ArticleAAPS PharmSciTech2023
Degradants of Tenofovir Disoproxil Fumarate Under Forced Yet Mild Thermal Stress: Isolation, Comprehensive Structural Elucidation, and Mechanism.
Article in AAPS PharmSciTech, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Rapid deprotection and purification of ceftaroline free base from its phosphoramidate prodrug.Journal of medical microbiology · 2025Article
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In addition to understanding the mechanism of action for a specific drug candidate, information regarding degradation pathways/products under various stress conditions is essential to know about their short- and long-term effects on health and environment. In line with that, tenofovir disoproxil fumarate (TDF, a co-crystal form of the prodrug tenofovir with fumaric acid), particularly used as an antiretroviral drug for treatment of HIV and hepatitis-B among others, is subjected to primarily thermal and other ICH-prescribed forced degradation conditions and their various degradation products are identified. Upon thermal degradation at 60°C for 8 h, five different degradants (namely DP-1 to DP-5) are isolated, and their structures are unambiguously confirmed using advanced analytical and spectroscopic techniques including ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), high-resolution mass spectrometry (HRMS), state-of-the-art 1- and 2-dimensional nuclear magnetic resonance (1D and 2D NMR), and Fourier-transform infrared spectroscopic (FT-IR) techniques. Among fully characterized five degradants, two new degradants (DP-2 and DP-4) are identified which can potentially impact the stability of TDF via different pathways. Plausible mechanisms leading to all five thermal degradation products are also proposed including the generation of carcinogenic formaldehyde for some cases. The present systematic structural study especially combining MS and advanced NMR investigations unequivocally confirms the structures of the degradants and opens opportunities for connecting the various degradation pathways especially for the TDF-related pharmaceutical candidates.
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Registered trials
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