ABSTRACT Voxelotor is the first oxygen‐affinity modulator for hemoglobin. It was demonstrated that voxelotor could potentially modify the disease condition by raising hemoglobin levels and lowering hemolysis markers in sickle cell patients. The voxelotor was exposed to various kinds of degradation conditions, including hydrolysis, oxidation, and photolysis according to the conditions suggested by the International Council for Harmonization (ICH). Two voxelotor degradation impurities were detected during acid hydrolysis and oxidation (H 2 O 2 ). The in silico degradation profile was predicted using Zeneth. The degradation impurities were separated using ammonium formate (pH 6.5) and acetonitrile as the mobile phase with gradient elution and Phenomenex Gemini C18 column (250 × 4.6 mm, 5 µm) as a stationary phase. Liquid chromatography–high resolution mass spectrometry (LC‐HRMS) was used to characterize the separated degradation impurities. The structures of each degradation impurity were ascertained using the accurate masses acquired from LC‐HRMS/MS. A suitable mechanism for the formation of degradation impurities was proposed. The in silico studies for mutagenicity and toxicity were conducted using DEREK and SARAH Nexus.
Prasad et al. (2026) studied this question.