George, Fanny
[UCL]
Cocrystals designate organic multicomponent crystals, containing a stoichiometric ratio of at least two components interacting through directional contacts, and that are not simple solvates or salts (at least one component is non ionized). Cocrystals have been especially developed in pharmaceutical sciences for their ability to modulate the physico-chemical properties of a drug product showing non-optimal parameters. Selecting likely coformers to form a cocrystal with a given active pharmaceutical ingredient (API) among the millions of potential candidates is however not trivial, as there are many factors coming into play in varying manners. This step is thus critical as the number of experiments that can be performed in practice is often quite limited due to materials, time and/or cost restrictions. In this thesis, we thus investigated ways of improving the selection of coformers to limit the trial-and-error proportion of the procedure. This was done by studying overall trends in cocrystal formation on one hand and by considering new screening methodologies on the other hand. For that matter, we first performed an extended and systematic experimental cocrystal screen on the enantiopure and racemic versions of a selected API, Levetiracetam. By comparing the results of their respective cocrystal screening, we first showed a tendency for enantiopure and racemic versions of a selected API to form cocrystals with identical non-chiral partners. Accordingly, we suggested a new procedure to identify cocrystals more efficiently especially when a limited amount of this compound is available. From this set of results, we also discovered a stable conglomerate of cocrystals, which is, to the best of our knowledge, only the second report of such a case. Conglomerates are indeed very rare in comparison with racemic crystals. Yet they are intensely researched as various chiral resolution techniques are conditioned by their existence. Notably, this conglomerate is formed with the lactol tautomer of alpha-ketoglutaric acid, which had never been isolated in the solid-state up to now. The existence of a stable conglomerate in this system was put in relation with the enantiospecificity of the niary Levetiracetam cocrystals. More generally, by comparing the peculiarities of the system in hand to the general behavior of cocrystallizing chiral systems with and without zwitterionic coformers, we suggested that for a pseudoquaternary cocrystal to exist, the pseudoternary combinations should exist and the enantiomers of the two compounds should form a diastereomeric pair at the binary level, rather than behave enantiospecifically. In a second phase, we examined the possibility of using Isothermal Titration Calorimetry (ITC) to measure interactions between an API and complexing agents in solution, to determine whether these are indicative of successful cocrystal formation. This technique is often used in biochemistry to measure macromolecule/ligand binding and kinetic interactions, but has never been employed to screen for cocrystals before. We showed that interactions in solution between non-charged compounds, despite being quite small, can be detected by ITC but that they are not sufficient to identify cocrystal formers of a given API, as one needs to also consider the feasibility of an efficient tridimensional packing involving the two molecular partners. Similarly, we considered the use of some of the CSD solid-form modules to validate the results of the experimental cocrystal screenings of Levetiracetam and Paracetamol. Doing so, we demonstrated how CSD knowledge-based informatics can help take decisions concerning coformer selection and experimental prioritization, and how one can optimally apply them to a given system. Finally, we suggested an overall methodology based on these modules, while highlighting that pertinence and complementarity of the different analyses varies from one system to another, depending on the relative strength of the interactions/influences in play.
Bibliographic reference |
George, Fanny. Insights and advances in cocrystal screening : a focus on Levetiracetam/Etiracetam with achiral coformers. Prom. : Leyssens, Tom |
Permanent URL |
http://hdl.handle.net/2078.1/178075 |