Objective: To establish a method for the determination of N-nitrosodimethylamine (NDMA) in metformin hydrochloride by gas chromatography tandem mass spectrometry (GC-MS/MS). Methods: A capillary column with 100% polyethylene glycol (PEG-20M) (Agilent VF-WAXms,30 m×0.25 mm,0.25 μm)as stationary liquid was used for separation. The mass spectrum was detected by EI ionization, positive ion mode and MRM mode. The quantitative ion pair of NDMA was m/z 74.0→44.0, and the collision energy (CE) was 8 eV. The qualitative ion pair was m/z 74.0→42.0, and the collision energy (CE) was 18 eV. Results: The specificity of the method was good, and the solvents and excipients did not interfere with the determination of NDMA. The linear range of NDMA was 0.296-59.2 ng·mL-1, the limit of detection (LOD) was 0.189 ng·mL-1 and the limit of quantitation (LOQ) was 0.592 ng·mL-1. The precision and stability tests met the detection requirements. The recoveries were 91.9%-101.0%, and RSDs were less than 2.5%. The method was used to determine NDMA in 67 batches of metformin hydrochloride preparations. NDMA were detected from 30 batches. Among them, 15 batches exceeded standard, and all were sustained-release tablets. The analysis of the corresponding active pharmaceutical ingredients (APIs) of some sustained-release tablets showed that the NDMA content of the sustained-release tablets increased significantly from the APIs to the preparations. Conclusion: This method is accurate, rapid, sensitive and specific, which can be used to control the content of NDMA in metformin hydrochloride. Enterprises should not only pay attention to the quality control of APIs, but also conduct process evaluation to reduce the increase of NDMA.
JING Yuan-chao, WANG Hai-yan, SUN Tao, KONG Ling-yang, BAI Hong
. Quality evaluation of N-nitrosodimethylamine (NDMA) in metformin hydrochloride preparation by gas chromatography tandem mass spectrometry*[J]. Chinese Journal of Pharmaceutical Analysis, 2022
, 42(12)
: 2122
-2128
.
DOI: 10.16155/j.0254-1793.2022.12.08
[1] 张素琴, 刘峰. 二甲双胍降糖外作用的研究进展[J].实用医药杂志, 2017, 34 (8): 750
ZHANG SQ, LIU F. Research progress on the metformin’s functions besides decreasing blood glucose level[J].Pract J Med Pharm, 2017, 34 (8): 750
[2] 杨洛, 郝亚荣. 二甲双胍的药理作用研究进展[J].医学综述, 2019, 25 (9): 1816
YANG L, HAO YR. Research progress in pharmacological effects of metformin[J].Med Recapit, 2019, 25 (9): 1816
[3] BERCU JP, DOBO KL, GOCKE E, et al. Overview of genotoxic impurities in pharmaceutical development[J].Int J Toxicol, 2009, 28 (6): 468
[4] 阮晓玲, 郑项元, 徐洁, 等. 药物中基因毒性杂质分析方法的研究进展[J].中国药科大学学报, 2016, 47 (3): 267.
RUAN XL, ZHENG XY, XU J, et al. Advances in analytical techniques for the determination of genotoxic impurities in pharmaceuticals[J].J China Pharm Univ, 2016, 47 (3): 267
[5] FDA. Updates on Angiotensin Ⅱ Receptor Blocker (ARB)Recalls Including Valsartan, Losartan and Irbesartan[EB/OL].[2020-01-12]. https://www.fda.gov/Drugs/Drug Safety/ucm613916.htmL
[6] Number of Countries Where Recalls Were Made and FDA’s Reaction[EB/OL]. [2020-01-12]. https://edition.cnn.com/2018/07/06/health/valsartan-heart-drug-recallintl/inde-x.htmL
[7] FDA.Statement Alerting Patients and Health care Professionals of NDMA Found in Samples of Ranitidine[EB/OL]. (2019-09-13)[2020-01-12]. https//www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine?detail
[8] International Agency for Reserch on Cancer(IARC). Agents Classified by the IARC Monographs[EB/OL].[2020-03-03]. https://monographs.iarc.fr/ENG/Classification/index.php
