According to swissmedic new requirement. If an API contains secondary amine in its structure, how can we identify which NDSRI would be formed. The API is not listed in the EMA list (Appendix 1) as a “source” and USFDA website also.
The NDSRI will simply be the attachment of a nitroso group (N=O) to that nitrogen, replacing the hydrogen currently there! It can (probably) be named N-nitroso-[API name], though if there are multiple secondary amines you may need to clarify. You could also look, assuming the API is a commercially-available drug, for it in the supporting information of Schlingemann et al (https://www.sciencedirect.com/science/article/pii/S0022354922005251) to confirm.
Thanks David for the resposne. But I am particularly seeking a solution for NDSRI for API for examples Aciclovir, data for which is not available online(EMA Appendix 1 list, FDA website). how can I find NDSRI for this and then the IUPAC Name CAs number and everything.
There are a few steps to take, in this case:
Firstly, if you have identified a novel NDSRI, it is likely that it has no CAS number; these are assigned when the structure is indexed by CAS, which is a manual process, and normally only performed when the compound first enters the public literature. If there is any known data about it, such as identifiers, CAS number, IUPAC name and so on, it would be available on Pubchem (which is searchable by SMILES): https://pubchem.ncbi.nlm.nih.gov/. If it’s not even on Pubchem, then for generating a IUPAC name the software package ChemDraw, and probably others, will do that for you.
The limit of a novel compound is also not going to be in the regulatory guidance; to the best of my knowledge they have only published limits for NDSRIs that they have been made aware of - from the Schlingemann et al paper, you will see that there are thousands of potential NDSRIs, and limits have only been published for a few hundred. This is therefore the point of the CPCA algorithm - which has been implemented into tools such as Derek Nexus - https://www.lhasalimited.org/solutions/nitrosamine-impurity-risk-assessment/
Since it is a novel compound, if you need a reference standard, therefore, you will be looking at custom synthesis in the first instance, rather than it being commercially available.
Finally, I should note that acyclovir itself, if that happens to be your compound, has no secondary amines! It has a bunch of aromatic nitrogens, which I have argued (https://pubs.acs.org/doi/full/10.1021/acs.oprd.3c00008) are outside the cohort of concern (nitrosation here would lead to a compound that is potentially mutagenic, yes, but via a different mechanism), and a primary amine, which is expected to generate only an unstable nitroso derivative and not be of concern.
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Thank you so much for the clarification.
@David Thanks for sharing in a very descriptive and easy to understand the step by step. I am tagging in our FAQ…
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