Novel NMR-based method could facilitate safer API manufacturing

A team of researchers have developed a novel, rapid nuclear magnetic resonance (NMR) spectroscopy-based methodology that can easily confirm or exclude the formation of every predictable nitrosamine for the active pharmaceutical ingredients (APIs) assessed. 

The early-stage tool combines the nitrosation assay procedure (NAP) with ¹⁵N-enriched nitrosating reagents and ¹⁵N NMR spectroscopy. It addresses the limitations of traditional mass-based techniques, according to Simonetto et al.

Enhancing nitrosamine assessment

The authors initiated the study in response to a regulatory requirement for a nitrosamine risk assessment concerning the API dexlansoprazole. Under stress, the API undergoes structural changes, “potentially forming unexpected nitrosamines beyond the scope of standard [nitrosamine drug-substance-related impurities] (NDSRIs).”

As such, they investigated whether the heterocyclic framework of dexlansoprazole could act as a precursor to nitrosamine formation.

Not only did the ¹⁵N-enriched NAP test distinguish between isomeric and degradation products, but overall the method acts as a rapid test for derisking “because if there are no ¹⁵N-nitroso signals, then the molecule can be considered not prone to nitrosation.”

Gabriele Razzetti, Global Director of R&D at Dipharma Francis S.r.l. said: “Thanks to our innovative approach, we can confirm or exclude nitrosamine formation with exceptional clarity, even in the most complex scenarios”. This includes challenging NDSRIs, added Razzetti.

“This integrated approach provides a robust and rapid tool for nitrosamine risk assessment and supports regulatory compliance by confirming or excluding nitrosamine formation under stress conditions.”

The novel technique offers promise for assessing nitrosamine formation during API development and manufacturing, “supporting impurity profiling, process understanding, and alignment with evolving regulatory expectations”.

The method was developed by Dipharma Francis S.r.l., a contract development and manufacturing organisation (CDMO) and active pharmaceutical ingredient (API) manufacturer. The research is published in Organic Process Research & Development (OPR&D).