Predicting Nitrosamine Formation in the Solid State

Here is the summary of a presentation that is being given at the AAPS Summer Scientific Forum in July (amongst others on nitrosamines and other topics).

Something new for us to consider in the formation of nitrosamines? Crystal defects and their impact, from the route of processing (both of the API and then during finished product manufacture??)

Adding a new supplier of your API to your product may have extra considerations that need to be thought about/explored.

The NMR testing is interesting as well.

Is anyone attending? Much as I 'd love a trip to Kansas, I’m not sure that I could attend.


Very interesting, but the global idea is not new actually, especially linked to ranitidine. In Europe it is even obliged to consider this in the risk assessment: Root cause 9 of template CMDh/439/2022:

Degradation processes of active substances, including those induced by inherent reactivity (e.g. presence of nitro-alkyl, oxime, or other functionality) or by the presence of an exogenous nitrosating agent. This could potentially occur during both active substance manufacturing processes or during storage and could be influenced by crystal structure, crystal habit and storage conditions (temperature, humidity etc.). For more details, refer to page 6 of Referral under Article 31 of Directive 2001/83/EC for ranitidine and published literature.

See point 1.6 for explanation on this template.

Primary this root cause is also included in the EMA Q&A n° 4:

Cited references: (discussing the element of crystal morphology of ranitidine hydrochloride) (discussing the element of crystal morphology of ranitidine hydrochloride as well)

Nonetheless always interesting to hear about new NMR studies on the crystal morphology role in NDMA formation from ranitidine. And in general of course, how crystal morphology (of API or other involved elements) is influencing nitrosamine formation at API and DP level is broader studied. Positive element is that this always raises awareness that solid state nitrosation cannot always be simplified with stoichiometric experiments in liquid phase (especially mechanistically and selectivity-wise) as an increasing number of papers points out. Surface properties/surface and contact area (think for example also on the fluctuating role of adsorbents like activated carbon) and morphology matter (often linked with the mobility of water as well) (think for example about wet granulation making API more amorphous, see also discussion in Mutagenic Impurities: Strategies for Identification and Control, Andrew Teasdale (Editor), Wiley, February 2022, 544 p. ISBN: 978-1-119-55121-8).

Also for other impurity formation in the solid state (API/DP) this is a known topic: Chemical reactivity in solid-state pharmaceuticals: formulation implications - PubMed (

For API source changes and their impact on nitrosamine risk assessment, it is indeed useful to do comparative simulation/stress trials in the lab mimicking potential DP formation potential and allowing relative comparison, while keeping in mind that also stress tests should include solid state nitrosation simulation for solid dose medicine (and not just comparing how the API behaves in solution under nitrosating conditions), just to avoid possible unexpected results during stability later on. (Of course only when as is there is a relevant nitrosamine formation risk and typically when control on/equivalence of morphology of the API might not be established).


Prof Munson presented at the recent GDUFA meeting to discuss the role of Solid State in the formation of NDMA in Ranitidine.

A fantastic reference to this findings is King et al. “Ranitidine investigations into the root cause for the presence of N nitroso N, N dimethylamine in ranitidine hydrochloride drug substances and associated drug products.” Organic process research & development 24 12 ): 2915 2926

Couple of his conclusions from my notes that day:

  • Crystal defects can be produced by physical transformations (milling, grinding, compression) and by crystallization
  • Extensive research has shown that materials containing more crystal defects have faster degradation rates compared to materials having fewer defects.

There is also interesting observation regarding n-nitroso hydrochlorothiazide formation in solid state during grinding decsribed in patent EP 4 234 542 A1