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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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2. Rentsch, K.M. Sensitive and specific determination of eight antiretroviral

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Table 3. Comparative studies for indinavir pharmaceutical dosage forms.

Analysis techniques CV LSV DPV SWV HPLC

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

Calculated t value 0.75 0.88 0.84 1.02

t, theoretical (p ¼ 0.05) 2.26 2.26 2.26 2.26

aTablet, 200.0mg per tablet (Crixivanw capsule).bEach value is the mean of ten experiments.

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Received June 16, 2003

Accepted August 8, 2003

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