Etude numérique et expérimentale de systèmes multicomposants d’intérêt pharmaceutique

Dans ce travail de thèse, nous avons étudié l'état physique de systèmes multicomposants pharmaceutiques, (cocristaux et co-amorphes) à partir de travaux expérimentaux et numériques. Ces investigations ont principalement porté sur la conception des matériaux, leurs modes de préparation spécifiques, et les analyses de leurs transformations de phase. Une analyse détaillée et critique de l'approche de calcul COSMO-RS utilisée pour prédire les tendances de la cocristallisation a été réalisée. La prédiction de l’affinité entre la carbamazépine et 75 co-formateurs différents a été testée. Cette étude a démontré la possibilité et les limites de l'approche numérique COSMO-RS et certaines améliorations possibles basées sur les contributions entropiques à la stabilité ont été vérifiées avec succès. La cocristallisation et les propriétés physiques du système carbamazépine + acide tartrique à différents rapports molaires ont été complètement revues. Deux techniques de cocristallisation différentes ont été testées, le broyage assisté par solvant et l'évaporation de la solution afin d'évaluer l'impact des méthodes de préparation. Deux cocristaux différents ont été obtenus : une forme ordonnée A et une forme B désordonnée dynamiquement avec une structure particulière sous forme de canaux de taille nanométrique dans lesquels les molécules d'acide tartrique sont confinées. La nature de ce désordre dynamique particulier a été étudiée à partir d'expériences de spectroscopie de relaxation diélectrique. Un système multicomposant amorphe très stable à base de simvastatine a été conçu. Il a été montré que sa recristallisation est inhibée sur une période de 2 ans dans les conditions ambiantes. Les mobilités moléculaires complexes de ce système ont été analysées, y compris l'origine moléculaire des processus de relaxation. Ces travaux ont été réalisés dans le cadre du projet européen IMODE (Innovative Multicomponent Drug Design) du programme Interreg des 2 Mers.In this thesis work, we have investigated the physical state of pharmaceutical multicomponent systems, co-crystalline and co-amorphous forms, from a joint computational and an experimental point of view. Our works mostly focused on the design of these materials, their specific synthesis methods, and the analyses of their phase transformations based on combined structural-dynamical-thermodynamical physical characterizations. A detailed and critical analysis of the computational COSMO-RS approach usually used to predict cocrystallization tendencies was realized. The affinity predictions between carbamazepine and 75 different coformers was tested. This study demonstrated the possibility and limitation of the COSMO-RS numerical approach and some possible improvements based on the entropic contributions to the stability were successfully checked. The cocrystallization and physical properties of the carbamazepine+tartaric acid system at different molar ratio were completely revisited. Two different cocrystallization techniques were tested, liquid assisted grinding and solution evaporation in order to assess the impact of the preparation methods. Two different cocrystals were obtained: an ordered Form A and a dynamically disordered Form B with a peculiar channel-like structure of nanometer size in which tartaric acid molecules are confined. The nature of this peculiar dynamical disorder was investigated from dielectric dynamical spectroscopy experiments. A very stable co-amorphous simvastatin-based multicomponent systems was designed. It was shown that recrystallization is inhibited over a period of 2 years under ambient conditions. The complex mobility dynamics of this system were analyzed including the molecular origin of the relaxational processes. This work has been performed in the framework of the IMODE (Innovative Multicomponent Drug Design) European project of the Interreg 2-Seas Program

Nature of the structural and dynamical disorder in organic cocrystals with a true nanometric size channel-like architecture

The nature of the structural and dynamical disorder of the nanoporous organic cocrystal carbamazepine-tartaric acid designed by liquid assisted grinding is investigated through complementary solid-state NMR, X-ray diffraction and broadband dielectric spectroscopy experiments combined with molecular dynamics simulations. In this article, we especially highlight that the tartaric acid molecules present in the channel-like cocrystalline architecture show both translational and rotational dynamical disorder. Such a disorder seems only partial since tartaric acid molecules are strongly hydrogen-bonded to the carbamazepine molecules which form the channels and they thus share with them some order. Tartaric acid species are organized as one-dimension interrupted single files of molecules weakly hydrogen bonded between them. Translational dynamics occurs by small hops of about 6 to 7 Å consistent with the distance between first neighbors. At short times, it can be described as a single-file diffusion process while at longer times the classical diffusion (Fickian) is recovered. Random motions are explained by the presence of several short single files of molecules in the channel instead of just one single file. Rotational dynamics is interpreted as rotational jumps between preferred orientations. It gives rise to a change of the molecular dipole moments orientations, which are detected by dielectric relaxation spectroscopy. Freezing out of the rotational molecular mobility is detected in the temperature range [173-193] K concomitantly with the presence of a kink in the temperature evolution of the crystalline cell volume which is usually associated with the glass transition phenomenon. It reveals a remarkable link between the molecular mobility of the tartaric acid molecules and the overall crystal anharmonicity. The present findings aim to demonstrate the interest of disordered channel-like cocrystals for investigation of dynamics in nanoconfinement environments