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caractérisation des processus de dégradation de nouveaux anticoagulants et d’un cytotoxique en milieu aqueux avec évaluation des impacts pharmaceutiques et environnementaux

Abstract : During its life cycle, an active substance is in solution for various reasons: in a liquid pharmaceutical form, in the body and in wastewater. However, compared to the solid state, the active substance in solution exposes it more to factors likely to cause its degradation. The transformations modify its chemical structure and thus potentially its pharmacological and toxicological activities.The objective of this thesis is to present a methodology and studies aiming to predict the fate in solution of active substances and the potential impacts following their degradation.Three active ingredients have been selected for this work. They have in common, on the one hand, a high pharmacological activity correlated to a potential toxicity of their degradation products and, on the other hand, the fact that there is little information on their behaviour in solution. In all cases, although the context is specific to each molecule, the methodological approach followed integrates both experimental work and ab initio and in silico studies.The first study concerns the fate of apixaban, an active substance currently marketed in solid oral form, in aqueous solutions. The experimental data made it possible to highlight chemical groups of the active ingredient that could contribute to its own instability. The ab initio approach explained the regio-specificity of the hydrolysis reaction as a function of pH. Based on the structure of the characterized degradation products, their toxic potential was studied using an in silico approach. These data contribute to the risk analysis and evaluation process deployed at different stages of development of liquid pharmaceutical forms or in particular situations involving the solution of apixaban at the time of administration.Such approaches have also been used to characterize the photodegradation mechanisms of argatroban and assess the toxic potential of degradation products. The processes that initiate photodegradation were also addressed by calculating the energies potentially involved. This knowledge provides a rational basis for the choice of processes and formulations to limit photodegradation of argatroban and its impact on patients. They also make it possible to anticipate situations where the benefit/risk ratio of the medicinal product may be modified, such as incorrect handling or modification of the pharmaceutical form administered.Finally, in a context other than the pharmaceutical context, a study of degradation of pemetrexed by photocatalysis via an advanced oxidation process was carried out. This process is particularly studied for its ability to reduce the environmental footprint of organic compounds by accelerating their degradation. The choice of this active substance as an anti-cancer agent was justified by its toxic and persistent nature in surface waters, making it a product with a high environmental risk. This work has shown that products of lower mass produced by photocatalytic transformation of pemetrexed are unfortunately more toxic and even more persistent than the parent molecule itself. These results underline the fact that advanced oxidation processes, although effective in removing drug pollutants, must be evaluated because of an increased risk to the environment before any prospect of large-scale use.The approaches and results presented in this thesis can be used for other studies to predict, prevent and reduce the impact of active ingredient degradation on the patient and the environment.
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Submitted on : Friday, February 8, 2019 - 2:59:06 PM
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Philippe-Henri Secrétan. caractérisation des processus de dégradation de nouveaux anticoagulants et d’un cytotoxique en milieu aqueux avec évaluation des impacts pharmaceutiques et environnementaux. Chimie analytique. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS481⟩. ⟨tel-02012160⟩



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