Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation

Dr. Berardi published a new paper comparing the best-case scenario with the worst-case scenario to evaluate the impact of excipient change on nitrosamine formation. We may avoid the generation of NDSRIs without adding antioxidants in DP manufacturing.

And supplementary materials help us evaluate the impact of excipient change through a spreadsheet. It’s excellent!!

Supplementary Materials: https://www.mdpi.com/article/10.3390/pharmaceutics15082015/s1

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I want to call all your attention to review the Excel calculation tool that Dr. Berardi et al. produced with the publication on the modeling of impact on nitrosamine formation.

Excel calculation tool:
https://www.mdpi.com/article/10.3390/pharmaceutics15082015/s1

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Hello all!

Just a question, we are reviewing the Excell worksheet of the paper published by Berardi, Jaspers and Dickhoff, and some of the tricks not explained in the topic “Lactose, Nitrosamine Risk?”, like how conversion factor should be applied, was very approached and well explained.

But a question that remain for me is if we use the rationale presented by Dr. Urquhart, I mean using the same example presented for him, the nitrosamine amount calculated in the Excell is not the same with the example. Is there another interpretation that we need considerer in this case?

And another doubt is why estimated weight of nitrite was multiplied by 6, if in the calculation we are already considering the maximum dosage of 300 mg? I mean we should multiply by 6 if we are using only one dosage e.g 50 mg? In the last column of the example, the title is “weight in a single dose”, but I just reach theses values using 300 mg in the calculation.

I’m right, or there is something hidden that I’m let getting away?

I will appreciate your help nitrosamines exchange community.

Thanks.

Hi, @CesarJr

Thank you for asking. First, I want to focus on Dr. Urquhart’s presentation held two years ago. He explained the Conversion Factor as 1% for Dry formulation. The value of 1% is from EFPIA Workflow ver.1. On the other hand, Dr. Berardi used 13% for direct compression and 29% for wet granulation as CF. These values are from Dr. Moser’s paper.

Second, the daily dose of 300 mg in Dr. Urquhart’s slide means the amount of API. Though it may confuse you, 300 mg is the same as the weight of a 50 mg tablet. Six of 50 mg tablets will be taken at most in a day.

I hope this is an answer to your question.

Dear @Yosukemino, many thanks for your reply. But only two more questions… If one tablet of 50 mg weight 300 mg, why the API was approached like 70 mg? And another question, I must to considerer the maximum daily dosage for a medicine or the weight of one tablet in the calculation?

Dear @CesarJr

API is a salt form such as hydrochloride salt. The maximum daily dose of 300 mg(amount of maximum API) should be included in the calculation.

Thank you @Yosukemino for your continuous support and for sharing these essential resources.

I’ve been using the Excel tool for Nitrosamine calculation, and I noticed that the tool only takes into account percentage of conversion for DC and WG formulations for secondary amines APIs in salt and base form. I’m currently working on a tertiary amine APIs formulations and was wondering if you have any ideas on percentage conversion for this specific category.

Hi, @Fatima-Ezzahra

Thank you for asking. As far as I know, 13% of the Conversion Factor for DG and 29% for WG are from Moser’s publication. In the same publication, tertiary amine shows a conversion of 0.53% for DG and 0.24% for WG. But you should carefully apply the Conversion Factor to your products because the feature of tertiary amine depends on its structure.

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Most likely the conversion rates need to be validated with experimental data…

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I agree with you, @Naiffer_Host. According to the paper, the conversion rate significantly depends on the conditions and structure of amines. And Swiss medic demonstrated the step 1 risk assessment by the pharmaceutical companies was sometimes unreliable.

Especially for high-risk nitrosamines such as Category 1 or 2, confirmatory testing may be required.

Thank you @Yosukemino and @Naiffer_Host for your response. Could you recommend any specific references that provide detailed information on the conditions and structural characteristics of terstiary amines APIs that could lead to the formation of NDSRIs and should therefore be taken into account in the Risk Evaluation ?

Here are some references regarding vulnerability of t-amines to nitrosation:

  • A Consideration of the Extent That Tertiary Amines Can Form N-Nitroso Dialkylamines (Ashworth et al., OPR&D, 2023)
  • Formation of Dialkyl‑N‑nitrosamines in Aqueous Solution…Comparison sec and trialkyl Amine Nitrosation (Ashworth, OPR&D, 2023)
  • Nitrosative Cleavage of Tertiary Amines (Smith & Loeppky J. Am. Chem. Soc. 1967, 89, 5, 1147–1157)
  • The Mechanistic Origin of Regiochemical Changes in the Nitrosative N-dealkylation of N, N-dialkyl Aromatic Amines (E. L. Teuten & R. N. Loeppky, OBC, 2005)
  • Rapid Nitrosamine Formation from a Tertiary Amine… (Loepky, Tetrahedron, 1983)
  • In silico prediction of N nitrosamine degradants in APIs that possess a secondary or tertiary amine functional group (Lhasa poster, 2022)
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Dear @Yosukemino, we would like to aks for your support. In our company nitrosamines topic is new and we are now using the excel file mentioned at the beggining. However, we have the same doubts as CesarJr had. In summary, in this part of the excel file, what should we use?

The weight of the tablet multiplied by the number of tablets needed to reach the maximum daily dose of API or the maximum daily dose of the API?

Dear @CesarJr may I ask for your support also here? At the end you figured out what value to use in:

Hi @anonymous86!
Initially, it was a little bit confusing for me too. But what I understood and based on the @Yosukemino help, maximum daily dosage should be considered. In the example, 300 mg is the same as the weight of a one 50 mg tablet. To reach the maximum daily dosage of the API (300 mg) is necessary 6 tablets of 50 mg each one, in other words, the maximum daily dosage was always behind the calculation strategy.

Anything else to comment or to correct @Yosukemino and @Naiffer_Host?

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HI @CesarJr !

Thanks for your answer. Just to kill the obvious, then in the case you mentioned what should be entered in “Dose weight” is the multiplication of 300mg * 6 = 1800 mg converted to grams?

My apologies, if it is still a bit confusing for us.

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You are right. You can think of the situation as simple. If you change the dose weight in the following example, you will find the amount of API is not included in the calculation.