MassChemSite for In-Depth Forced Degradation Analysis of PARP Inhibitors Olaparib, Rucaparib, and Niraparib

Abstract

Drugs must satisfy several protocols and tests before being approved for the market. Among them, forced degradation studies aim to evaluate drug stability under stressful conditions in order to predict the formation of harmful degradation products (DPs). Recent advances in LC-MS instrumentation have facilitated the structure elucidation of degradants, although a comprehensive data analysis still represents a bottle-neck due to the massive amount of data that can be easily generated. MassChemSite has been recently described as a promising informatics solution for LC-MS/MS and UV data analysis of forced degradation experiments and for the automated structural identification of DPs. Here, we applied MassChemSite to investigate the forced degradation of three poly(ADP-ribose) polymerase inhibitors (olaparib, rucaparib, and niraparib) under basic, acidic, neutral, and oxidative stress conditions. Samples were analyzed by UHPLC with online DAD coupled to high-resolution mass spectrometry. The kinetic evolution of the reactions and the influence of solvent on the degradation process were also assessed. Our investigation confirmed the formation of three DPs of olaparib and the wide degradation of the drug under the basic condition. Intriguingly, base-catalyzed hydrolysis of olaparib was greater when the content of aprotic-dipolar solvent in the mixture decreased. For the other two compounds, whose stability has been much less studied previously, six new degradants of rucaparib were identified under oxidative degradation, while niraparib emerged as stable under all stress conditions tested.