In solid dosage manufacturing, particularly during fluid bed granulation, it’s common to use povidone to prepare the binder solution. Based on my current understanding, this process might carry a relatively high risk for potential nitrosamine formation. I’d appreciate your feedback on whether my reasoning below makes sense.
From what I’ve gathered, the three key elements required for nitrosamine formation may all be present in this process:
Acidic Conditions: When povidone is dissolved in water, the resulting solution can have a pH between 3.5–5, depending on the concentration.
Amine Source: In addition to potential amines in other excipients, the mildly acidic povidone solution, combined with the high temperature of fluid bed processing, could possibly promote the hydrolysis of amides, potentially generating amines. For example, the pyrrolidone group in povidone might generate secondary amine functionalities under such conditions.
Nitrosating Agents: Beyond nitrite or nitrate impurities in other excipients, if the water used to prepare the binder solution is not sufficiently purified, it may also contain nitrite/nitrate residues.
Considering the above, I personally think this step in the process poses a relatively high risk for nitrosamine formation. Does these line of reasoning sound valid to you? Have others encountered or evaluated similar concerns?
You are correct. You can probably do the following
Conduct a drug excipient compatibility study to assess the increase in levels of nitrosamines. Incorporate antioxidants, pH modulating agents or organic solvents to get more data.
Check the nitrite levels in your water and excipients and maybe opt for excipients with lower nitrite levels
Introduce an organic solvent for granulation if feasible (for eg. ethanol or IPA)
Add an antioxidant if you see significant increase in nitrosamine levels or modulate the pH, based on drug excipient outcome.
Use nitrogen for drying step if feasible. Air as a potential source of NOx is being investigated.
theoretically every suggestion is right, but from a practical point of view, in my opinion you shoot flies with a gun.
Acidic Conditions: When povidone is dissolved in water, the resulting solution can have a pH between 3.5–5, depending on the concentration. OK, right.
2. Amine Source
Generally, amides can be hydrolyzed in either acidic or basic solution. The mechanisms are much like those of ester hydrolysis, but the reactions are very much slower. Hydrolysis under acidic conditions requires strong acids such as sulfuric or hydrochloric, and temperatures of about 100°C for several hours. In alkaline hydrolysis the amide is heated with boiling aqueous sodium or potassium hydroxide. Hydrolysis of Amides
3. Nitrosating Agents: I do not know your local requirement for Purified Pharmaceutcal water, but according to Ph.Eur monograph nitrates (and consequently nitrites) should be practically absent (maximum 0.2 ppm).
Morover, “If purified water in bulk complies with the requirements for conductivity prescribed for Water for injections (0169) in bulk, it is not necessary to carry out the test for nitrates prescribed above.”
Summarizing, in my opinion the possible formation of nitrosamines during the granulation is negligible respect to the possible increase during the shelf-life due to nitrite impurities in critical excipients.
If I may second your comment. I fully agree. We would have a complete crisis if the hydrolisis of Povidone would be so straightforward considering how much is used and its fuction as a critical excipient in a formulation.
However, in the case of amides such as povidone, the risk of hydrolysis is quite low. The conditions required to hydrolyze it and subsequently release the corresponding secondary amine would have to be very harsh, making this risk unlikely under milder conditions.
One point that I want to add in above discussion is peroxide content of povidone. By controlling peroxide content also you can control the NDSRI generation to some extent.
Dear Nirav,
this is an interesting point.
Could you please elaborate on this a little bit more? what is the connection between peroxides and nitrosation ability?
kind regards
Christos
Unless in your product you have a residual secondary amine that formed the amide, it would be overstated to consider the nitrosation of a secondary amine formed from the amide hydrolysis. Amides are not as easy as you thought to get hydrolyzed.
For example, the NTTP nitrosamine impurity in Sitagliptin is mainly derived from the Sitagliptin impurity 100 carried over from the drug substance, rather than from the same impurity from the Sitagliptin hydrolysis. If you synthesize Sitagliptin through other routes without using the impurity 100 as a starting material, the risk of NTTP in the product would be so minimal that you can completely neglect it.
I am not sure but when we add antioxidant in the composition to prevent nitrosation reaction, the antioxidant will be consumed for the same. If there will be higher peroxide content in the composition, antioxidant will also react with hydrogen peroxide. Other experts can also share their views on my hypothesis.
The peroxide-promoted hydrolysis of tertiary amide bonds may afford secondary amines. A related mechanism may operate in the case of metformin, in which the guanidine structure’s lability in the presence of peroxides was confirmed.
Peroxides could be directly involved in the formation of N-nitrosamines by oxidative processes in drug (degradant) molecules that bear a hydrazine or hydrazone moiety (e.g., gliclazide, rifampicin). (Bream, R. et al. Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies Org. Process Res. Dev. 2023, 27, 1736-1750).
You may find the N-nitrosamines of glicazide and rifampicin (potentially formed from the hydrazine motifs) listed in the EMA’s list. . However, to me this is intriguing; while oxidation of hydrazines or hydrazones should yield nitrosamines, subsequent oxidation of nitrosamines should result in the formation of non-cohort of concern nitramines.
You may also refer to Journal of Pharmaceutical Sciences 112 (2023) 1166−1182 for the risk of nitrosamines from peroxides.