| Abstrakt: |
Sonidegib (SDG) is a USFDA-approved anticancer drug developed for treating basal cell carcinoma. The presented study is focused on forced degradation studies of SDG with special emphasis on oxidative and photolytic degradation. Stress testing was performed as per ICH guidelines in hydrolytic, oxidative, and photolytic stress, revealing the formation of 15 transformation products. The results demonstrated the sensitivity of SDG to photolytic exposure under UV-A light, as well as to oxidative stress conditions involving hydrogen peroxide and a radical initiator. The observed DPs are separated and identified using RP-LC-PDA using a linear gradient program equipped with C18 (4.6 ×250 mm, 5 µm) column. All the DPs with >0.1 % concentration are characterized using tandem mass spectrometry and DPs with complex, unstable and isomeric nature are enriched and studied using solution NMR. Enrichment studies unveiled the formation of DP-6, DP-11, DP-12 and DP-13 as major transformation products. Interpretation of characteristic fragments from MS/MS spectra, NMR chemical shifts, and NOEs are utilized to solve the structure of the DPs. Further elucidated structures are employed to propose the involved mechanisms in degradation pathway. In addition, the DPs are studied for toxicity in silico and the potential/plausible carcinogenic, genotoxic and mutagenic nature of the DPs are illustrated. [Display omitted] • Hydrolytic, oxidative and photolytic degradation behaviour of sonidegib (SDG) according to ICH Q1A (R2) guidelines. • Fifteen degradation products, including N-oxide isomers, an amide, a dioxo impurity, and a nitrated adduct, are analysed. • Enrichment studies unveil the susceptibility of SDG to photolytic and oxidative stress with transformation to oxidized forms. • 2D NMR studies are utilized to elucidate the unstable positional N-oxide isomers and dioxo oxidative product. • Mechanistic transformation is proposed and in silico toxicity predicting mutagenicity and carcinogenicity of oxidative DPs. [ABSTRACT FROM AUTHOR] |
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