Stress-Induced Structural Divergence of Selpercatinib, a RET Inhibitor: Application of HRMS and NMR for the Discovery of Unique Degradation Products.

Selpercatinib (SPB) is a selective RET kinase inhibitor used to treat non-small cell lung cancer and thyroid cancer. Separation and identification of impurities formed during the manufacturing or storage of drug substances play a key role in determining their stability under various conditions during the life cycle of the drug. Hence, in the present study, SPB was exposed to different stress conditions like hydrolytic (acid, base and neutral), oxidative, thermal and photolytic stress conditions. A total of five degradation products were formed under the specified conditions. A UHPLC-PDA method employing Agilent Zorbax Extend C18 RRHD (100 × 2.1 mm, 1.8 μm) column with mobile phases of 0.1% formic acid in HO (A) and 0.1% formic acid in MeOH: ACN (70:30 v/v) (B) in gradient elution at a flow rate of 0.3 mL/min was developed to separate the potential degradation products. LC-QToF-MS/MS was used for the structural characterisation of the impurities. One of the degradation products (DP-2) was isolated and characterised through 1D and 2D NMR experiments. The developed method was validated as per ICH Q2 (R2) guidelines and provides valuable information about the stability of SPB, which can offer a strong foundation for its formulation development, quality control and regulatory compliance in bulk drug and dosage forms.