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Current Pharmaceutical Analysis

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ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

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Research Article

Simultaneous Determination of Two Potential Genotoxic Impurities in L-Malic Acid by Liquid Chromatography-Tandem Mass Spectrometry

Author(s): Jia Qian Pang, Ling Ling Zhang, Yu Bin Xu, Qing Fan and Zhen Xiong Zhao*

Volume 19, Issue 1, 2023

Published on: 17 October, 2022

Page: [83 - 90] Pages: 8

DOI: 10.2174/1573412918666221003100204

Price: $65

Abstract

Background: Genotoxic impurities (GTIs) are produced during the synthesis of active pharmaceutical ingredients and pharmaceutical excipients. L-malic acid, an important active pharmaceutical ingredient and excipient, is widely used in the pharmaceutical industry. However, the detection of potential GTIs in L-malic acid has not been reported.

Objective: This study aims to establish a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine the concentration of potential GTIs in L-malic acid, including N-nitroso-aspartic (NASP) and 2-chlorosuccinic acid (CSA).

Methods: In this work, GTIs were separated by a reverse-phase Accucore C18 column (100 mm × 2.1 mm, 2.6 μm), with gradient elution using methanol and 0.05% ammonia. The multiple reaction monitoring (MRM) negative mode was used to detect GTIs, with transitional ion pairs of m/z from 131.6 to 88.0 for NASP, and from 150.9 to 70.9 for CSA.

Results: The limit of detections (LODs) of NASP and CSA were 2 ng/mL (0.02 ppm) and 5 ng/mL (0.05 ppm), respectively. Both the limit of quantifications (LOQs) of NASP and CSA were 20 ng /mL (0.2 ppm). Good linearity of calibration curves in the concentration ranging from 10 to 500 ng/mL was obtained. The precision was less than 5%, and the intermediate precision was less than 10%. The accuracy ranged from 95.4% to 102.4%, with a relative standard deviation (RSD) of less than 5%. Also, the solution's stability and robustness were acceptable.

Conclusion: Compliant with requirements from (International Council for Harmonization) ICH guidelines, this method can be used for routine analysis and stability studies for GTIs’ levels in pharmaceutical quality control.

Keywords: Genotoxic impurities, L-malic acid, LC-MS/MS, Method validation, Precision, Accuracy

