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Photo-Oxidation Mechanisms in Liquid Pharmaceutical Formulations: The Overlooked Role of Singlet Oxygen Presented as a Case Study

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Abstract

Purpose

Oxidation is one of the most common degradation pathways for active pharmaceutical ingredients (APIs) in pharmaceutical formulations, mostly involving 1-electron processes via peroxy radicals and 2-electron processes by peroxides. In liquid pharmaceutical formulations, several factors can impact oxidative instabilities including pH, excipient impurities, headspace oxygen, and the potential for photo-oxidation. Photo-oxidation can be particularly challenging to characterize given the number of oxidative mechanisms which can occur. This was observed during formulation development of a new chemical entity, MK-1454, where a degradation peak was observed during photostability studies which was not previously observed during peroxide and peroxyradical forced stress studies.

Methods

To gain a fundamental understanding of reactive oxygen species generation and its role in degradation of MK-1454, experiments were performed with materials which either generate or measure reactive oxygen species including organic hydroperoxides, singlet oxygen, and superoxide to fundamentally understand a photodegradation mechanism which was observed in the original formulation. LC-MS experiments further elucidated the structure and mechanism of this observed degradation pathway.

Results

A clear relationship between the decrease in dissolved oxygen after light exposure and the loss of MK-1454 was established. The data indicate that singlet oxygen is the most likely contributor of a particular photodegradation product. The singlet oxygen was generated by the inactive ingredients in the formulation, and LC-MS confirm this as the most likely pathway.

Conclusion

This work highlights the importance of understanding photochemical degradation of APIs in solution formulations and provides approaches which can better elucidate those mechanisms and thereby control strategies.

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Data Availability

The datasets generated or analzyed during the current study are not publicly available due to the novel drug, MK-1454, and its formulations being the intellectual property of Merck & Co., Inc., Rahway, NJ, USA but are available from the corresponding author in reasonable request.

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Acknowledgements

The authors would like to thank Erin Guidry, Eric Kemp, Yash Kapoor, Alexandra Andrews, John Lena, Erika Walsh, and Leonardo Allain for their helpful conversations.

Funding

The funding for all work performed in the preparation of the manuscript came from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA internal budgets. MK-1454 was synthesized by and is the intellectual property of Merck & Co., Inc., Rahway, NJ, USA.

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  1. Merck & Co., Inc., 126 E. Lincoln Ave, Rahway, NJ, 07065, USA

    Margaret Brunell, Steven Tignor, Elizabeth Pierson & Paul L. Walsh

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  1. Margaret Brunell
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  2. Steven Tignor
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  3. Elizabeth Pierson
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Correspondence to Paul L. Walsh.

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Brunell, M., Tignor, S., Pierson, E. et al. Photo-Oxidation Mechanisms in Liquid Pharmaceutical Formulations: The Overlooked Role of Singlet Oxygen Presented as a Case Study. Pharm Res 39, 2529–2540 (2022). https://doi.org/10.1007/s11095-022-03374-z

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