Nitrosamine formation in HPMC capsules

Root Causes Excipients
1

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.

1 Like
2

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.

1 Like