nortriptyline ecs

7/31/2019 Nortriptyline ECS

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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

[email protected], 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 mL-

1

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.

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

10.1149/1.3010727 The Electrochemical Society

21Downloaded 21 Mar 2009 to 202.141.112.226. Redistribution subject to ECS license or copyright; see http://www.ecsdl.org/terms_use.jsp
mailto:[email protected]:[email protected]:[email protected]


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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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3CH

H

N

Scheme 1

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 pre-

concentrated 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 non-

reversibility of this process.

According to the Randles-Sevick equation in a linear diffusion-controlled process,

ip1/2

, 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/naF) 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 interceptKf 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,Fis Faradays constant andNis 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].

3CH

H

N

+ 2e-

+ 2H+

N

H

CH3

Scheme 2

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.

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.

plot of taccvs ip

0

500

1000

0 100 200 300 400

tacc

ip(n

A)




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plot tacc vs ip

0

200

400

600

800

1000

0 100 200 300 400

tacc

ip(nA)

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, frequencyf= 50Hz,

pulse amplitudeEsw = 50 mV and scan increment s = 10 mV.

plot of Eacc vs ip

0

200

400

600

800

1000

0 0.5 1 1.5

Eacc

ip(nA)

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; frequencyf

= 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.




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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 Optimized value

Solvent type 0.1 M TEAP containing DMFPurge time (s) 300

Accumulation potential (V) -0.1

Pre-concentration time (s) 200

Rest period (s) 10Mercury drop size (cm

2) 4

Stirring rate (rpm) 2000

Frequency (Hz) 50Scan increment (mV) 10

Pulse amplitude (mV) 50




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Table 2. Analytical parameters for voltammetric determination of nortriptyline hydrochloride using

SWCAdSV and DPCAdSV modes.

Parameter SWCAdSV DPCAdSV

Conc. Range (g mL-1) 0.1 4.5 0.1 - 5.5

LOD (g mL-1) 0.05 0.057LOQ (g mL-1) 0.1 0.1Mean found(%) 99.5 100.1

Correlation coefficient(r2) 0.999 0.999

Slope(A/g mL-1) 2.26 x 10-7 2.1 x 10-7

Intercept(A) 4.7 x 10-7 2.48 x 10-7Sy/x 1.4 x 10

-88 x 10

-7

Sa 4 x 10-9 4 x 10-9

Sb 5 x10-9

3 x10-9

% Error 0.94 0.67

Applications Tablets 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-1bulk 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 Sensivaltablets using

SWCAdSV and DPCAdSVmode.

Sample SWCAdSV DPCAdSV

Added

amount

(ng)

Amount

found

(ng)

Percent

recovery

Added

amount

(ng)

Amount

found

(ng)

Percent

recovery

Intra-dayprecision

100 99.6 99.6 100 98.9 98.9

100 99.8 99.8 100 99.4 99.4

100 100.1 100.1 100 99.6 99.6

100 99.2 99.2 100 99.9 99.9

Mean 99.67 99.45

S.D. 0.37 0.41Inter-dayprecision

100 100.5 100.5 100 99.7 99.7

100 98.5 98.5 100 99.2 99.2

100 99.3 99.3 100 101 101100 99.7 99.7 100 100.3 100.3

Mean 99.5 100

S.D. 0.83 0.77

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.




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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

sensivaltablets 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 differentconcentrations; 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) 2.5g (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, pulseamplitude 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.

a 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-1by

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.

Concentration

addeda

(g)

Concentration

founda

(g)

%R %R.S.D.

0.1 0.099 99 1.5

0.5 0.498 99.6 1.1

1.0 0.997 99.7 0.8




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