Jessica Albers

Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion

The aim of the study was the formulation of solid dispersions of the poorly water-soluble drug celecoxib and a polymethacrylate carrier by hot-melt extrusion. The objectives were to elucidate the mechanism of drug release from obtained extrudates and milled strands addicted to the solid-state properties of the solid dispersions and to examine and eliminate stability problems occurring under storage, exposure of mechanical stress, and in vitro dissolution. Transparent extrudates containing up to 60% drug could be prepared with a temperature setting below the melting point of celecoxib. XRPD and DSC measurements indicated the formation of a glassy solid solution, where the drug is molecularly dispersed in the carrier. The amorphous state of the glassy solid solution could be maintained during the exposure of mechanical stress in a milling process, and was stable under storage for at least 6 months. Solid-state properties and SEM images of extrudates after dissolution indicated a carrier-controlled dissolution, whereby the drug is molecularly dispersed within the concentrated carrier layer. The glassy solid solution showed a 58-fold supersaturation in 0.1 N HCl within the first 10 min, which was followed by a recrystallization process. Recrystallization could be inhibited by an external addition of HPMC.

Evaluation of predictive models for stable solid solution formation.

The objective of this study was to evaluate predictive models for stable solid solution formation and to find a quick and successful approach for miscibility screenings. The results show that the interpretation of the chemical structure and the crystallinity by X-ray powder diffraction measurements as well as the determination of melting point depressions and melting enthalpies are beneficial tools to predict the miscibility of drugs and carriers. A combined approach of prediction tools is highly appropriate, as no single technique may yield all the required information. Nevertheless, the evaluation of the melting behavior via differential scanning calorimetry has the highest impact.