The recurrence of the same NDSRI in the same drug product is a useful reminder that these are not isolated events. It raises renewed questions around where the impurity may be originating, how it is being controlled, and whether the finished product environment may be contributing to its presence or growth over shelf life.
For the community, this may be another important signal to discuss:
whether N-nitroso-prazosin impurity C is being seen primarily as an API-related carryover
whether there is evidence of formation or increase in the finished product during stability, and
what analytical and risk-assessment approaches are proving most helpful to detect and understand this impurity early?
Given this second recall, prazosin may be becoming another important case study in the broader discussion of recurrent NDSRIs in finished products.
Would be very valuable to hear whether others in the community have seen similar concerns with prazosin or related structures.
Hi, Naiffer, thanks for continuing to share the latest updates on this topic, which never ceases to amaze us.
Beyond the second recall of prazosin I’ve been arised the doubt on how companies determine that an NDSRI is above the acceptable limit if there isn’t available an analytical standard by part of agencies such as USP or EP
I mean, the companie synthetize their own analytical standards? or how do the get them? How confident could these be?
It’s a question about a challenge that we all will probably face in the future.
Prazosin being an amide of piperazine is very vulnerable to forming a nitrosamine, kind of like Sitagliptin. The amides like prazosin do not usually directly nitrosate, but the degrade to produce the free amine (impurity E) in this case, which can undergo facile nitrosation. The problem is that amides break down in acidic as well as alkaline conditions. So it is challenging to reformulate. It is best to keep the pH of the formulation around 6-7, since it serves a double purpose, slows the nitrosation as well as the hydrolysis of amides to amines. Making the nitrosamine reference standard should not be a big challenge in this case.
The analogy with sitagliptin raised in the comments is indeed very appropriate, particularly regarding the potential formation of a nitrosatable amine impurity via degradation. However, in the case of sitagliptin, we found experimentally that chemical stability in terms of amide hydrolysis was not the determining factor for nitrosamine risk. Instead, polymorphism and polymorphic transitions, likely associated with energy release and changes in the solid-state environment, played a key role.
Importantly, we also observed that the pure sitagliptin hydrochloride degraded at essentially the same rate as samples spiked with the corresponding amine and nitrites, indicating that external addition of typical nitrosation precursors was not the driving factor.
In this context, while the discussion points to hydrolysis of the amide to a free amine (impurity E) as a precursor to nitrosation, it is worth considering whether solid-state factors could also contribute. The recurrence of the same NDSRI in the finished product and the question of growth over shelf life may suggest that processes beyond simple solution-phase hydrolysis are involved.
Therefore, in addition to controlling pH to mitigate both hydrolysis and nitrosation, it may be important to evaluate the role of polymorphism, potential polymorphic transitions during storage, and their impact on local environments that could facilitate impurity formation. A similar mechanism to that observed for sitagliptin cannot be excluded here.
This is one of the biggest discrepancies between regulatory expectations and industry. Industry is no where near the point of really looking at nitrosamines from impurities.
Excellent analysis. You are right in that the kinetics of the nitrosation of an amide of a secondary amine is not easy to explain as it may vary from case to case depending on the pKa of the amine. Lets not forget that many of the nitrite scavengers have the ability of shift the pH one way or another. There is not a single boring moments with nitrosamines.
This recall highlights the ongoing challenge with nitrosamine impurities. In China, NMPA has been increasing scrutiny on API quality control. Has anyone tracked how many total recalls have been issued globally for nitrosamine issues in 2025-2026?