Elsevier

Analytica Chimica Acta

Volume 417, Issue 2, 24 July 2000, Pages 143-148
Analytica Chimica Acta

Voltammetric behavior of sildenafil citrate (Viagra) using square wave and adsorptive stripping square wave techniques: Determination in pharmaceutical products

https://doi.org/10.1016/S0003-2670(00)00932-6Get rights and content

Abstract

The behavior of sildenafil citrate (SC) was studied by square wave technique, leading to two methods for its determination in aqueous samples (pH 2.0) and pharmaceutical formulations. The application of the square wave (SW) without the adsorptive accumulation shows the maximum response at –1.03 V. Besides, SC gave two adsorptive stripping voltammetric (AdSV) peaks at –1.03 and −1.15 V using an accumulation potential of −0.80 V. The effect of experimental parameters that affect this determination are discussed. For the stripping technique, SC proved to be more sensitive, yielding signals three or four times larger than those obtained by applying a square wave scan without the previous accumulation. The calibration graph to determine SC was linear in the range 5×10−9 to 9×10−7 M by stripping mode with a time of accumulation tacc of 10 s. The relative standard deviations obtained for concentration levels of SC as low as 1.0×10−7 M with square wave was 2.5% (n=10) and for 1.0×10−7 M with stripping square wave was 3.1% (n=10) in the same day. The two proposed methods (SW and SWAdSV) were applied to the determination of SC in three pharmaceutical products (Viagra 25, Viagra 50 and Viagra 100) with very good recoveries with respect to the labelled values.

Introduction

Viagra, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase Type 5 (PDE5).

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1-H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate (structural formula in Fig. 1).

The physiological mechanism of erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme, guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

SC is a novel oral agent under development for the treatment of penile erectile dysfunction. It is a potent and selective inhibitor of 5-cyclic GMP-specific phosphodiesterase [1], [2].

The effects of SC on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes was determined by Ballard et al. [3].

Osterloh and co-workers [4] determined the efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. The sildenafil was a very effective and well tolerated treatment for the erectile dysfunction.

SC is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 h.

An isocratic HPLC method [5] using acetonitrile–phosphate buffer–water (28:4:68 v/v/v) with detection at 230 nm was utilised as routine analysis of SC in pharmaceutical products. In this paper, it has also been proposed as a procedure for the simultaneous determination of sildenafil and its metabolite (UK-103,320) using automated sequential trace enrichment of dialysates (ASTED) and HPLC.

Adsorptive stripping voltammetry (AdSV) has been demonstrated to be a useful technique for the study and determination of many molecules of biological importance [6]. The high sensitivity of adsorptive stripping methods is obviously their greatest advantage. If the sample contains interesting compounds that are electrochemically active but are not absorbed on the electrode surface, then classical separation procedures are not necessary. Another advantage is the possibility of working with very diluted samples with the corresponding decrease in interference in pharmaceutical analysis.

This paper shows that the SC compound is a drug, which suffers a strong absorption process onto a mercury electrode. By using this phenomenon and by accumulation of this compound at hanging mercury dropping electrode (HMDE) prior to square wave voltammetric measurement, higher sensitivities can be readily achieved. The influence of several experimental (pH, ionic strength) and instrumental (step increment, pulse amplitude, frequency, drop size) variables on the square wave and on the stripping square wave response has been evaluated. The proposed method was applied in the determination of SC in presence of other components (excipients) in three different presentations of the same product Viagra (25, 50 and 100 mg).

Section snippets

Materials

All solvents and reagents were of analytical reagent grade unless indicated otherwise. Solutions for voltammetric study were made with deionized water (Milli-Q quality). Stock solutions of 0.011 M HClO4 were prepared using suprapure grade reagent.

Sildenafil citrate was obtained from Pfizer. Standard solutions (16.0 mg/l) were prepared in water and stored at 4°C. Their stability was evaluated over a period of 15 days by electrochemistry. Diluted solutions of SC were prepared daily in water.

Apparatus

Results and discussion

The preconcentration of SC at the HMDE and the application of a subsequent differential pulse voltammetric (DPV) scan in the negative direction gave rise to two stripping reduction peaks (Ep=−0.95 and −1.020 V) at pH 2.0 (HClO4) (Fig. 2). As seen in Fig. 2, a large response is obtained only after 30 s of accumulation time for an assayed concentration of 5.0×10−7 M of the drug. On the contrary, the solution phase response (direct response, tacc=0 s) shows a very small reduction peak as expected for

Conclusions

This work shows that the SC can be determined using voltammetric techniques on the basis of its reduction process over the hanging mercury drop electrode. This behaviour provides a useful tool for its detection and quantification at low levels of concentration.

A faster analysis can be performed by direct measurement from the calibration graph established for SW. This method is sensitive enough, the accumulation time is removed and there are no interference in the analysis from the other

Acknowledgements

The authors wish to thank Pfizer Spain (Medical Division) and Pfizer Central Research for their help in the research sample contribution of sildenafil citrate and also to the DGES of the Ministerio de Educación y Ciencia of Spain for the financial support (Project PB-97-0431).

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