Hello Nitrosamine Forum,
I would be interested to hear whether anyone has observed nitrosamine formation in drug products where the API is filled into HPMC capsules.
There appears to be very limited published information regarding nitrite and formaldehyde levels specifically within finished HPMC capsule shells. In the absence of such data, would it be reasonable to assume that similar nitrosating agent precursors (e.g., nitrites) and potential catalysts (e.g., formaldehyde) may be present at levels comparable to those reported for standard HPMC excipient grades?
More specifically, has anyone observed the formation of nitrosamines, particularly NDSRIs, during long-term or accelerated stability studies when a potentially vulnerable amine functionality (e.g., secondary amine or other nitrosatable amine precursor) is present in the API?
Any experience, case studies, published data, or practical insights would be greatly appreciated.
Thank you in advance for your feedback and discussion.
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I want to be really clear on this. This is just my thoughts. I have no data to support this. Simply based on the limited direct contact and interaction, unless a formulation is otherwise extremely low in nitrite, I don’t see how HPMC capsules can greatly increase the speed or extent of nitrosation. The capsules just will not be a significant source of nitrite available to react with the API.
In terms of levels, I’ve heard and seen that cellulose products vary greatly from supplier to supplier. I would hypothesize many excipients of natural origin are similar.
To your question about NDSRI formation, you’ll need to be a little more specific. NDSRI formation during shelf life and stability studies is well established. If you’re meaning within HPMC capsules, yes to that, too. However, that does not mean that the capsules are to blame.
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I would ask the supplier if they have any inforamtion on the nitrite content or test for it. Gelatin capsules are a risk. I have seen them having significant amount of nitrite. Again, this could be a variable based on the supplier.
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Hi Jason, thanks for your prompt response. very much appreciated and apologies if wasnt clear enough to phrase my question. Regarding NDSRI formation, yes, I meant within the capsule shell as the formulation is only API in capsule and no nitrosating agent or precursors were identified in the DS assessment, unless nitrosating precursors could be introduced from external factors e.g NOx?..Thanks again. Diego
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Thanks for your response Aloka, we are now embarking in an experimental design to understand the root cause. We have requested some information but as expected, nothing tangible in the technical information shared by the supplier. We will also looking to perform some nitrite testing as well as you suggested. Thanking you again for your insights.