A Selective and Sensitive Lc-MS/MS Method for Quantification of Four Potential Genotoxic Impurities in Atazanavir Sulfate Drug Substance in Trace Level

Abstract

Objective: The main objective of current research work is to develop and validate a rapid, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the trace analysis of four potential genotoxic impurities in Atazanavir Sulfate drug substance.
 Methods: LC-MS/MS analysis of four potential genotoxic impurities was done on Acquity UPLC CSH C18 (100 mm × 2.1 mm, 1.7 μm) column. In this method, mobile phase A (10 mM ammonium acetate) mobile phase B (methanol: acetonitrile (90:10, v/v) with gradient run with the flow rate of 0.2 ml/min. The method was developed with the short run time of 13 min. Triple quadrupole mass detector coupled with positive electrospray ionization was used for the quantification of genotoxic impurities in multiple reaction monitoring (MRM) mode.
 Results: The method was linear in the range of 0.3 ppm to 4.5 ppm for BOC Hydrazine Acid impurity, BOC Epoxide and Keto impurity with a correlation coefficient not less than 0.9994. The accuracy of the method was in the range of 99.26% to 105.71% for all four potential genotoxic impurities (PGIs). No impurities were identified in the Atazanavir Sulfate active pharmaceutical ingredient sample.
 Conclusion: The proposed method is specific, linear, precise, accurate, robust and stable for the quantification of the four genotoxic impurities at very low levels.

Analytical determination of ethylenediamine impurity in tripelennamine hydrochloride by gas chromatography–mass spectrometry using phthalaldehyde as the derivatizing agent

“…Most pharmaceutical companies utilize the guidelines provided by the European Medicines Agency and the ICH M7(R1) to regulate toxic impurities in drug substances (European Medicines Agency, 2006;ICH Harmonised Guideline, 2017). Following this, further research studies have been conducted to assess the carcinogenic and genotoxic contaminants found in pharmaceutical drug substances using a variety of analytical techniques including HPLC, ultra-performance liquid chromatography, GC, LC-tandem mass spectrometry, and GC-MS. (Babu et al, 2018;Balaji et al, 2022;Balaji & Sultana, 2017;Chen et al, 2020;Chittireddy et al, 2023;Feng et al, 2016;Gopalakrishnan & Devi, 2016;Grace et al, 2019;Kosuri et al, 2023;Lee et al, 2022;Louati et al, 2018;Narapereddy & Alladi, 2023;Nekkala et al, 2017;Neyer et al, 2020;Pandey et al, 2011;Sajan et al, 2015;Siva Jyothi & Venkatnarayana, 2021;Sojitra et al, 2019;Tatipamula et al, 2019;Uppala & Arthanareeswari, 2021;Vijaya Bhaskar Reddy et al, 2014;Wang et al, 2016;Yelampalli et al, 2019).…”

Gas chromatography mass spectrometer determination of dimethylamine impurity in N,N‐dimethylformamide solvent by derivatization of N,N‐dimethylbenzamide with benzoyl chloride agent

“…Various derivatization agents are utilized to estimate the amine impurities and genotoxic impurities in different analytical techniques like high-performance liquid chromatography, ion chromatography, GC, gas chromatography mass spectrometer (GCMS), and liquid chromatography mass spectrometry (Ajay Babu et al, 2018;Asif Iqbal et al, 2014;Balaji & Sultana, 2017;Balaji et al, 2022;Chandrakant et al, 2019;Chittireddy et al, 2023;Caroline et al, 2019;Eswara Raju et al, 2023;Gao et al, 2019;Gopalakrishnan & Ashadevi, 2016;Jenny et al, 2016;Kaouthar et al, 2018;Kousrali et al, 2024;Krishan Prasad & Devi, 2023;Kyoungmin et al, 2022;Mori et al, 2004;Nekkala et al, 2017;Peter et al, 2020;Sajan et al, 2015;Saurabh et al, 2011;SivaJyothi & Venkat, 2021;Suresh Reddy et al, 2019;Tatipamula et al, 2019;Uppala & Arthanareeswari, 2021;Vijaya Bhaskar Reddy et al, 2014;Xiao et al, 2016;Yuyuan et al, 2020;Zhou et al, 2018). However, the present method relying on benzoyl chloride as the derivatization agent is a simple, cost-effective, and time-saving analytical method for the quantitative estimation of dimethylamine in N,N-dimethylformamide solvent.…”