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This article was downloaded by: [Florida Atlantic University]On: 02 September 2013, At: 00:37Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: MortimerHouse, 37-41 Mortimer Street, London W1T 3JH, UK
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Voltammetric Behavior of Indinavir andDetermination in Pharmaceutical Dosage FormsNevin Erk aa Department of Analytical Chemistry, Faculty of Pharmacy, Ankara University, Ankara,Turkey, 06100Published online: 16 Aug 2010.
To cite this article: Nevin Erk (2004) Voltammetric Behavior of Indinavir and Determination in Pharmaceutical DosageForms, Analytical Letters, 37:1, 47-63, DOI: 10.1081/AL-120027773
To link to this article: http://dx.doi.org/10.1081/AL-120027773
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PHARMACEUTICAL ANALYSIS
Voltammetric Behavior of Indinavir
and Determination in Pharmaceutical
Dosage Forms
Nevin Erk*
Department of Analytical Chemistry, Faculty of Pharmacy,
Ankara University, Ankara, Turkey
ABSTRACT
The oxidative behavior of indinavir has been investigated by cyclic, linear
sweep, differential pulse, and square-wave voltammetry using a glassy
carbon electrode in different buffer systems. Cyclic voltammetry was used
to study the influence of pH on the peak current and peak potential. The
solution conditions and instrumental parameters were optimized to obtain
a good sensitivity. The Britton–Robinson buffer of pH 6.0 was selected as
a suitable analytical medium in which indinavir exhibited a sensitive
diffusion controlled oxidative peak at þ892.0mV (vs. Ag/AgCl). Theoxidation process was shown to be irreversible. The peak current
varied linearly with drug concentration in the range between 2.8 � 1027
and 5.0 � 1025M. The proposed voltammetric techniques have been
47
DOI: 10.1081/AL-120027773 0003-2719 (Print); 1532-236X (Online)
Copyright# 2004 by Marcel Dekker, Inc. www.dekker.com
*Correspondence: Nevin Erk, Department of Analytical Chemistry, Faculty
of Pharmacy, Ankara University, 06100 Ankara, Turkey; E-mail: erk@pharmacy.
ankara.edu.tr.
ANALYTICAL LETTERS
Vol. 37, No. 1, pp. 47–63, 2004
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applied to the determination of the drug in pharmaceutical dosage forms
with good recoveries. For comparative purposes a HPLC with a diode
array and multiple wavelength UV/VIS detection determination also was
developed.
Key Words: Indinavir; Cyclic voltammetry; Linear sweep voltammetry;
Differential pulse voltammetry; Square-wave voltammetry; Pharmaceu-
tical dosage form; HPLC.
1. INTRODUCTION
Human immunodeficiency virus (HIV) protease inhibitors are new and
potent antiretroviral drugs that have changed the treatment of infection with
HIV dramatically. Inhibition of HIV protease activity by representatives of
this class of antiretroviral drugs leads to production of non-infectious virions,
which have the morphological features of immature particles.[1] To date, four
protease inhibitors have been approved by the FDA under its accelerated
approval regulations (i.e., indinavir, nelfinavir, ritonavir, and saquinavir) and
others are currently being investigated in phase III clinical trials (such as
amprenavir, formerly known as 141W94/VX-478).The chemical name, indinavir, is N-[2(R)-hydroxy-1(S)-indanyl]-5-
f[2(S)-tertiary-butylaminocarbonyl]-4-(3-pyridyl-methyl)piperazinog-4(S)-
hydroxy-2(R)-phenyl-methyl-pentanamide (Sch. 1).
In the open literature, a lot of high performance liquid chromatographic
(HPLC) methods have already been developed for the simultaneous deter-
mination of indinavir and other compounds belonging to the same class, such
as zidovudine, stavudine, lamivudine, and squinavir, and their metabolites in
human plasma.[2 –21] To the best of my knowledge, there are no available
literature data on electroanalytical investigations based on as cyclic
voltammetry (CV), linear sweep voltammetry (LSV), differential pulse
Scheme 1. Chemical structure of indinavir.
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voltammetry (DPV), square-wave voltammetry (SWV) for the determination
of indinavir in pharmaceutical dosage forms and human plasma. Furthermore,
an official method for the determination of this compound in pharmaceutical
dosage forms has not been yet described in any pharmacopeia. Chromato-
graphic methods need sophisticated equipment or require lengthy extraction
and clean-up procedures. The voltammetric techniques offer another
possibility for the estimation of this compound. Hence the development of
electrochemical determination assumes importance.
