Thesis of Jeanne Annick BAMA

Thesis defense of Jeanne Annick BAMA   - laboratory UMET Abstract : The main objective of this thesis is to acquire a thorough fundamental understanding of amorphous solid dispersions (ASD) of pharmaceutical interest in which a hydrophobic active substance in amorphous form is dispersed at the molecular scale in a polymeric matrix in order to inhibit its recrystallization and increase its bioavailability. In this work, we were interested in the link between the stability of ASD and their complex molecular dynamics, and especially their possible heterogeneity. These studies were carried out by means of crossed experimental investigations combining dielectric relaxation spectroscopy (DRS), thermal analysis (DSC/TGA) and X-ray powder diffraction. The work focused on mixtures of Terfenadine (TFD) dispersed in a polyvinylpyrrolidone polymeric matrix (PVP K12).
A first part of this work was devoted to the study of pure compounds and the impact of the amorphisation process (melt-quenching or milling), in particular for TFD. We evidenced that these two methods did not generate major difference in the as-processed amorphous state, although the TFD glass obtained by milling shows a higher physical instability. However, the sensitivity of the dielectric spectroscopy allowed us to highlight two differences concerning the dynamics. For the TFD amorphised by milling, an incomplete recrystallisation is detected: 1-2% of the sample remains in the amorphous state and shows an increased mobility (the Tg is depressed by 9°C). This remarkable behaviour can be explained by an original "self-confinement" effect of this residual amorphous phase into the interstices formed by the surrounding crystallites. For the glass obtained by melt/quenching and annealed several days at room temperature, an additional secondary relaxation is observed. This relaxation has been linked to the dynamic of a residual water fraction (1 to 2%) very strongly trapped in the amorphous TFD that requires a specific thermal treatment to be removed. An in-depth study of the dynamics was also conducted on PVP K12 which allowed for the first time to characterise the α-mode of this polymer.
A second part of the thesis work focused on the study of ASD and their physical nature (homogeneous or heterogeneous) and the link with recrystallisation. Investigations carried out by thermal analysis allowed us to determine the evolution of two key parameters as a function of the mixture composition: i) the glass transition temperature Tg of the mixture and ii) the temperature corresponding to the solubility limit of the active ingredient in the polymer. The domains delimited by these curves enable to locate the mono- and bi-phasic domains which differ by their structure and their dynamics. The obtained results systematically reveal a single glass transition, which generally constitutes the criterion of a mixture homogeneity. The fitting of the Tg evolution and the solubility respectively by the Gordon-Taylor and Flory-Huggins law suggests weak interactions between TFD and PVP. This result is also confirmed, on the one hand, by the TGA results related to the degradation temperatures and, on the other hand, by the evidence by DRS of the same secondary relaxation modes in mixtures and pure compounds. In contrast to these results, the study of the molecular mobility above Tg reveals in a very original and reproducible way that, for TFD concentrations higher than 70%, the mixtures are heterogeneous and consist of two amorphous phases of different compositions, each with its own main dynamic (α1 and α2). Several hypotheses are proposed in the thesis manuscript to explain the observed differences between dynamic and thermodynamic results. The time evolution of these dynamics has also been investigated and discussed in connection with the stability of ASD.