Stability Study of Ranitidine
Emery Pharma presented this work at the 68th American Society for Mass Spectrometry (ASMS) Conference in June 2020. Ranitidine, an H2 histamine receptor blocker, is extensively used for heartburn and other stomach acid-related diseases. Recently, the detection of the probable human carcinogen N-Nitrosodimethylamine (NDMA) as an impurity resulted in extensive recalls of ranitidine medicines.
We played an instrumental role in this discovery and demonstrated that ranitidine is an inherently unstable compound, spontaneously forming NDMA at elevated temperatures. This thermal instability of ranitidine limits the use of headspace (HS)-GC-MS for NDMA quantification in ranitidine, as is commonly employed for other pharmaceuticals.
Herein, we describe a MS ultra-high performance liquid chromatography–electrospray ionization–multiple reaction monitoring mass spectrometry (UHPLC-ESI-MRM) method for the quantification of NDMA in drug products and biological matrices. The method allows for quantification of trace, low nanogram levels of NDMA per sample and was applied to evaluate both the thermal and biological stability of ranitidine.
Additionally, to demonstrate whether NDMA is formed upon ingestion of ranitidine, an incubation study using ranitidine in simulated gastric fluid (SGF, containing added NaNO₂) was performed. Results indicated a substantial increase in NDMA levels when incubated in SGF.
The propensity of ranitidine to generate NDMA in SGF suggests that such accumulation is highly plausible in vivo upon ranitidine ingestion. Our work highlights the importance of stringent nitrosamine impurity specifications and risk assessment in pharmaceutical testing.
Ranitidine has been widely used across the world for many years; it remains to be seen if the plausible NDMA exposure due to this instability has resulted in any adverse health outcomes. Contact us today if you have questions about NDMA and how to detect it in pharmaceutical products!
About the Author
Originally authored by Dr. Eshani Nandita. This article was reviewed and updated on July 11, 2025 by Dr. Ryan Cheu, current Director of Chemistry.
