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Pharmaceutics
Volume 17
Issue 10
10.3390/pharmaceutics17101299
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Lifitegrast Degradation: Products and Pathways

by
Leo Štefan
1,
Ivan Sušanj
1,
Jadranka Buljević
1,
Marin Roje
2,
Mladenka Jurin
2,
Anđela Buljan
2,
Tamara Rinkovec
3,
Robert Vianello
3,
Marijana Pocrnić
4,
Nives Galić
4 and
Ana Čikoš
5,*
1
JGL d.d. Jadran Galenski Laboratorij, 51000 Rijeka, Croatia
2
Laboratory for Chiral Technologies, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
3
Laboratory for the Computational Design and Synthesis of Functional Materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
4
Department of Chemistry, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
5
NMR Centre, Ruđer Bošković Institute, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Pharmaceutics 2025, 17(10), 1299; https://doi.org/10.3390/pharmaceutics17101299 (registering DOI)
Submission received: 1 September 2025 / Revised: 1 October 2025 / Accepted: 2 October 2025 / Published: 4 October 2025
(This article belongs to the Section Drug Targeting and Design)
Versions Notes

Abstract

Background/Objectives: Lifitegrast is a recent therapeutic agent provoking scientific and regulatory interest due to its outstanding safety profile and high efficacy in the treatment of dry eye disease. Methods: Herein we employ NMR spectroscopy and mass spectrometry to investigate the weak spots of lifitegrast under standard to extreme stress conditions, resulting in the characterization of three known and nine new degradation products (of which DP7 presented the greatest structural challenge, but was eventually determined as C10 hydroxy derivative, warranting a revision of its previously suggested structure). Results: The first weak spot is identified as a N1–C40 amide bond, and its high susceptibility to hydrolysis is explained through computational DFT analysis. The second and third weak spots are elucidated through bond dissociation energy (BDE) calculations which highlighted the oxidative vulnerabilities of both the piperidine and benzofuran ring. Conclusions: Additionally, two degradation products, observed in initial, extended, and targeted oxidative forced degradation studies, were selected for in silico toxicity assessment and were predicted to have toxicity profiles comparable to or lower than lifitegrast.
Keywords: lifitegrast; degradation products; NMR; HRMS; DFT calculations lifitegrast; degradation products; NMR; HRMS; DFT calculations

Share and Cite

MDPI and ACS Style

Štefan, L.; Sušanj, I.; Buljević, J.; Roje, M.; Jurin, M.; Buljan, A.; Rinkovec, T.; Vianello, R.; Pocrnić, M.; Galić, N.; et al. Lifitegrast Degradation: Products and Pathways. Pharmaceutics 2025, 17, 1299. https://doi.org/10.3390/pharmaceutics17101299

AMA Style

Štefan L, Sušanj I, Buljević J, Roje M, Jurin M, Buljan A, Rinkovec T, Vianello R, Pocrnić M, Galić N, et al. Lifitegrast Degradation: Products and Pathways. Pharmaceutics. 2025; 17(10):1299. https://doi.org/10.3390/pharmaceutics17101299

Chicago/Turabian Style

Štefan, Leo, Ivan Sušanj, Jadranka Buljević, Marin Roje, Mladenka Jurin, Anđela Buljan, Tamara Rinkovec, Robert Vianello, Marijana Pocrnić, Nives Galić, and et al. 2025. "Lifitegrast Degradation: Products and Pathways" Pharmaceutics 17, no. 10: 1299. https://doi.org/10.3390/pharmaceutics17101299

APA Style

Štefan, L., Sušanj, I., Buljević, J., Roje, M., Jurin, M., Buljan, A., Rinkovec, T., Vianello, R., Pocrnić, M., Galić, N., & Čikoš, A. (2025). Lifitegrast Degradation: Products and Pathways. Pharmaceutics, 17(10), 1299. https://doi.org/10.3390/pharmaceutics17101299

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