Ranitidine: A Proposed Mechanistic Rationale for NDMA Formation and a Potential Control Strategy

Abstract

The formation of N-nitrosodimethylamine (NDMA) in ranitidine hydrochloride drug substance (DS) and drug products has attracted considerable attention over the last few years. The drug structure is unusual in that it contains a vinyl nitro moiety. Although a variety of studies have been carried out to understand how NDMA is formed in the DS solids, a mechanistic description of NDMA formation has remained elusive. A new mechanistic view of NDMA formation is detailed here. Autoxidation of ranitidine can rationalize nitrite ion and dimethylamine liberation from ranitidine. The subsequent nitrosation is argued to be due to conversion of nitrite ion to the gas phase nitrosating agent nitrosyl chloride, NOCl. Oxygen scavenging packaging systems should be able to stop the autoxidation, and thus shut down the nitrite release from ranitidine. Without nitrite release NDMA cannot form. This may provide a practical means to stabilize ranitidine DS and solid dosage formulations against NDMA formation.