Identification and characterization of alkaline hydrolytic degradation products of ivacaftor by UPLC-PDA and UPLC-ESI-QTOF-MS techniques.

Rationale: The study of inherent stability characteristics of drugs has been advocated to be important by various regulatory agencies like the ICH, USFDA, and others. The current work was envisaged to investigate the forced degradation profile of the drug ivacaftor under ICH-prescribed stress conditions, identification of its potential degradants, and postulation of the degradation routes for their generation.

Methods: The stress degradation studies were performed on the drug as per the ICH guideline Q1A(R2). A UPLC-photodiode array-based chromatographic method was developed to satisfactorily resolve the drug from its degradation products, validated in accordance with various ICH prescribed parameters, and assessed for its BAGI practicality index. The degradation products were identified and characterized by UPLC-ESI-QTOF-MS studies.

Results: The drug was found to significantly degrade under conditions of alkaline hydrolytic stress and it was found to be stable under all other stressor environments including acid/neutral hydrolytic, photolytic, thermal, and oxidative stress. Four alkaline hydrolytic degradation products (I-IV) were revealed by UPLC-QTOF-MS studies which were well-resolved from the drug over a C18 UPLC column by the developed UPLC-PDA method. The detection wavelength was selected as 310 nm. Characterization of the four degradation products (I-IV) was carried out by their mass spectral data and their respective degradation routes were elucidated.

Conclusions: A UPLC-PDA method was developed and validated for ivacaftor and its practicality BAGI index was computed. Four alkaline hydrolytic degradation products of ivacaftor were revealed through UPLC-ESI-QTOF-MS studies and corresponding degradation routes were elucidated.