[9] International Council for Harmonization(ICH). ICH Harmonised Guideline,Assessment and Control of DNA reactive(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1)[EB/OL]. (2017-3-31). https:www.europa.eu/en/documents/scientific-guideline/guideline-assessment-contral-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential_en.pdf
[10] FDA. Updates on Angiotensin Ⅱ Receptor Blocker(ARB)Recalls Including Valsartan Losartan and Irbesartan[EB/OL].[2020-01-12]. https://www.fda.gov/Drugs/Drug Safety/ucm613916.htm
[11] Number of Countries Where Recalls Were Made and FDA’s Reaction[EB/OL].[2020-01-12]. https//edition.cnn.com/2018/07/06/health/valsartan-heart-drug-recall-intl/index.html
[12] 叶晓霞, 葛雨琦, 乐健,等. 缓释制剂辅料导致盐酸二甲双胍降解产生N-亚硝基二甲胺的影响因素研究[J].药物分析杂志, 2021, 41(2): 293
YE XX, GE YQ, LE J, et al. Study on influencing factors of metformin hydrochloride’s degradation to N-nitrosodimethylamine induced by sustained-release excipients[J].Chin J Pharm Anal, 2021, 41(2): 293
[13] 张岩琛, 刘晓强, 黄海伟, 等. 采用不同方法评估二甲双胍原料药及其制剂中N-亚硝胺二甲胺含量[J].药物分析杂志, 2021, 41(6): 1036
ZHANG YC, LIU XQ, HUANG HW, et al. Different methods to evaluate the content of N-nitrosodimethylamine in metformin and its preparations[J].Chin J Pharm Anal, 2021, 41(6): 1036
[14] LIN CH, WANG PH, WANG TH, et al. The surface-enhanced Raman scattering detection of N-nitrosodimethylamine and N-nitrosodiethylamine via gold nanorod arrays with a chemical linkage of zwitterionic copolymer[J].Nanoscale, 2020, 12(2): 1075
[15] XAVIER C, SAINT CP, CHOW C, et al. Electrochemical detection of N-nitrosodimethylamine using a molecular imprinted polymer[J].Sens Actuat B: Chem, 2016, 237: 613
[16] Hitoshi, Kodamatani, Hitomi, et al. Rapid method for monitoring N-nitrosodimethylamine in drinking water at the ng/L level without pre-concentration using high-performance liquid chromatography-chemiluminescence detection[J].J Chromatogr A, 2016, 1460:202
[17] 郭常川, 刘琦,张雷, 等. 高效液相色谱-串联质谱法测定盐酸二甲双胍及其制剂中痕量N-亚硝基二甲胺[J].色谱, 2020, 38(11):40
GUO CC, LIU Q, ZHANG L, et al. Determination of N-nitrosodimethylamine in d metformin hydrochloride its preparations by high performance liquid chromatography-tandem mass spectrometry and ranitidine by precipitation and solid phase extraction and gas chromatography-tandem mass spectrometry[J].Chin J Chromatogr, 2020, 38(11):40
[18] LIM HH, OH YS, SHIN HS. Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography-tandem mass spectrometry[J].J Pharm Biomed Anal, 2020, 189: 113460
[19] GB/T30919-2014. 苯乙烯-丁二烯生橡胶N-亚硝基胺化合物的测定气相色谱-热能分析法[S].2014
GB/T30919-2014 Styrene-butadiene Rubber,Raw-Determination of N-Nitrosamines Content by Gas Chromatography-Thermo Energy Analyzer Method[S].2014
[20] CHOI RN, KIM YP, JI WH, et al. Identification and quantification of seven volatile n-nitrosamines in cosmetics using gas chromatography/chemical ionization-mass spectrometry coupled with head space-solid phase microextraction[J].Talanta, 2016,148:69
[21] 徐小力, 青旺旺, 邹佳佳, 等. 气相色谱-质谱联用法测定不同厂家盐酸二甲双胍缓释片中N-亚硝基二甲胺的含量[J].中国医院药学杂志, 2020, 41(24):2531
XU XL, QING WW, ZOU JJ, et al. Determination of N-nitrosodimethylamine in metformin hydrochloride sustainedrelease tablets from different manufacturers by gas chromatography-mass spectrometry[J].Chin J Hosp Pharm, 2020, 41(24):2531
[22] 田珩, 吴纯敏, 贝琦华. 离子色谱法测定雷尼替丁原料药及制剂中亚硝酸根含量[J].中国药业, 2021, 30(15):74
TIAN H, WU CM, BEI QH. Content determination of nitrite ion in ranitidine raw materials and preparations by ion chromatography[J].China Pharm, 2021, 30(15):74
