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Etude du cycle de vie du Ticagrelor par une approche combinée prédictive et caractérisation structurale

Abstract : Tragedies caused by the misuse of pharmaceuticals have put the drug safety at the core of the concerns of healthcare providers. Throughout its life cycle, a drug may be subjected to environmental stresses, which can lead to its degradation. Thorough understanding about the susceptibility of a drug to degrade is an essential step to avoid it. This problem is in particular relevant in a hospital setting, where commercial drugs are usually applied to specific cases without a clear understanding of its limitations. As part of this PhD project, a life cycle study strategy for a commercial drug has been implemented in order to increase its safety in use. Given the prominence of solid forms in the therapeutic arsenal, ticagrelor, a recent antiplatelet agent (APA) in tablet form, was chosen for this study. The first step was devoted to the evaluation of the intrinsic stability and the structural elucidation of the degradation products making use of LC-HR-MSn, providing access to the elemental composition. Degradation pathways have been proposed and the safety of the products has been evaluated via an in silico toxicological approach. Furthermore because antiplatelet agents are often used in combination therapy, in the second part, a preformulation strategy with aspirin in the solid state has been studied using the complementary techniques LC-HR-MSn, DSC, PXRD, and TGA. The mixture of the two active pharmaceutical ingredients gave rise to a simple eutectic. We have demonstrated that the degradation of ticagrelor in these mixtures is closely related to the stability of aspirin, which is modulated by environmental conditions. The ticagrelor study provides a model for the safety management of other drugs and can contribute to their appropriate recycling.
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Submitted on : Friday, April 13, 2018 - 4:12:06 PM
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Hassane Sadou Yaye. Etude du cycle de vie du Ticagrelor par une approche combinée prédictive et caractérisation structurale. Sciences pharmaceutiques. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS024⟩. ⟨tel-01766476⟩

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