Determination of N-nitrosodimethylamine in Ranitidine Dosage Forms by ESI-LC-MS/MS; Applications for Routine Laboratory Testing

Document Type : Research article


Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.



A practical high-performance liquid chromatography-mass spectrometry method was developed for the analysis of N-nitrosodimethylamine (NDMA) characterized as an impurity, in combination with reports of the carcinogen found in ranitidine samples. After simple extraction of ranitidine samples, all compounds were analyzed with a high-performance liquid chromatography-mass spectrometry. Sensitivity was enhanced by employing the ten-way valve switching technology, which was examined to allow NDMA to enter the mass spectrometry and cut out the ranitidine samples extremely. A good linear relationship was observed within 3-100 ng·mL−1 (r = 0.9992). The validated approach was effectively used to evaluate the NDMA contents in ranitidine samples in circulation, which revealed a difference among 21 batches. Quantitative determination of NDMA was within the scope of 3.38-57.05 ng·mL-1. Moreover, the contamination levels of NDMA in seven batches of products from six manufacturers were listed to exceed the acceptable daily intake. The sensitive method was verified to be appropriate to determine NDMA, even with low contents of NDMA in ranitidine products; the analysis of the selected samples reveals that some samples exceeded the national limit requirements. Therefore, it is worthwhile to conduct comprehensive quality control of the other drugs containing NDMA.

Graphical Abstract

Determination of N-nitrosodimethylamine in Ranitidine Dosage Forms by ESI-LC-MS/MS; Applications for Routine Laboratory Testing


