Ranitidine—Investigations into the Root Cause for the Presence of N-Nitroso-N,N-dimethylamine in Ranitidine Hydrochloride Drug Substances and Associated Drug Products

The presence of low levels of N-nitroso-N,N-dimethylamine (NDMA) in ranitidine hydrochloride drug products has been reported by regulatory agencies. GlaxoSmithKline undertook a root cause analysis to investigate this observation using contemporaneous, highly sensitive analytical methodologies. The root cause analysis suggested that the presence of NDMA results from a slow degradation of the ranitidine molecule. Analysis using suitably isotopically labeled ranitidine hydrochloride confirmed the formation of NDMA solely from an intermolecular reaction of ranitidine hydrochloride without involvement of impurities. Factors that influence the rate of degradation include heat, humidity, and the crystal morphology of ranitidine hydrochloride with the material exhibiting a columnar habit showing a slower rate of degradation.