Modelling drug degradation of amorphous solid dispersion during twin-screw extrusion

Abstract

Twin-screw extrusion is one of the major technologies for solid dispersion in the pharmaceutical industry. However, the thermal exposure to the drug during extrusion can easily trigger and exacerbate drug degradation. A conventional method for investigating drug degradation in extrusion is trial-and-error, which can consume much time and material. We propose to model drug degradation kinetics and combine it with thermal history simulation to predict drug degradation. Ritonavir and copovidone were used as a model system of solid dispersion. Hydantoin aminoalchol was the major degradant of RTV in extrudate. In studying the RTV degradation kinetics, only in nitrogen atmosphere, RTV degradation pathway in TGA or DSC was like the degradation pathway in extrusion. The mixing and solubilization of RTV in copovidone also prevented RTV from degrading to oxazolidine derivative. The degradation samples were collected at various temperatures and at different times. The data was fitted into first-order kinetics model to get degradation rates constant at each temperature. The degradation rate constants were fitted into the Arrhenius equation with an activation energy of 159.3 kJ/mol, and a pre-exponential of 1.23 × 1017. An array of extrusion conditions was developed and analyzed via design of experiment (DOE). Relying on the measured melt temperature and residence time after kneading element and die, we simulated the thermal history in the section between kneading element and die. The RTV degradation kinetics in conjunction with simulated thermal history predicted degradation and achieved a 78% regression.