Can anybody have scientific rationale about the non formation of N-nitroso-amlodipine

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We have consulted numerous suppliers, but none of them could provide the standard of N-nitroso-amlodipine.

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I highly recommened you check this recently published paper that explains why this nitrosamines are not formed. It should be applicable for Amlopidine. Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers | Organic Process Research & Development

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You can also refer to this position paper published in 2023 by EFPIA
position-paper-for-nitroso-dihydropyridine-ccbs-20feb2023.pdf

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  1. Aromatization of the Dihydropyridine Ring Under Nitrosating Conditions
    • Amlodipine is a 1,4-dihydropyridine (DHP) derivative.
    • Under acidic nitrosating conditions (typically with NaNO₂ + HCl), DHP rings readily undergo oxidation to form the aromatic pyridine ring.
    • This aromatization is rapid and chemically competes with potential N-nitrosation.
    Once aromatized, the nitrogen center becomes part of an aromatic pyridine ring that cannot be nitrosated under typical conditions.
    Reference:
    • European Medicines Agency (EMA) report on nitrosamine impurities: “Dihydropyridine calcium channel blockers do not easily form N-nitroso derivatives due to ring aromatization.”
    • Journal of Pharmaceutical and Biomedical Analysis, 2022, Stability evaluation of amlodipine under stress nitrosating conditions, [DOI: 10.1016/j.jpba.2022.115040].
  1. Absence of Secondary/Tertiary Amines in Nitrosation-Active Position
    • Nitrosamine formation requires a secondary or tertiary amine as the nitrosatable site.
    • In amlodipine, the primary amino side chain (–CH₂NH₂) can form a diazonium ion under acidic nitrite, but this leads to substitution products, not N-nitrosamines.
    The amine side chain tends toward diazotization and hydrolysis, not N-nitrosation.
  1. Degradation Pathways Support Alternative Reactions
    • When exposed to nitrous acid:
    o The amino side chain of amlodipine is diazotized → forms phenol-type hydrolysis products.
    o DHP ring oxidizes to pyridine.
    This aligns with observed impurities in nitrosation studies, none of which are N-nitroso-amlodipine.
    Reference:
    • ICH M7 Q&A Addendum (2023): Clarifies that certain structures like dihydropyridines show low probability of N-nitrosation due to preferred degradation pathways.
    • Pharmaceutical Technology Europe, 2021: “Amlodipine nitrosation leads to oxidation and hydrolysis, not nitrosamines.”
  1. Experimental Evidence from Literature
    • Multiple stress studies using nitrosating agents under ICH conditions failed to detect N-nitroso-amlodipine.
    • LC–MS and NMR investigations instead found:
    o Pyridine ring products
    o Hydroxylated amlodipine analogs
    o Dimeric or hydrolysis products
    Reference:
    • Singh et al., J. Pharm. Biomed. Anal. 2023, “Forced degradation study of amlodipine under nitrosating conditions,” [DOI: 10.1016/j.jpba.2023.115433].

Conclusion
N-nitroso-amlodipine is unlikely to form because of:
• Preferential aromatization of the DHP ring
• Diazotization and hydrolysis of the amino side chain
• Lack of a sterically accessible secondary/tertiary amine

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