Soutenance de thèse Yevhenii VAKSLER

26 mai 2021 par Myriam Moreau [TheChamp-Sharing]
28 mai 2021 09:30 AM Paris ID de réunion : 978 4473 6709 Code secret : 714221

Synthesis, structure and properties of polymorphic modifications of bioactive molecules

This thesis was carried out in the frame of cotutelle agreement between the university of Lille and the university of Kharkiv in Ukraine

Active pharmaceutical ingredients can retain their properties indefinitely in a solid state.
As a result, numerous drugs are produced and stored in the most stable solid phase among the known ones. However, more than 50% of solid-state drugs may have more than one polymorphic modification. Different polymorphic forms of the same compound can possess different properties, which affect significantly the effectiveness of a drug, its abilities to be manufactured and stored. The control of polymorphism in active pharmaceutical ingredients is a relatively new approaching problem, whose regulations just start to develop. To achieve effective monitoring of the properties during the production and dosage forms predictable characteristics, it is necessary to control the root causes of polymorphism. They are a molecule
conformational change and / or the formation of a new set of intermolecular interactions.
In the first part of this thesis, two experimental methods for the control over the
polymorphic composition of the active pharmaceutical ingredients and their selective
crystallization from the supercritical carbon dioxide are presented. The first is the monitoring of the conformations of bioactive molecules with
in situ infrared and Raman spectroscopies.
The relationships between conformations in solution and recrystallized polymorphic
modifications are shown in the example of mefenamic acid and carbamazepine, substances especially susceptible to polymorphism. The second complementary method allows one to grow high-quality single crystals directly from the solution in carbon dioxide, to determine their structure by single-crystal X-ray diffraction and, as a result, to clearly establish a reference for fast methods of analysis of polymorphic composition (vibrational, thermal analysis, etc.). It is studied for a co-crystal of mefenamic acid and nicotinamide (vitamin B3).
In the second part of the current thesis, the approach for the analysis of mechanical
response of individual polymorphic forms and the probability of their transformations under external influences (pressure, milling, etc.) and in case of low stability of a crystalline form is proposed. It is a multi-step method, where calculations of the pairwise interaction energies in crystals allow to identify the most strongly bound fragments of crystalline arrangements (building units, columns, layers, etc.). The building unit and a part of the neighboring layer are used as a model system for the further study. The probable directions of molecular layers shear
are assumed from topological analysis. The final step is precise quantum-chemical calculations of shift energy profiles and barriers for the layers displacement in these directions. This approach is applied to popular drugs: aspirin, piracetam and ibuprofen.