Development of the stability-indicating method, structural elucidation of new photodegradation products from terconazole by LC-MS TOF, and in vitro toxicity

Silva, José Wellithom Viturino da; Ribeiro, José Izak; Souza, Larissa Xavier de; Aquino, Kátia Aparecida da Silva; Kishishita, Juliana; Sobrinho, José Lamartine Soares; Leal, Leila Bastos; Santana, Davi Pereira de; Castro, Whocely Victor de; Bedor, Danilo César Galindo

doi:10.1016/j.jpba.2022.114794

Cited by 2 publications

(1 citation statement)

References 23 publications

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“…On a practical level, we have already had the experience of such work [14,15] and were inspired both by similar studies [11,16] and by the recommendations of the ICH [17]. As we are in a predictive approach, there was no other way to work on degradation products than to have generated them by exposing ONC201 to various stress conditions, on condition of applying them in such a way as to have a certain predictive value [18,19].…”

Section: Introductionmentioning

confidence: 99%

Identification of Degradation Products of the New Anticancer Drug Substance ONC201 by Liquid Chromatography–High-Resolution Multistage Mass Spectrometry

et al. 2023

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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–high-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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Section: Introductionmentioning

confidence: 99%

Identification of Degradation Products of the New Anticancer Drug Substance ONC201 by Liquid Chromatography–High-Resolution Multistage Mass Spectrometry

et al. 2023

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Interactions of triazole terconazole with copper and zinc cations

et al. 2023

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Terconazole is one of the triazole derivatives with an antifungal effect. It is used locally to treat vaginal yeast infections. Terconazole could interact with copper cations in the vagina or uterus of women who use an intrauterine device releasing copper cations. Other triazole derivatives in complexes with copper cations differ in their properties like toxicity or mobility. Cu2+ can be reduced in the presence of triazoles, which can lead to a Fenton-like reaction and the production of free radicals. Thus, the Cu2+/Cu+ terconazole system can be potentially dangerous. Stoichiometry, fragmentation, and stability of forming complexes were studied with tandem mass spectrometry. The Cu2+/Cu+ terconazole system was measured within the pH range of 4.0–7.2, with a concentration ratio of CuCl2 and terconazole 1:5 to 20:1, with water and ethanol as solvents (1:1). The achieved results suggest that terconazole is partially oxidized in the Cu2+/terconazole system and that this oxidation depends on the pH of a solution. Apart from the oxidized and protonated terconazole, other detected ions and complexes were not significantly affected by pH. The detection of complexes containing Cu+ is alarming because this could correspond to the occurrence of a Fenton-like reaction. Graphical abstract

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Development of the stability-indicating method, structural elucidation of new photodegradation products from terconazole by LC-MS TOF, and in vitro toxicity

Cited by 2 publications

References 23 publications

Identification of Degradation Products of the New Anticancer Drug Substance ONC201 by Liquid Chromatography–High-Resolution Multistage Mass Spectrometry

Identification of Degradation Products of the New Anticancer Drug Substance ONC201 by Liquid Chromatography–High-Resolution Multistage Mass Spectrometry

Interactions of triazole terconazole with copper and zinc cations

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