Describing the Influence of Ball-milling on the Amorphization of Flubendazole Using the PDF and RMC Methods with X-ray Powder Diffraction Data

Flubendazole (FBZ) is a poorly water-soluble drug, and different methodologies have been proposed to improve its oral bioavailability. Obtaining the amorphous drug phase is an alternative to improve its water solubility. Several techniques for drug amorphization, such as spray drying, lyophilization, melt quenching, solvent-evaporation, and ball milling, can yield various types of structural disorder and possibly render variations in physicochemical properties. Herein, we focus on evaluating the influence of the ball-milling process on the amorphization of FBZ. The characterization of the average global and local structures before, during, and after the milling process is described by sequential Rietveld refinements, pair distribution function analysis, and the Reverse Monte Carlo method. We show that preserving the local structure (nearest molecules) can be responsible for avoiding the fast structure recrystallization commonly observed when using the solvent-evaporation process for the studied drug.