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[1]
Benigni, R. In silico assessment of genotoxicity. Combinations of sensitive structural alerts minimize false negative predictions for all genotoxicity endpoints and can single out chemicals for which experimentation can be avoided. Regul. Toxicol. Pharmacol., 2021, 126, 105042.
[http://dx.doi.org/10.1016/j.yrtph.2021.105042] [PMID: 34506881]
[2]
Li, S.; Dong, L.; Tang, K.; Lan, Z.; Liu, R.; Wang, Y.; Wang, R.; Lin, H. Simultaneous and trace level quantification of two potential genotoxic impurities in valsartan drug substance using UPLC-MS/MS. J. Pharm. Biomed. Anal., 2022, 212, 114630.
[http://dx.doi.org/10.1016/j.jpba.2022.114630] [PMID: 35158183]
[3]
Tao, X.; Tian, Y.; Liu, W.H.; Yao, S.; Yin, L. Trace level quantification of 4-methyl-1-nitrosopiperazin in rifampicin capsules by LC-MS/MS. Front Chem., 2022, 10, 834124.
[http://dx.doi.org/10.3389/fchem.2022.834124] [PMID: 35237562]
[4]
Mohan, B.; Sharma, R.S.K.; Kumar, D.R.; Murali, M.R.S.V.; Satya Venugopal, N.V. Determination of genotoxic alkyl p-toluene sulfonates in cabazitaxel using LC-MS method. Curr. Pharm. Anal., 2019, 15(7), 753-761.
[http://dx.doi.org/10.2174/1573412915666190522085818]
[5]
Hou, D.; Fan, J.; Han, L.; Ruan, X.; Feng, F.; Liu, W.; Zheng, F. Determination of small halogenated carboxylic acid residues in drug substances by high performance liquid chromatography-diode array detection following derivatization with nitro-substituted phenylhydrazines. J. Chromatogr. A, 2016, 1438, 46-56.
[http://dx.doi.org/10.1016/j.chroma.2016.02.002] [PMID: 26893023]
[6]
Mitra, M.S.; Datta, K.; Hutchinson, R.; Nicolette, J.J.; Pettersen, J.C.; Wegesser, T.C.; Bercu, J.P. Harmonized 3Rs-based non-mutagenic impurity qualification study designs developed using the results of an IQ consortium survey. Regul. Toxicol. Pharmacol., 2021, 122, 104895.
[http://dx.doi.org/10.1016/j.yrtph.2021.104895] [PMID: 33610610]
[7]
Baber, N. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). Br. J. Clin. Pharmacol., 1994, 37(5), 401-404.
[http://dx.doi.org/10.1111/j.1365-2125.1994.tb05705.x] [PMID: 8054244]
[8]
Weidolf, L.; Andersson, T.; Bercu, J.P.; Brink, A.; Glowienke, S.; Harvey, J.; Hayes, M.A.; Jacques, P.; Lu, C.; Manevski, N.; Muster, W.; Nudelman, R.; Ogilvie, R.; Ottosson, J.; Teasdale, A.; Trela, B. Qualification of impurities based on metabolite data. Regul. Toxicol. Pharmacol., 2020, 110, 104524.
[http://dx.doi.org/10.1016/j.yrtph.2019.104524] [PMID: 31734179]
[9]
Wahid, M.; Saqib, F.; Qamar, M.; Ziora, Z.M. Antispasmodic activity of the ethanol extract of Citrullus lanatus seeds: Justifying ethnomedicinal use in Pakistan to treat asthma and diarrhea. J. Ethnopharmacol., 2022, 295, 115314.
[http://dx.doi.org/10.1016/j.jep.2022.115314] [PMID: 35490899]
[10]
Hernandez-Baixauli, J.; Abasolo, N.; Palacios-Jordan, H.; Foguet-Romero, E.; Suñol, D.; Galofré, M.; Caimari, A.; Baselga-Escudero, L.; Del Bas, J.M.; Mulero, M. Imbalances in TCA, short fatty acids and one-carbon metabolisms as important features of homeostatic disruption evidenced by a multi-omics integrative approach of LPS-induced chronic inflammation in male wistar rats. Int. J. Mol. Sci., 2022, 23(5), 2563.
[http://dx.doi.org/10.3390/ijms23052563] [PMID: 35269702]
[11]
Yin, X.; Li, J.; Shin, H.; Du, G.; Liu, L.; Chen, J. Metabolic engineering in the biotechnological production of organic acids in the tricarboxylic acid cycle of microorganisms: Advances and prospects. Biotechnol. Adv., 2015, 33(6), 830-841.
[http://dx.doi.org/10.1016/j.biotechadv.2015.04.006] [PMID: 25902192]
[12]
He, S.; Jacobsen, J.; Nielsen, C.U.; Genina, N.; Østergaard, J.; Mu, H. Exploration of in vitro drug release testing methods for saquinavir microenvironmental pH modifying buccal films. Eur. J. Pharm. Sci., 2021, 163, 105867.
[13]
Han, Y.; Du, J.; Wang, Y. Effect of bentonite and calcium chloride on apple wine. J. Sci. Food Agric., 2022, 102(1), 425-433.
[http://dx.doi.org/10.1002/jsfa.11373] [PMID: 34143901]
[14]
Wang, R.; Zhang, F.; Zan, S.; Gao, C.; Tian, C.; Meng, X. Quality characteristics and inhibitory xanthine oxidase potential of 21 sour cherry (Prunus Cerasus L.) varieties cultivated in China. Front. Nutr., 2021, 8, 796294.
[http://dx.doi.org/10.3389/fnut.2021.796294] [PMID: 34957190]
[15]
Chi, Z.; Wang, Z.P.; Wang, G.Y.; Khan, I.; Chi, Z.M. Microbial biosynthesis and secretion of L -malic acid and its applications. Crit. Rev. Biotechnol., 2016, 36(1), 99-107.
[http://dx.doi.org/10.3109/07388551.2014.924474] [PMID: 25025277]
[16]
Reddy, A.V.B.; Jaafar, J.; Umar, K.; Majid, Z.A.; Aris, A.B.; Talib, J.; Madhavi, G. Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review. J. Sep. Sci., 2015, 38(5), 764-779.
[http://dx.doi.org/10.1002/jssc.201401143] [PMID: 25556762]
[17]
Jacobsonkram, D.; McGovern, T. Toxicological overview of impurities in pharmaceutical products. Adv. Drug Deliv. Rev., 2007, 59(1), 38-42.
[http://dx.doi.org/10.1016/j.addr.2006.10.007] [PMID: 17188779]
[18]
Popovska, O.; Kavrakovski, Z.; Rafajlovska, V. A RP-HPLC method for the determination of ketoconazole in pharmaceutical dosage forms. Curr. Pharm. Anal., 2017, 13(6), 1-1.
[http://dx.doi.org/10.2174/1573412912666160610104703]
[19]
Holzgrabe, U.; Nap, C.J.; Almeling, S. Control of impurities in l-aspartic acid and l-alanine by high-performance liquid chromatography coupled with a corona charged aerosol detector. J. Chromatogr. A, 2010, 1217(3), 294-301.
[http://dx.doi.org/10.1016/j.chroma.2009.11.036] [PMID: 19954785]
[20]
Jarukas, L.; Mykhailenko, O.; Baranauskaite, J.; Marksa, M.; Ivanauskas, L. Investigation of organic acids in saffron stigmas (Crocus sativus L.) extract by derivatization method and determination by GC/MS. Molecules, 2020, 25(15), 3427.
[http://dx.doi.org/10.3390/molecules25153427] [PMID: 32731562]
[21]
Yu, C.; Wang, Y.; Cao, H.; Zhao, Y.; Li, Z.; Wang, H.; Chen, M.; Tang, Q. Simultaneous determination of 13 organic acids in liquid culture media of edible fungi using high-performance liquid chromatography. BioMed Res. Int., 2020, 2020, 1-7.
[http://dx.doi.org/10.1155/2020/2817979] [PMID: 32802838]
[22]
Chen, L.; Zhong, Z.; Liu, J.; Wen, C.; Jin, Y.; Wang, X. Metabolic changes in mouse plasma after acute diquat poisoning by UPLC-MS/MS. Curr. Pharm. Anal., 2021, 17(7), 903-907.
[http://dx.doi.org/10.2174/1573412916999200624160304]

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