N-nitrosodimethylamine (NDMA) Contamination of Ranitidine Products: A Review of Recent Findings

Overview

Journal J Food Drug Anal

Specialties Nutritional Sciences
Pharmacology
Toxicology

Date 2022 Jun 13

PMID 35696227

Authors

Fahad S Aldawsari

Yahya M Alshehry

Thamer S Alghamdi

Affiliations

Soon will be listed here.

Abstract

Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, we review and discuss the results of the United States Food and Drug Administration and the Australian Therapeutic Goods Administration laboratory testing of ranitidine products and the detected NDMA levels. Finally, the case of NDMA generation in Angiotensin II Receptor Blockers (ARBs) and ranitidine were compared in an attempt to address the circumstances leading to the current contamination.

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References

Castegnaro M, Pignatelli B, Walker E . Analysis of volatile N-nitrosamines in commercial drugs. Food Cosmet Toxicol. 1981; 19(4):489-91. DOI: 10.1016/0015-6264(81)90455-7. View

White C . Understanding and Preventing (-Nitrosodimethylamine) NDMA Contamination of Medications. Ann Pharmacother. 2019; 54(6):611-614. DOI: 10.1177/1060028019892222. View

Vehabovic M, Hadzovic S, Stambolic F, Hadzic A, Vranjes E, Haracic E . Stability of ranitidine in injectable solutions. Int J Pharm. 2003; 256(1-2):109-15. DOI: 10.1016/s0378-5173(03)00067-x. View

Loeppky R, Tomasik W, Millard T . Ester-mediated nitrosamine formation from nitrite and secondary or tertiary amines. IARC Sci Publ. 1984; (57):353-63. View

Teraoka R, Otsuka M, Matsuda Y . Effects of temperature and relative humidity on the solid-state chemical stability of ranitidine hydrochloride. J Pharm Sci. 1993; 82(6):601-4. DOI: 10.1002/jps.2600820611. View

Le Roux J, Gallard H, Croue J . Chloramination of nitrogenous contaminants (pharmaceuticals and pesticides): NDMA and halogenated DBPs formation. Water Res. 2011; 45(10):3164-74. DOI: 10.1016/j.watres.2011.03.035. View

Liu Y, Selbes M, Zeng C, Zhong R, Karanfil T . Formation mechanism of NDMA from ranitidine, trimethylamine, and other tertiary amines during chloramination: a computational study. Environ Sci Technol. 2014; 48(15):8653-63. PMC: 4123930. DOI: 10.1021/es500997e. View

Seid M, Cho K, Lee C, Park H, Hong S . Nitrite ion mitigates the formation of N-nitrosodimethylamine (NDMA) during chloramination of ranitidine. Sci Total Environ. 2018; 633:352-359. DOI: 10.1016/j.scitotenv.2018.03.181. View

Masada S, Tsuji G, Arai R, Uchiyama N, Demizu Y, Tsutsumi T . Rapid and efficient high-performance liquid chromatography analysis of N-nitrosodimethylamine impurity in valsartan drug substance and its products. Sci Rep. 2019; 9(1):11852. PMC: 6694186. DOI: 10.1038/s41598-019-48344-5. View

10.

Le Roux J, Gallard H, Croue J, Papot S, Deborde M . NDMA formation by chloramination of ranitidine: kinetics and mechanism. Environ Sci Technol. 2012; 46(20):11095-103. DOI: 10.1021/es3023094. View

11.

Alshehri Y, Alghamdi T, Aldawsari F . HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products. J Pharm Biomed Anal. 2020; 191:113582. DOI: 10.1016/j.jpba.2020.113582. View

12.

Guerrieri P, Smith D, Taylor L . Phase behavior of ranitidine HCl in the presence of degradants and atmospheric moisture--impact on chemical stability. Langmuir. 2008; 24(8):3850-6. DOI: 10.1021/la703031c. View

13.

Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H . Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets. Chem Pharm Bull (Tokyo). 2020; 68(10):1008-1012. DOI: 10.1248/cpb.c20-00431. View

14.

Jamrogiewicz M, Wielgomas B, Strankowski M . Evaluation of the photoprotective effect of β-cyclodextrin on the emission of volatile degradation products of ranitidine. J Pharm Biomed Anal. 2014; 98:113-9. DOI: 10.1016/j.jpba.2014.05.014. View

15.

Shen R, Andrews S . Demonstration of 20 pharmaceuticals and personal care products (PPCPs) as nitrosamine precursors during chloramine disinfection. Water Res. 2010; 45(2):944-52. DOI: 10.1016/j.watres.2010.09.036. View

16.

Selbes M, Beita-Sandi W, Kim D, Karanfil T . The role of chloramine species in NDMA formation. Water Res. 2018; 140:100-109. DOI: 10.1016/j.watres.2018.04.033. View

17.

Ahmed S, Elshaboury S, Mohamed N, Farrag S . Development of a Validated Comparative Stability-Indicating Assay Method for Some H2-Receptor Antagonists. J Chromatogr Sci. 2017; 55(8):818-831. DOI: 10.1093/chromsci/bmx042. View

18.

Jamrogiewicz M, Wielgomas B . Detection of some volatile degradation products released during photoexposition of ranitidine in a solid state. J Pharm Biomed Anal. 2013; 76:177-82. DOI: 10.1016/j.jpba.2012.12.019. View