Risk Assessemento of Nitrosamines in soft capsule

Risk Assessment Strategy / Tools & Technology
1

Hi Nitrosamines Exchange Comunity

I would like to start a new discussion about risk assessment of nitrosamines in soft capsules whose the matrix is oily. It is known that nitrosamines can be formed in specific conditions like acid pH, amine and nitrite and some factors like humidity in tablets , for example, can contribute to formation of nitrosamine. Thinking in a matrix oily, what is the probability of nitrosamine formation in secondary amine? and in the tertiary amine? What is it your opinion?

If you have any paper to guide me in my discussion, please, describe it for me.

1 Like
2

The risk for formation is there - there will still be levels of nitrite present within the rest of the excipients and so there is the potential for formation of nitrosamines. Although the pH is not going to be optimal for the formation and so levels could be lower, if the API contains a secondary amine then there is a likelihood. Nitrosamines have been detected in dry powder blends - so the chance for the formation is always there, no matter the format of the product.

Depending on the constituents of your matrix then there are also other watch-outs - presence of formaldehyde (which can be a catalyst in nitrosamine formation according to some literature) and also anything that can leach from the gel capsule.

1 Like
3

In regard capsules…

1 Like
4

Nice MarkS

On this case, the API has a tertiary amine and the constituents of capsule and matrix oily has not possibility to carry any formaldehyde as impurity, only low amount of nitrite. Since nitrosamine formation from tertiary amine is formed slower than secondary amine, is it possible conclude that presence of nitrosamine derived from API is minimum? Considering the matrix is a oil.

5

@ederljr , pelo que você já trouxe de dado, parece não haver, a princípio, possibilidade de presença de formaldeído como impureza, apenas uma baixa quantidade de nitrito, correto?

Colocarei 2 (dois) pontos para ajudar você na análise de risco que você vem conduzindo:

  1. Aminas terciárias e seus sais de amônio são conhecidos por reagir diretamente com nitritos para formar nitrosaminas por meio de um mecanismo de desalquilação. Em muitos casos, a nitrosação ocorre em condições ácidas. No entanto, também foi observada nitrosação em condições neutras ou básicas, por exemplo, quando catalisada por um grupo carbonila (Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals).

  2. Outros derivados de carbonila também são impurezas conhecidas em excipientes, como o acetaldeído e os derivados heteroaromáticos derivados de açúcar, furfural e 5-hidroximetilfurfural (Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies).

Outra sugestão de referência é esta aqui: Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility.

3 Likes
7

Hi, Would be interested for more details availability for the pathway for Nitrosamine impurity generation in Hard Fat and/or MCT based oil matrix formulations in soft gelatin capsules. Pl arrange to share literature and reference available in the group for the Nitrosamine formation in oil based formulation in soft gelatin capsules/thanks

8

Hi, Would be interested for more details availability for the pathway for Nitrosamine impurity generation in Hard Fat/MCT based oil matrix formulations in soft gelatin capsules. Pl arrange to share literature and reference available in the group for the Nitrosamine formation in oil based formulation in soft gelatin capsules/thanks