Isolation, LC–MS/MS, NMR Characterization, In Silico Toxicity, and ADME Evaluation of Stress‐Degradation Products of Sunitinib With Optimized Stability‐Indicating HPLC Method for Quantification of Sunitinib and its Impurities

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ABSTRACT Sunitinib belongs to the tyrosine kinase inhibitors class of medical drugs prescribed to treat various types of cancers, including renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors by blocking the action of enzymes that promote cancer cell growth. Forced degradation studies are crucial for assessing drug stability and will be helpful in drug discovery and development. In this study, sunitinib underwent different stress testing according to ICH guidelines to identify and analyze its degradation products (DPs). The stress study findings proved that sunitinib is highly sensitive to acid (2DPs), base (1 DP), and oxidation (1 DP) degradation but remains stable in other stress conditions with significantly less degradation. The separation of sunitinib and its impurities and four DPs was achieved using a Waters XBridge C18 column (250 mm × 4.6 mm, 5 µm) with 0.7 mL/min gradient flow of ammonium formate buffer (pH 4.8) and acetonitrile with a detection wavelength of 258 nm. These conditions produce well‐retained and resolved peaks corresponding to sunitinib at 8.4 min, whereas 4.8, 3.5, and 1.9 min are noticed for impurities 1, 2, and 3, respectively. These study findings provide a comprehensive analysis of sunitinib, its impurities, and DPs, offering crucial insights into its stability and toxicity that can enhance drug development and safety profiling. The study also detailed the degradation pathway of sunitinib, its impurities, and the fragmentation patterns of DPs, which had not been previously reported in any other studies. All these four DPs belong to Class 4 (moderate) toxicity with distinct pharmacokinetic profiles. Hence, it can be concluded that these study findings provide a comprehensive analysis of sunitinib, its impurities, and DPs, offering crucial insights into its stability and toxicity that can enhance drug development and safety profiling.

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