Thesis of Charline Henaff

Defense of thesis  Charline Henaff - laboratory UMET

Formulation in the amorphous state: the cases of chlorhexidine and of riboflavin

Abstract :

Poor aqueous drug solubility is a major hurdle for the development of innovative medical treatments. This thesis project is dedicated to optimizing the therapeutic efficacy of two model drugs whose crystalline forms exhibit a very low solubility: chlorhexidine (free base) and riboflavin (free base). The aim is to improve the solubility of these drugs by formulating them in an amorphous state as molecular dispersions in a polymer matrix. To that extend, detailed characterization of the physical properties of the stable crystalline drugs, their metastable polymorphic forms, and their amorphous forms obtained directly in the solid state by mechanical milling were required. Moreover, an evaluation of their respective dissolution kinetics was performed. In addition, the possibility of producing molecular dispersions of each drug in polymeric matrices (PVPK12 and Lycoat RS720) in the solid state by mechanical milling was demonstrated, and their release kinetics determined. These dissolution kinetics were compared with those of a physical mixture in which the drug is crystalline and of a physical mixture in which the drug is amorphous, in order to determine both the influence of the drug’s physical state and to assess the advantage of having the amorphous drug molecularly dispersed in the polymer. The physical characterizations are performed using TGA, XRD, DSC and SEM and the dissolution performances are evaluated using different experimental set-ups including: powder dissolution, intrinsic dissolution and tablet dissolution.

Keywords : amorphous solid dispersions,solubility enhancement,physical characterisation,polymer,Formulation,Drug release