Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule.
ONC201 (dordaviprone) is a new drug substance used in a compassionate manner to treat patients with glioblastoma. Given the clinical context and the particularly promising preclinical results, we have been asked by the medical authorities to make a first treatment available throughout France as a hospital preparation to allow access to treatment and to conduct clinical trials. However, to control the quality and safety conditions inherent in this academic manufacturing process, while there is virtually no data available to date to understand the stability of ONC201, we had to determine the stability profile of ONC201, i.e., its sensitivity to different stressors and the types of impurities that could form during its degradation. We found that ONC201 was sensitive to oxidation in the presence of hydrogen peroxide or under light irradiation. Both conditions resulted in the formation of 20 degradation products detected and identified by liquid chromatography鈥揾igh-resolution mass spectrometry. Their structural elucidation required an in-depth study of the fragmentation pattern of protonated ONC201, described for the first time. The product ions of the degradation products were compared to those of ONC201 protonated ion to assign the most plausible structures for all the detected degradation products. Of these degradation products, those that were rapidly produced, of high intensity and/or identified as potentially having a different toxicity profile to ONC201 by in silico studies, were selected to be monitored during batch release testing and stability studies.
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