Investigation\nof the Influence of Copovidone Properties\nand Hot-Melt Extrusion Process on Level of Impurities, In Vitro Release,\nand Stability of an Amorphous Solid Dispersion Product

Hot-melt extrusion (HME) is a widely used method for\ncreating amorphous\nsolid dispersions (ASDs) of poorly soluble drug substances, where\nthe drug is molecularly dispersed in a solid polymer matrix. This\nstudy examines the impact of three different copovidone excipients,\ntheir reactive impurity levels, HME barrel temperature, and the distribution\nof colloidal silicon dioxide (SiO<sub>2</sub>) on impurity levels,\nstability, and drug release of ASDs and their tablets. Initial peroxide\nlevels were higher in Kollidon VA 64 (KVA64) and Plasdone S630 (PS630)\ncompared to Plasdone S630 Ultra (PS630U), leading to greater oxidative\ndegradation of the drug in fresh ASD tablets. However, stability testing\n(50 °C, closed container, 50 °C/30% RH, open conditions)\nshowed lower oxidative degradation impurities in ASD tablets prepared\nat higher barrel temperatures, likely due to greater peroxide degradation.\nPlasdone S630 is suitable for ASDs with drugs prone to oxidative degradation,\nwhile standard purity grades may benefit drugs susceptible to free\nradical degradation, as they generate fewer free radicals post-HME.\nASD tablets exhibited greater physical stability than milled extrudate\nsamples, likely due to reduced exposure to stability conditions within\nthe tablet matrix. Including SiO<sub>2</sub> in the extrudate composition\nresulted in greater physical stability of the ASD system in the tablet;\nhowever, it negatively affected chemical stability, promoting greater\noxidative degradation and hydroxylation of the drug substance. No\nimpact of the distribution of SiO<sub>2</sub> on drug release was\nobserved. The study also confirmed the congruent release of copovidone,\nthe drug substance, and Tween 80 using flow NMR coupled with in-line\nUV/vis. This research highlights the critical roles of peroxide levels\nand SiO<sub>2</sub> in influencing the dissolution and physical and\nchemical stability of ASDs. The findings provide valuable insights\nfor developing stable and effective pharmaceutical formulations, emphasizing\nthe importance of controlling reactive impurities and excipient characteristics\nin ASD products prepared by using HME.