Abstract
<p><strong>Objective: </strong>The objective of this work is method development and validation study for quantitative determination of 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole, a genotoxic impurity and its precursor in a fluconazole drug sample by liquid chromatography–tandem mass spectrometry.</p><p><strong>Methods: </strong>LC-MS/MS analysis of these impurities was performed on Hypersil BDS C18 (100 mm x 4.0 mm, 3 µm) column. 5 mmol ammonium acetate and acetonitrile in the ratio of 65:35 (v/v) was used as the mobile phase with a flow rate of 0.4 ml/min. The developed method was accomplished with a short run time of 10 min. Triple quadrupole mass detector coupled with positive electrospray ionization was used for the quantification of genotoxic impurities in multiple reaction monitoring (MRM).</p><p><strong>Results: </strong>The method was validated as per International Conference on Harmonization (ICH) guidelines. The method was linear in the range of 0.30 µg/g to 11.37 µg/g for impurity A and 0.30 µg/g to 11.34 µg/g for impurity B with a correlation coefficient of 0.999. The accuracy of the method was in the range of 98.25 % to 100.53 % for both impurities.</p><p><strong>Conclusion: </strong>A specific, selective, highly sensitive and more accurate analytical method using LC-MS/MS coupled with positive electrospray ionization has been developed for the quantification of genotoxic impurity (1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole) and its precursor (1-(2,4-difluorophenyl)-2-[1,2,4]triazol-1-yl-ethanone) at 0.3 µg/g with respect to the 5.0 mg/ml of fluconazole.</p>
Highlights
Genotoxic impurities manifestation in active pharmaceutical ingredient (API), as well as products of drugs, received more attention by industries and various governing agencies because of their toxic effect on human health [1]
Fluconazole, impurity A and impurity B were eluted at 2.31 min, 3.84 min and 4.75 min, respectively and separated from each other and from the active pharmaceutical ingredient
The results showed that the retention times and peak areas of fluconazole and two impurities were with relative standard deviation of lower than two and that no significant degradation is observed within the given period, indicating that the solutions are stable
Summary
Genotoxic impurities manifestation in active pharmaceutical ingredient (API), as well as products of drugs, received more attention by industries and various governing agencies because of their toxic effect on human health [1]. Even lower concentration (
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