Thesis defense of Vaksler Yevhenii

Thesis defense of  Vaksler Yevhenii - laboratory LASIRE Abstract : Active pharmaceutical ingredients can retain their properties constant 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 new quantum-chemical method for the analysis of a crystal structure transformation under external (pressure, milling, etc.) and internal (low stability of a form) influences is proposed. Based on the approach of pairwise interactions in crystals it allows one to define the most strongly bound parts of crystalline arrangements and probable directions of shear deformations. Thereby, this technique helps to determine the probable mechanical properties of individual polymorphic modifications and the entailed polymorphic transformations of the active pharmaceutical ingredients. The calculations are performed for the popular drugs: aspirin, piracetam and ibuprofen. Keywords : Polymorphism,Vibrational spectroscopy,Quantum chemical calculation,Supercritical fluids,In situ analysis,X-ray diffraction