In recent years, modern electroanalytical methods, such as CV, LSV, and
DPV, have been widely applied for the determination of compounds of
pharmaceutical interest.[22–28]
The principal aim of the present study has been to examine the
voltammetric behavior of indinavir based on the oxidation on the surface of
glassy carbon electrode, by using CV, LSV, DPV, and SWV techniques. The
developed voltammetric methods were applied to the analysis of this
compound in pharmaceutical dosage forms. Furthermore, the HPLC method
was chosen as the comparative method in evaluating the techniques. The
obtained data were analyzed statistically.
2. EXPERIMENTAL
2.1. Reagents and Drug
Bulk indinavir drug was kindly supplied by MSD Pharm. Co. (Rahway,
NJ). The indinavir capsules labelled as containing 200mg/capsule, werepurchased from the local pharmacy of Turkey.
Analytical grade phosphoric acid and HPLC grade methanol, and
acetonitrile were purchased from Merck Chem. Ind. (Darmstadt, Germany).
All other chemicals were of analytical-reagent grade and were used as
received.
Deionized water was obtained in the laboratory, using Milli-Q equipment.
2.2. Apparatus
Voltammetric measurements were taken and curves were obtained using a
BAS 100W/B electrochemical analyser and a HP 1100 laserjet printer.
Working and counter electrodes were a BAS MF 2012 glassy carbon disc with
a diameter of 3mm and a BAS MV 1032 platinum, respectively. A BAS MF
1063 type silver/silver chloride electrode was used as reference. The
potentials in the text were given vs. silver/silver electrode.
Voltammetric Behavior of Indinavir 49
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The HPLC system consisted of a membrane degasser, binary solvent
delivery system, a Rheodyne injector equipped with a 20mL sample loop, a
diode array, and multiple wavelength UV/VIS detectors (1100 Series, Agilent
Technologies, USA). The detection wavelength was at 270 nm, and the peak
areas were integrated automatically with Windows NT based LC ChemStation
Software.
2.3. Solutions Preparation
2.3.1. Buffer Solutions
Britton–Robinson buffers of 0.04M (acetic acid/boric acid/phosphoricacid) and 0.05M buffer phosphate solution (disodium hydrogen phosphate
anhydrous salt) for voltammetric experiments was used. The desired pH was
adjusted with concentrated solutions of NaOH or HCl.
2.3.2. Stock Drug Solution
Indinavir of 10mg was dissolved and diluted up to 100mL with methanol,
to obtain a final concentration of 1.4 � 1024M indinavir. The stock solution
was stored in brown bottles at þ48C.
2.3.3. Work Solutions
The working solutions voltammetric investigations were prepared by
dilution of the stock solution with selected 0.04M Britton–Robinson buffer
pH 3.0–10.0 and 0.2M phosphate buffer pH 5.3–8.3 were used. Also
the working solutions HPLC investigations were prepared by the appropriate
dilutions of the stock standard with mobile phase. The working solutions were
prepared freshly every day. The indinavir solutions were stable and their
concentrations did not change with time.
2.4. Pretreatment of the Working Electrode
Before each experiment surface of the glassy carbon (GC) electrode was
polished using alumina (f ¼ 0.01mm) on a polishing pad and then carefully
washed with bidistilled water and dried on a filter paper.
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2.5. Chromatographic Conditions
The chromatographic analysis was performed at ambient temperature
onto a Supelcocil C18 column (150 � 4.6mm i.d. 5mm particle size) and a
mobile phase composed of acetonitrile : methanol : water (45 : 45 : 10, v/v/v).The flow rate was maintained at 1.0mLmin21. A diode array detector was
fixed at 270 nm.
All solvents were filtered through 0.45mm milipore filter to use and
degassed in an ultrasonic bath.
2.6. Calibration Plot Preparation
2.6.1. Voltammetric Techniques
By diluting the indinavir stock solution with Britton–Robinson buffers
and phosphate buffer, working solutions ranging between 2.8 � 1027 and
5.0 � 1025M were prepared.
2.6.2. High Performance Liquid Chromatography
By diluting the indinavir stock solution with mobile phase, working
solutions ranging between 4.0 � 1026 and 5.0 � 1025M were prepared. The
solutions were injected and chromatographed according to the working
conditions previously given.
