Quantitative determination of potential genotoxic impurities in metformin hydrochloride and empagliflozin tablets through ultra-performance liquid chromatographymass spectrometry
An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studi...
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| Vydané v: | Journal of pharmaceutical and biomedical analysis Ročník 241; s. 116000 |
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| Hlavní autori: | , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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England
Elsevier B.V
15.04.2024
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| Abstract | An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin–empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2–95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug.
•A potentially new genotoxic impurity, benzyl peroxide, was identified.•Impurities in metformin–empagliflozin combination formulations were detected.•Hydroperoxide is unstable and produces reactive free radicals that attack DNA.•A method was developed and validated for trace–level quantification of impurities |
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| AbstractList | An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin-empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2-95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug. An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin–empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2–95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug. •A potentially new genotoxic impurity, benzyl peroxide, was identified.•Impurities in metformin–empagliflozin combination formulations were detected.•Hydroperoxide is unstable and produces reactive free radicals that attack DNA.•A method was developed and validated for trace–level quantification of impurities An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin-empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2-95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug.An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin-empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2-95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug. |
| ArticleNumber | 116000 |
| Author | Lin, Huaqing Xiao, Tingyu Chen, Yucheng Hu, Xin |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38280234$$D View this record in MEDLINE/PubMed |
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| References_xml | – reference: ICH, Validation of analytical procedures: Text and methodology. https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf. Vol. 2. International Conference on Harmonization, Geneva, 2005. Q2, (p. R1). – volume: 175 start-page: 927 year: 2022 end-page: 937 ident: bib15 article-title: Cardiovascular outcomes in patients initiating first-line treatment of Type 2 diabetes with sodium-glucose Cotransporter-2 inhibitors versus metformin: a cohort study publication-title: Ann. Intern. Med. – reference: Medicines and Healthcare Products Regulatory Agency, Interim guidance on a strategy for genotoxicity testing and mutagenic hazard assessment of impurities in chemical substances, 2012. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/315779/impurities.pdf. – reference: U.S. Food, D. Administration, Guidance for industry. Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches [EB/OL], 2016-12–05. http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0629-gdl.pdf. – volume: 273 start-page: 529 year: 2013 end-page: 543 ident: bib4 article-title: The role of mitochondrial DNA mutations and free radicals in disease and ageing publication-title: J. Intern. Med. – volume: 101 start-page: 127 year: 2012 end-page: 139 ident: bib1 article-title: Effect of antioxidants and silicates on peroxides in povidone publication-title: J. Pharm. Sci. – volume: 50 start-page: 114 year: 2021 end-page: 118 ident: bib5 article-title: The determination of genotoxic impurity in compound preparation of canagliflozin and metformin by LC-MS/MS, Bull. Ferment publication-title: Sci. Technol. – volume: 101 start-page: 34 year: 2018 end-page: 42 ident: bib2 article-title: Reactive impurities in large and small molecule pharmaceutical excipients – a review publication-title: TrAC Trends Anal. Chem. – volume: 75 start-page: 422 year: 2020 end-page: 434 ident: bib14 article-title: Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review publication-title: J. Am. Coll. Cardiol. – volume: 57 start-page: 136 year: 2007 end-page: 143 ident: bib12 article-title: A cluster randomised controlled trial of the effect of a treatment algorithm for hypertension in patients with type 2 diabetes publication-title: Br. J. Gen. Pract. – reference: European Medicines Agency, Guidelines on the limits of genotoxic impurities [EB/OL], 2016-12–05. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002903.pdf. – reference: ICH, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Current Step 4 Version Dated 31 March 2017, p. M7(R1). – volume: 20 start-page: 953 year: 2014 end-page: 966 ident: bib11 article-title: Metformin: from mechanisms of action to therapies publication-title: Cell Metab. – volume: 44 year: 2021 ident: bib13 article-title: Professional practice committee, standards of medical care in diabetes—2021 publication-title: Diabetes Care – volume: 19 start-page: 141 year: 1993 end-page: 158 ident: bib3 article-title: Free radicals in disease processes: a compilation of cause and consequence publication-title: Free Radic. Res. Commun. – reference: National Pharmacopoeia Commission, Guidelines for the control of genotoxic impurities (First draft), 2019. https://www.chp.org.cn/ydw/upload/userfiles/20190123/641548209919095.pdf. |
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| SubjectTerms | Benzhydryl Compounds Chromatography, High Pressure Liquid - methods Empagliflozin Genotoxic impurity Glucosides Humans Metformin Metformin - analysis Peroxide Peroxides Spectrum Analysis Tablets UPLC3MS/MS |
| Title | Quantitative determination of potential genotoxic impurities in metformin hydrochloride and empagliflozin tablets through ultra-performance liquid chromatographymass spectrometry |
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