Hi everyone,
I would like to ask a question, taking advantage of the group’s expertise, regarding nitrosamines. Specifically, the doubt concerns the role of pH: is it an essential parameter for the formation of nitrosamines? In other words, in the presence of amines and nitrosating agents, does the absence of an acidic pH prevent nitrosation? Or is this parameter relevant only for specific nitrosating agents? Additionally, what would be the critical pH range to consider?
Dear Elisa,
in general pHs between 3-5 are considered of high risk and pHs>7 of low risk.
Nevertheless, as Eleni mentioned above, in case you have a secondary amine in your formulation (either the API or an impurity of it) then a confirmatory test should be performed independently of the pH of the formulation.
kind regards
Christos
Further to Christos feedback, it has been observed that nitrosation of secondary amines can occur in the presence of formaldehyde, chloral, and benzaldehyde at neutral to basic pH, as well.
The higher pH, more than 7, helps in prevention of formation of N-nitroso impurity. Also, use of non-aqueous solvents in place of aqueous helps. The confirmatory tests are needed during process and during stability as well.
dear Sarvesh,
just to add that we have noticed nitrosamine formation in tablet with pH nearly 8. So, i would rather say that the pH over 7 ‘‘delays’’ the nitrosamine formation than ‘‘prevents’’
thanks
Christos
Dear Mark,
please see at page 1563 of the very nice paper of Rocío López-Rodríguez, in
Organic Process Research & Development 202024 (9), 1558-1585 https://pubs.acs.org/action/showCitFormats?doi=10.1021/acs.oprd.0c00323&ref=pdf
‘‘However, in the presence of some
carbonyl compounds, N-nitrosation can be achieved in neutral
and basic solutions. Formaldehyde, pyridoxal, and several
benzaldehydes (but not acetone or acetaldehyde, which are
activated/electron-deficient carbonyls) produce nitrosamines from secondary amines in neutral and alkaline solutions of
NO2
−. The reaction rates vary with steric accessibility to the
nitrogen atom, but all are much slower than classic Nnitrosation
in acidic solutions. The mechanism proposed by
Keeper and Roller involves nucleophilic attack by NO2
− on an
iminium ion intermediate, derived from the amine and
aldehyde reactants, followed by collapse of the adduct to the
nitrosamine’’
best regards
Christos
One Question, is it possible that NDSRI can be formed “in-situ”? like…
during sample preparation? if yes, then how the method development approach should be?
both, mostly with the Finished product analysis, when you do method development for NDSRI, do we have to consider that if can form during sample preparation?
I have also asked this previously as I am also interested in FPF.
I think that we cannot apply purge analysis or stuff like that which could be potentially mitigate any risk and followed for the API.
I trust that you can control the impurity as in-process control, at critical manuf. points (for instance after wet granulation?!). But I trust that control in finished product may be requested from Authorities.
I dont know if this supports you in any way, and please feel free to share your thoughts too
If you were referring to the formation of artifacts during sample preparation or analysis, the method @Naiffer_Host mentioned at the FDA-CRCG seminar may be useful. Pyrrolidine is added to the sample solution to avoid target NDSRI formation during preparation. Alternatively, antioxidants such as ascorbic acid may be effective.
Day 2, Session 2B:
Discussing the Pitfalls and Challenges of Nitrosamines Confirmatory Testing
Yes, I was thinking about the formation of NDSRI during analytical sample preparation? example: most commonly used MPs are 0.1% formic acid and 0.1% formic acid in solvent using diluent either 50% methanol or acetonitrile but during extraction\sonication, can it be formed using certain steps? how Pyrrolidine will help to resolve? is it derivatizing agent>?
During analysis, the sample solution may contain secondary amines and unreacted nitrite. In that case, NDSRI may increase over time in the sample solution. Pyrrolidine traps unreacted nitrite to form NPYR and prevents the target NDSRI from increasing.
oh great. the concentration of that solution is fixed? we should be using in std and sample preparation both , right?
also, can you share some thoughts how i can decrease matrix affect in sample preparation except internal std way. (Since many of NDSRI, internal std is not availble\synthesize…)
