abridged in Table 3. The results confirmed both the good precision of the proposed procedure and stability of the drugs solution.
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Table 3. Stripping voltammetric determination of nortriptyline hydrochloride in Sensival tablets using SWCAdSV and DPCAdSVmode.
Sample
SWCAdSV
DPCAdSV
Added Amount Percent Added Amount Percent amount found amount found (ng) (ng) recovery (ng) (ng) recovery Intra-day 100 precision 100 100 100 Mean S.D. Inter-day 100 precision 100 100 100 Mean S.D. 4.6 Ruggedness The ruggedness test of the analytical assay method is defined as degree of reproducibility of assay results obtained by the successful applications of the assay over time and multiple laboratories and analysts. Two analysts analyzed the same standard with SWCAdSV and DPCAdSV methods using the same instrument. The methods were found to be rugged with the results of variation coefficients 0.8 and 1.2 % for SWCAdSV, 1.1 and 1.7 % for DPCAdSV methods for first and second analysts, respectively. The results show no statistical differences between different analysts. 99.6 99.8 100.1 99.2 100.5 98.5 99.3 99.7 99.6 99.8 100.1 99.2 99.67 0.37 100.5 98.5 99.3 99.7 99.5 0.83 100 100 100 100 100 100 100 100 98.9 99.4 99.6 99.9 99.7 99.2 101 100.3 98.9 99.4 99.6 99.9 99.45 0.41 99.7 99.2 101 100.3 100 0.77
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5. Applications Voltammograms of nortriptyline hydrochloride in 0.1 M TEAP containing DMF exhibit very well defined cathodic peak. The current is mainly adsorption-controlled and proportional to the concentration over a convenient range. The analytical performance data of the proposed method are compiled in the Table 2. Statistical evaluation of the experimental data regarding S.D. of the residual (Sy/x), slope (Sb), intercept (Sa) gave the values cited in the same table. The small values point out to the high precision of the method [57]. The good linearity of the calibration graph and the negligible scatter of the experimental points are clearly evident by the correlation coefficients (close to one in both cases). To establish the reproducibility of the electrode response, seven replicate concentrations were tested at nortriptyline hydrochloride concentration of 0.1, 0.5, 1.0, 1.5, 2.5, 3.5, 4.5 g ml-1 using SWCAdSV mode (Fig. 6). Mean current values of 0.49 0.004; 0.57 0.007; 0.7 0.005; 0.82 0.005; 1.05 0.006; 1.25 0.009; 1.49 0.004 respectively were obtained. These small values of standard deviations indicate a highly precise electrode response. The proposed procedure was also applied to the analysis of sensival tablets using DPCAdSV. The precision was estimated for 0.1, 0.5 and 1.0 g of the drug using the calibration graph and standard addition method. Representative voltammograms are shown in (Fig. 7). The obtained mean percentage recoveries (%R) and the relative standard deviations (%R.S.D.) based on the average of five replicate measurements were found to be 99 99.7 and 0.8 1.5 respectively (Table 4). The procedure did not require any time consuming extraction steps prior to the assay of the drug.
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Fig. 6. The dependence of the SWCAdS voltammetric current for nortriptyline hydrochloride at different concentrations; in 0.1 M TEAP containing DMF, Eacc = -0.1V, tacc = 200s, frequency f = 50Hz, pulse amplitude Esw = 50 mV and scan increment s = 10 mV. (a)0.1 g (b) 0.5 g (c) 1.0 g (d) 1.5 g (e) 2.5 g (f) 3.5 g (g) 4.5 g.
Fig. 7. The dependence of the DPCAdS voltammetric current for nortriptyline hydrochloride at different concentrations; in 0.1 M TEAP containing DMF, Eacc = -0.1V, tacc = 200s, frequency f = 50Hz, pulse amplitude Esw = 50 mV and scan increment s = 10 mV. (a) 0.1 g (b) 0.5 g (c) 1.0 g.
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Table 4. Quantification of nortriptyline hydrochloride in Sensival tablets by the proposed SWCAdS voltammetric procedure.
Concentration addeda (g) 0.1 0.5 1.0

a
Concentration founda (g) 0.099 0.498 0.997
%R 99 99.6 99.7
%R.S.D. 1.5 1.1 0.8
Average of five replicate measurements.
6. Conclusion The proposed methodology of nortriptyline hydrochloride analysis that was developed in this work allows quantitative determination of this compound in pharmaceutical dosage forms. The direct dissolution of pharmaceutical tablets in supporting electrolyte containing dimethylformamide solutions allows a fast, economical and reproducible determination of this compound with no interference of additional substrates of pharmaceutical tablets. The developed method with detection limit of 0.05 g mL-1 is more sensitive to already reported spectroscopic method [13] and calorimetric method [21] for determination in pharmaceutical dosage form with concentration range 24-216 g mL-1 and 50-180 g mL-1 respectively. The working concentration range of 0.1 to 4.5 g mL-1 by SWCAdSV and 0.1-5.5 g mL-1 by DPCAdSV of nortriptyline hydrochloride in dosage form is in good agreement with the HPLC method [14] with concentration range 0.6-3.6 g mL-1. The proposed methods have distinct advantages over other existing methods regarding sensitivity, time saving and minimum detectability. In addition no sophisticated instrumentation is required. Consequently, the proposed methods have the potential of a good analytical alternative for determining nortriptyline hydrochloride in pharmaceutical formulation.
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ECS Transactions, 13 (20) 21-46 (2008) 10.1149/1.

3010727 The Electrochemical Society

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

1000 i p (nA) 500 0 0 100 200 tacc 300 400

ECS Transactions, 13 (20) 21-46 (2008)

1000 800 600 400 200 0 0 0.5 Eacc 1 1.5

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

Concentration addeda (g) 0.1 0.5 1.0

Concentration founda (g) 0.099 0.498 0.997

%R.S.D. 1.5 1.1 0.8

Average of five replicate measurements.

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

ECS Transactions, 13 (20) 21-46 (2008)

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