(1) ICH M7, Assessment and control of DNA reactive
(mutagenic) impurities in pharmaceuticals to
limit potential carcinogenic risk. In: International
Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use
(ICH). Group IEW, Ed. (2017) 1–27.
(2) Zhang LY, Liu XL and Guo TS. Analysis on control
of genotoxic impurities in drug research. Chem.
Ind. (2020) 49: 92-6.
(3) White CM. Understanding and preventing
(N-nitrosodimethylamine) NDMA contamination
of medications. Ann. Pharmacother. (2020) 54:
(4) Roux JL, Gallard H, Croué JP, Papot S and
Deborde M. NDMA formation by chloramination
of ranitidine: kinetics and mechanism. Environ.
Sci. Technol. (2012) 46: 11095-103.
(5) Eads AV. Pharmacists are the key in interpreting
clinical implications of N-nitrosodimethylamine
contamination in medications. J. Am. Pharm.
Assoc. (2020) 60: 100-4.
(6) Kong N. A comparative study of the clinical
efficacy of omeprazole and ranitidine in the
treatment of peptic ulcer. Guide. Chin. Med. (2020)
18: 123-4.
(7) Zeng T, Mitch WA. Oral intake of ranitidine increases
urinary excretion of N-nitrosodimethylamine.
Carcinogenesis (2016) 37: 625-34.
(8) Lv J, Wang L and Li YM. Characterization of
N-nitrosodimethylamine formation from the
ozonation of ranitidine. J. Environ. Sci. (2017) 58:
(9) Shaik KM, Sarmah B, Wadekar GS and Kumar P.
Regulatory updates and analytical methodologies
for nitrosamine impurities detection in sartans,
ranitidine, nizatidine, and metformin along with
sample preparation techniques. Crit. Rev. Anal.
Chem. (2020) 21: 1-19.
(10) Dyer O. All ranitidine should be discarded, says
US drug agency. BMJ. (2020) 369: 1390.
(11) Dong C. The potential safety risks of the common
gastric drug: ranitidine. J. Health Times (2020) 13:
(12) Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N,
Kanno H, Masada S, Yokoo H, Tsuji G, Uchiyama
N, Hakamatsuka T, Demizu Y, Izutsu K, Goda Y
and Okuda H. Temperature-dependent formation
of N-nitrosodimethylamine during the storage
of ranitidine reagent powders and tablets. Chem.
Pharm. Bull. (2020) 68: 1008-12.
(13) Masada S, Tsuji G, Arai R, Uchiyama N, Demizu
Y, Tsutsumi T, Abe Y, Akiyama H, Hakamatsuka T,
Izutsu K, Goda Y and Okuda H. Rapid and efficient
high performance liquid chromatography analysis
of N-nitrosodimethylamine impurity in valsartan 
Liu J et al. / IJPR (2021), 20 (4): 255-264
drug substance and its Products. Sci. Rep. (2019) 9:
(14) Xia XM. An immediate withdrawal of all ranitidine
products were ordered by the FDA. China. Pharm.
Univ. (2020) 36: 19-20.
(15) Ryan ME, Barker C and Hawcutt DB. Ranitidine
in short supply: why now, and where next. Arch.
Dis. Child. (2020) 105: 382-3.
(16) The China Center for Drug Evaluation. Technical
guidelines for the study of nitrosamines impurities
in chemical drugs (Trial). The National Medical
Products Administration. [serial online] 2020 Mar
8. Available from: URL:
(17) Parr MK and Joseph JF. NDMA impurity in
valsartan and other pharmaceutical products:
Analytical methods for the determination of
N-nitrosamines. J. Pharm. Biomed. Anal. (2019)
164: 536-49.
(18) Tsutsumi T, Akiyama H, Demizu Y, Uchiyama N,
Masada S, Tsuji G, Arai R, Abe Y, Hakamatsuka
T, Izutsu K, Goda Y and Okuda H. Analysis of an
impurity, N-nitrosodimethylamine, in valsartan
dug substances and associated products using GCMS. Biol. Pharm. Bull. (2019) 42: 547-51.
(19) Shen CY, Cai HQ, Pei SF and Zhang Y.
Determination of nine nitrosamines in water by
solid phase extraction and gas chromatography
mass spectrometry. J. Occup. Environ. Med. (2019)
36: 1060-5.
(20) Liu H, Zhang YC, Lu YF, Shi J and Gu WB.
Determination of N-nitrosodimethylamine in
tobacco by gas chromatography-tandem mass
spectrometry. Physical. J. Anal. Test. (2017) 53:
(21) Lim HH, Oh YS and Shin HS. Determination of
N-nitrosodimethylamine in drug substances and
products of sartans, metformin and ranitidine by
precipitation and solid phase extraction and gas
chromatography-tandem mass spectrometry. J.
Pharm. Biomed. Anal. (2020) 189: 113460.
(22) Fan TT and Zhang XD. Determination of
N-nitrosodimethylamine in valsartan by high
performance liquid chromatography. J. Nutr. Med.
(2019) 15: 16-9.
(23) Li WX, Chen N, Zhao YG, Guo WQ, Muhammd
N, Zhu Y and Huang ZP. Online coupling of
tandem liquid-phase extraction with HPLC-UV for
the determination of trace N-nitrosamines in food
products. Anal. Methods. (2018) 15: 1733-9.
(24) Sherf-Clavel O, Kinzig M, Besa A, Schreiber A,
Bidmon C, Abdel-Tawab M, Wohlfart J, Sörgel F
and Holzgrabe U. The contamination of valsartan
and other sartans, Part 2: Untargeted screening
reveals contamination with amides additionally to
known nitrosamine impurities. J. Pharm. Biomed.
Anal. (2019) 172: 278-84.
(25) Zhang WW, Zhao CH, Fu M and Sun Q.
Determination of N-nitrosodimethylamine in
food by HPLC-MS/MS with steam distillation
separation. J. Anal. Test. (2019) 55: 1028-31.
(26) Řemínek R, Foret F and Chung DS. Application
of capillary electrophoresis-nano-electrospray
ionization-mass spectrometry for the determination
of N-nitrosodimethylamine in pharmaceuticals.
Electrophoresis. (2021) 42: 334-41.
(27) Giménez-Campillo C, Pastor-Belda M,
Campillo N, Hernández-Córdoba M and Viñas
P. Development of a new methodology for the
determination of N-nitrosamines impurities in
ranitidine pharmaceuticals using microextraction
and gas chromatography-mass spectrometry.
Talanta (2021) 223: 121659.
(28) Sörgel F, Kinzig M, Abdel-Tawab M, Bidmon C,
Schreiber A, Ermel S, Wohlfart J, Besa A, SherfClavel O and Holzgrabe U. The contamination of
valsartan and other sartans, part 1: New findings. J.
Pharm. Biomed. Anal. (2019) 172: 395-405.
(29) Guo CC, Liu Q, Zhang L, Zheng J, Wang Y, Yang
SJ, Chu ZJ, Niu C and Xu YW. Determination
of N-nitrosodimethylamine in metformin
hydrochloride and its preparations by high
performance liquid chromatography-tandem mass
spectrometry. Chromatography (2020) 38: 1288-
(30) The Food and Drug Administration. Zantac
(ranitidine): Safety information – NDMA found
in samples of some ranitidine medicines. The U.
S. Food and Drug Administration. [online] 2019
Sep 13 [cited 2020 Jun 15]. 2019 Sep 13. Available
from: URL:
(31) The National Medical Products China Food
and Drug Administration. WHO international
agency for research on cancer list of carcinogens.
[online] 2017 Qct 30 [cited 2020 Jun 15].
[serial online] Available from: URL: http://