2.7. Analysis of Capsules
Crixivanw capsules was obtained in a local pharmacy. The amounts
declared of indinavir are 200mg per capsule. The contents of 10 capsules were
completely removed from shells. The accurately weighted quantities of these
powders equivalent to 200mg of indinavir were transferred to 50mL
volumetric flasks. About 25mL of methanol was added to dissolve the active
material. After sonicating and shaking the mixture for 15min, it was
completed to volume with the same solvent, mixed and passed through
Whatman no. 42 filter. An aliquot of the filtrate was then transferred into a
calibrated flask and series of dilutions was made with Britton–Robinson
buffer at pH 6.0 as supporting electrolyte containing 10% methanol for
voltammetric techniques. The content of the drug in pharmaceutical
preparations was determined referring to the regression equation.
Voltammetric Behavior of Indinavir 51
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The HPLC determination of indinavir was made by adding an aliquot of
the above mentioned solution to the mobile phase and then these solutions
were filtered through 0.45mm membrane filters. Triplicate 20mL injections
were made for each solution.
2.8. Synthetic Samples
Excipients (cornstarch, magnesium stearate, lactose, sodium laurly
sulfate, polyethylene-glycol 6000, titanium dioxide, carboxymethylcellulose,
hydroxypropylmethyl-cellulose, and talc) were added to the drug for recovery
studies, according to manufacturer’s batch formulas for 200.0mg indinavir
per capsule.
3. RESULTS AND DISCUSSION
3.1. Voltammetric Methods
In this work the idea was to propose a simple and fast method for the
determination of indinavir. The voltammetric behavior of indinavir has been
examined in Britton–Robinson buffers of pH range 3.0–10.0 and in phosphate
buffers of pH 5.3–8.3 by using CV, LSV, DPV, and SWV.
Figure 1 displays a cyclic voltammogram of 1.0 � 1025M indinavir in
Britton–Robinson buffer of pH 6.0 having 10% methanol at scan rate of
100mV s21 on a glassy carbon electrode. A well-definite anodic peak, corres-
ponding the oxidation of the drug is observed at þ892.0mV. No peaks are
observed in the cathodic branch, indicating that the indinavir oxidation is an
irreversible process. The anodic peak may be attributed to the irreversible
oxidation of the piperazine moiety of molecule, in accordance with the redox
mechanism postulated by Kauffmann et al.[29] and Bard and Faulkner[30] for
oxidation of piperazine ring in trazodone molecule. The effect of the potential
scans rate, between 10 and 1000mV s21, on the peak current and the peak
potential of indinavir was evaluated. Scan rate, n, studies were then carried out
to assess whether the processes on glassy carbon electrode were under
diffusion or adsorption control. The linear increase in the oxidation peak
current with the square root of the scan rate with a slope of 0.87, showed the
diffusion control process. The variation of log ip vs. log n is linear over the
scan range 10 and 1000mV s21, and corresponds to equation: log ip ¼ 0.69
logn 2 0.58 (n in mV s21 and r ¼ 0.9987). Slopes of 0.50 and 1.0 are
expected for ideal reactions of solution and surface species, respectively.[30]
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The value of an, product of transfer coefficient and number of electrons
transferred in the rate determining step, was determined from Tafel plot (log i
vs. E) of the voltammetric curves obtained. The an value obtained (0.31) show
the total irreversibility of the electron transfer process. It was also
demonstrated by the linear relationship obtained between the peak potential
Ep and the logarithm of scan rate in the range 10–1000mV s21.
The influence of several electrolytes (Britton–Robinson, phosphate buffer
and 0.5M H2SO4) on the analytical signal was studied using different electro-
analytical techniques. Phosphate and 0.5M H2SO4 yielded approximately the
Figure 1. Cyclic voltammogram of indinavir (1.0 � 1025M) in Britton–Robinson
buffer of pH 6.0, containing 10% methanol, at scan rate of 100mV s21.
Voltammetric Behavior of Indinavir 53
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same results with those obtained in Britton–Robinson buffer. Britton–
Robinson buffer was selected for further work because it not only gave the
highest peak current but also gave the best peak shape; this electrolyte was
used throughout this study
In general, pH is one of the variables that commonly and strongly influences
the shapes of cyclic voltammograms, and therefore it is important to investigate
the effects of pH on electrochemical systems. The peak potential was pH
independent below pH 3.0 and above pH 10.0. The linearity was observed in the
pH range 3.0–10.0 giving a negative slope of 39.0mV per pH unit (Fig. 2). The
intersections observed in the plot at pH 3.0 and 10.0 may be explained by
changes in protonation of the acid–base functions in the molecule.
