Determination of Genotoxic Azide Impurity in Cilostazol API by Ion Chromatography with Matrix Elimination

Boglárka Páll,Zsuzsa Gyenge,Krisztián Horváth,Róbert Kormány

doi:10.3390/separations8100162

Boglárka Páll, Zsuzsa Gyenge + Show 2 more

Open Access

https://doi.org/10.3390/separations8100162

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Abstract

Cilostazol is a commonly used active pharmaceutical ingredient (API) to treat and reduce the symptoms of intermittent claudication in peripheral vascular disease. Recently, it was found to be a potential medicine in the effective treatment of COVID-19. In addition to the positive effects of this API, genotoxic sodium azide is used in the synthesis of cilostazol that can appear in the API. In this work, a method was developed for the determination of sodium azide (as azide anion) in cilostazol API at 7.5 ppm limit level by using ion chromatography (IC) and liquid–liquid extraction (LLE) sample preparation. The liquid–liquid extraction allows the application of high sample concentrations. Because of the low limit concentration (7.5 ppm), 500 mg sample was dissolved in 5 mL solvent. By using LLE for sample preparation, the huge amount of cilostazol was omitted and column overload was avoided. The developed method was validated in accordance with the relevant guidelines. Specificity, accuracy, precision, limit of detection and limit of quantification parameters were evaluated. The calculated limit of detection was 0.52 ppm (S/N:3) and the limit of quantification was 1.73 ppm (S/N:10) for sodium azide. The recovery of the sodium azide was 102.4% and the prepared solutions were stable in the sample holder for 24 h.

Highlights

The cilostazol is a platelet-aggregation inhibitor and arterial vasodilator, its long-term use may prevent stroke [1]
Because of the low concentration limit of sodium azide, large amount of cilostazol active pharmaceutical ingredient (API) is needed for the determination
The high concentration of API may have a negative impact on the ion chromatographic determination of azide ion

Summary

Introduction

The cilostazol is a platelet-aggregation inhibitor and arterial vasodilator, its long-term use may prevent stroke [1]. Several studies were published about cilostazol long-term treatment safety. It was found by W.R. Hiatt et al that the mortality was not higher in the treatment group, than the placebo group during the examined 42 months [3]. In addition to the long-term treatment safety of cilostazol, attention should be drawn to the possible impurities because these can cause deteriorate side effect for patients in the long term. It can be seen that sodium azide is used for forming the tetrazole ring [4]. Death can occur within an hour by hypotension [5]

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