Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers

[MarkS]

This was published yesterday, showing that it was not possible to produce N-nitrosamines from Dihydropyridine Calcium channel blockers.

Synthesis of Nitroso Derivatives of Dihydropyridine Calcium Channel Blockers - ScienceDirect

[Naiffer_Host]

Thanks for sharing @MarkS
I am sharing the abstract of the article here and the conclusion. Revealing the mechanism and findings reported.

Abstract:

Regulatory authorities issued guidance on acceptable intake limits for nitrosoamine drug substance-related impurities. However, the formation of these potential nitrosamine contaminants in the dihydropyridine class of drugs has not been clearly established. In this work, the nitrosation of six dihydropyridine calcium channel blockers was investigated under a set of conditions. The nitrosation products were isolated and characterized by MS, NMR, and XRD. The results show that nitrosation occurred on the carbon atom instead of the nitrogen atom. Nifedipine exhibited the highest reactivity via oxidative aromatization and reduction to produce a C-nitroso compound. Treatment with nitrite in either 1 M hydrochloric acid or 30% acetic acid resulted mainly in pyridine products via oxidation. In contrast, the other dihydropyridine derivatives studied generated C-nitrosated products in addition to aromatized products upon treatment with butyl nitrite. The findings provide direct evidence to rule out the possibility of N-nitroso impurities being present in the dihydropyridine class of drug substances and products.

Conclusions:

In summary, N-nitrosamine drug substance-related impurities have emerged as a concern in the pharmaceutical industry. A set of conditions was utilized to investigate the nitrosation products of six dihydropyridine calcium channel blockers. The reaction was monitored by TLC, and the mixture was separated by preparative HPLC for structure determination. Under conditions 1 and 2, most of the DHPs generated the oxidized pyridine analogues. Due to its high reactivity, nifedipine underwent intramolecular elimination and oxidative aromatization to form the C-nitroso- and nitro-phenylpyridine products. By using butyl nitrite, other DHPs resulted in the formation of C-nitroso dihydropyridine isomers. The C-nitroso dihydropyridine products were confirmed by NMR, HRMS, and XRD. This work demonstrates the absence of N-nitroso compounds in the dihydropyridine class of drug substances and products.

[Naiffer_Host]

As both a scientist and a quality scientist, it pains me to see this pattern repeat:

• A simple Google search for “reference materials” yields dozens of suppliers for n‑nitroso‑felodipine—most with no traceable qualification data.
• Yet too many testing laboratories continue to use these standards “blindly,” without any documented supplier audit, or proper performance verification.

Where is our supplier‑qualification rigor? Without it, we risk:

1. Compromised data integrity—are we truly measuring what we think we’re measuring?
2. Regulatory non‑compliance—how will we defend our results if challenged?
3. Patient safety—faulty standards lead directly to flawed risk assessments.

I’m calling on this community to:

• Share your supplier‑qualification best practices.
• Transparent audit trails and failure reporting.
• Discuss how you’ve integrated reference‑standard verification into your QA/QC workflows.

We need to raise the voice together. Let’s tackle this head‑on—because the quality of our confirmatory testing results depends on the quality of these reference materials. Your experiences and insights could save a lot of time (and headaches) for labs everywhere.

What steps have you taken to ensure your reference materials are fit for purpose?

[Naiffer_Host]

Don’t forget @conudel already warned us about this family of compounds!!

N-nitroso-amlodipine ; N-nitroso-felodipine ; synthesis not successfull but still listed by FDA and EMA as NDSRIs

Dear Nitrosamines Exchange team, For the nitrosamines N-nitroso-amlodipine and N-nitroso-felodipine, official limits are published by the FDA. FDA Guidance In the past, we contacted several suppliers who offered the N-nitroso-amlodipine on their web pages: However, N-nitroso-amlodipine could not be synthesized in the end. This outcome is confirming the EFPIA position paper. Position Paper (efpia) Does anyone from the community know if the FDA or EMA have been contacted to remove these com…

[jason.brown]

I haven’t purchased a standard I really questioned in advance, but if in doubt, I would ask for the characterization data before purchase