My initial understanding of nitrosamine formation was that acidic pH and elevated temperature (>50°C) are both required to be present, preferably simultaneously, in presence of nitrites and vulnerable amines in order to form nitrosamines.
What is your experience and approach in this topic, can nitrosamines be formed in solid/liquid drug products if the pH is neutral or basic and the temperature is below 50°C during the manufacturing process (assuming that both vulnerable amines and nitrites are present)?
You should evaluate each situation individually. Nitrosation does not occur only under ideal pH and temperature conditions; although these factors influence the reaction, nitrosation can still happen outside the optimal range. Because acceptable nitrosamine limits are extremely low, even trace amounts or minor reaction products may require extrapolation of limits.
Each case must be assessed carefully whenever amines and nitrites are present. Consider the amine structure and pKa. For predicting potential formation, the Ashworth et all (2023) article is very helpful, though its temperature assumptions can be limiting.
From a practical standpoint, I’ve seen nitrosamine formation in high pH products, both solid and liquid, and at various manufacturing temperatures. While higher temperatures typically increase formation, I have also observed it in steps controlled at room temperature.
high temperatures and low acidic pH (3-5) favor their formation and usually leads to higher quantities but higher pHs or/and lower temperatures do not stop their formation.
We have seen formation of NDSRIs in formulations with pH >5 and even close to 8!!
Berkeley Madonna Software for Nitrosation Kinetic Calculations - Risk Assessment Strategy / Tools & Technology - Nitrosamines Exchange