On the other hand, the effect of pH on the peak current shows a maximum at
pH 6.0 (Britton–Robinson buffer) (Fig. 3). This indicates that the mechanism of
the oxidation is different strongly acid and strongly basic conditions.
In Fig. 4 differential pulse voltammograms obtained in Britton–Robinson
buffer solutions of different pH were given. The best curve and the highest
current were obtained in the solution of pH 6.0. The effect of the indinavir
concentration on peak current at 840.0mV was investigated, and a linear
relationship was obtained between peak current and concentration. The
quantitative determination of indinavir could be made by DPV and the
optimum conditions were obtained in Britton–Robinson buffer of pH 6.0,
10% (v/v) methanol; 20mV s21 scan rate, 50mV pulse amplitude, 17ms
sample width, 50ms pulse width, 200ms pulse period.
In Fig. 5 square-wave voltammograms taken in Britton–Robinson buffer
solutions are seen. The higher peak currents were observed in the Britton–
Robinson buffer solution of pH 6.0. The best peak definition was found with a
pulse amplitude, 25mV; frequency, 15Hz; and potential step 4mV.
Figure 2. Effect of pHon peak potentials for 1.0 � 1025Mindinavir solutions inBritton–
Robinson buffer of pH 6.0 by means of cyclic voltammetry at a glassy carbon electrode.
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3.1.1. Analytical Application
On the basis of the electrochemical oxidation of indinavir at glassy carbon
electrode, analytical methods were developed involving CV, LSV, DPV, and
SWV for the determination of the drug. A linear calibration plots were obtained
for indinavir in the range of 2.8 � 1027 and 5.0 � 1025M for all pro-
posed techniques. The characteristics of the calibration plots are listed in Table 1.
Validation of the procedures for the quantitative assay of the drug were
examined via evaluation of the limit of detection (LOD), limit of quantitation
(LOQ), repeatability, recovery, specificity, and robustness. The LOD and
LOQ were calculated from the calibration curves as kSD/b where k ¼ 3
for LOD and 10 for LOQ, SD is the standard deviation of the intercept and b is
the slope of the calibration curve. The values of LOD and LOQ were
calculated and shown in Table 1.
Repeatability and recovery were examined by performing five replicate
measurements for the concentration of 2.8 � 1027 and 5.0 � 1025M for all
proposed techniques. The results obtained were summarized in Table 2, that
indicated high precision of the all proposed methods.
The reproducibility of the methods were evaluated for five independent
determinations of 1.0 � 1025M solutions, yielding relative standard devia-
tions of 0.35%, 0.46%,0.64%, and 0.86%, for CV, LSV, DPV and SWV,
respectively, indicating good repeatability and accuracy of the methods.
Specificity of the optimized procedure for assay of indinavir was examined in
presence of some common excipients in the same ratios usually used in
pharmaceutical preparations (cornstarch, magnesium stearate, lactose, sodium
laurly sulfate, polyethyleneglycol 6000, titanium dioxide, carboxymethylcel-
lulose, hydroxypropylmethyl-cellulose, and talc). The mean percentage
Figure 3. Influence of pH on peak current for indinavir (1.0 � 1025M) in Britton–
Robinson buffer of pH 6.0,containing 10% methanol.
Voltammetric Behavior of Indinavir 55
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Figure 4. Differential pulse voltammograms recorded in Britton–Robinson buffers
of different pH having 1.0 � 1025M indinavir, scan rate 20mV s21. (a) pH 3.0;
(b) pH 4.0; (c) pH 5.0; (d) pH 6.0; (e) pH 7.0; (f) pH 8.0; (g) pH 9.0; (h) pH 10.0. Scan
rate 20mV s21, pulse amplitude, 50mV; sample width 17ms, pulse width, 50ms; and
pulse period, 200ms.
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Figure 5. Square wave voltammograms curves obtained in Britton–Robinson buffers
of different pH having 1 � 1025M indinavir pulse amplitude, 25mV; freq-
uency, 15Hz; potential step, 4mV. (a) pH 3.0; (b) pH 4.0; (c) pH 5.0 ; (d) pH 6.0;
(e) pH 7.0; (f) pH 8.0; (g) pH 9.0; and (h) pH 10.0.
Voltammetric Behavior of Indinavir 57
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Table
1.
Statistical
analysisofcalibrationcurves
inthedeterminationofindinavirbyCV,LSV,DPV,SWV,andHPLC.
Param
eters
CV
LSV
DPV
SWV
HPLC
Range(M
)2.8
�1027–5.0
�1025
2.8
�1027–5.0
�1025
2.8
�1027–5.0
�1025
2.8
�1027–5
�1025
4.0
�1026–5.0
�1025
LOD
(M)
1.2
�1028
1.2
�1028
4.4
�1028
4.4
�1028
2.4
�1028
LOQ
(M)
3.8
�1027
7.0
�1027
2.7
�1027
2.5
�1027
3.7
�1027
Regressionequation(Y)a
Slope(b)
9.71�
105
5.24�
105
8.73�
104
6.32�
105
4.32�
1024
Std.dev.onslope(S
b)
1.43�
1025
5.53�
1025
8.31�
1024
3.54�
1026
3.73�
1026
Intercept(a)
0.63
0.48
0.31
2.34�
1022
2.83�
1022
Std.dev.onintercept(S
a)
1.19�
1027
7.54�
1026
5.28�
1024
5.62�
1026
3.15�
1026
Std.errorofestimation(S
e)
5.15�
1026
4.21�
1025
3.24�
1023
8.47�
1027
3.64�
1027
Correlationcoefficient(r)
0.9983
0.9998
0.9995
0.9981
0.9986
aY¼
aþ
bCwhereCisconcentrationin
MandYin
peakarea
andcurrentunitsforandvoltam
metricmethods,respectively.
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recovery of 1.0 � 1025M indinavir (99.1 + 0.84) showed no significant
excipients interference, thus the procedure was able to assay indinavir in the
presence of excipients and hence it can be considered specific.
3.2. High-Performance Liquid Chromatography
The reversed-phase HPLC method was developed to provide a specific
procedure suitable for the rapid quality control analysis of indinavir and as
referee method for the developed voltammetric methods.
The mobile phase was investigated after several trials with acetonitrile:
methanol :water in various proportions. A mobile phase of acetonitrile:
methanol :water (45 : 45 : 10 v/v/v) and flow rate selection was based on peak
parameters (height, asymmetry, tailing), baseline drift, run time, ease of
preparation of mobile phase. A diode array detector was fixed at 270 nm. An
internal standard was not used as there was no extraction in the estimation of
indinavir in pharmaceutical dosage forms. The system appears to be quite robust.
3.2.1. Determination of Indinavir in Capsules
The proposed procedure was successfully applied for the determination of
indinavir in its capsules. The mean recoveries based on five replicated
measurements were 98.8–100.1% RSD of 0.45–0.91%. The proposed methods
proved to have precision and accuracy adequate for the reliable analysis of
Table 2. Recovery test of indinavir.
Added (M) Recovery (%) RSD (%)
CV
2.8 � 1027 98.8 1.22
5.0 � 1025 98.7 1.29
LSV
2.8 � 1027 98.8 0.57
5.0 � 1025 98.7 0.37
DPV
2.8 � 1027 99.8 1.52
5.0 � 1025 99.0 1.90
SWV
2.8 � 1027 97.5 1.38
5.0 � 1025 98.2 0.73
Voltammetric Behavior of Indinavir 59
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indinavir. The HPLC method was chosen as the analytical reference method.
The proposed voltammetic techniques were compared with HPLC method. The
results obtained were summarized in Table 3. No significant differences were
found between the results obtained by the HPLC method, the voltammetric
techniques, for same batch at the 95% confidence level (student’s t-test).
CONCLUSION
In the present paper, the electrochemical behavior of indinavir at the
glassy carbon electrode in Britton–Robinson buffers and in phosphate buffers
were studied and discussed. In addition, a fully validated voltammetric
techniques for the determination of indinavir in bulk form and pharmaceutical
formulations was described. The procedures were simple, fast, sensitive,
precise, and low in cost. The voltammetric techniques are a direct method for
the determination of indinavir and does not include any extraction process. All
the developed methods may be recommended for routine and quality control
analysis of the investigated drug in pharmaceutical dosage forms.
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Commercial tableta
Meanb 199.1 198.8 199.7 199.1 200.1
R.S.D (%) 0.91 0.86 0.67 0.45 0.09
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t, theoretical (p ¼ 0.05) 2.26 2.26 2.26 2.26
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Received June 16, 2003
Accepted August 8, 2003
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