Hot-melt extrusion (HME) is a widely used method for
creating amorphous
solid dispersions (ASDs) of poorly soluble drug substances, where
the drug is molecularly dispersed in a solid polymer matrix. This
study examines the impact of three different copovidone excipients,
their reactive impurity levels, HME barrel temperature, and the distribution
of colloidal silicon dioxide (SiO2) on impurity levels,
stability, and drug release of ASDs and their tablets. Initial peroxide
levels were higher in Kollidon VA 64 (KVA64) and Plasdone S630 (PS630)
compared to Plasdone S630 Ultra (PS630U), leading to greater oxidative
degradation of the drug in fresh ASD tablets. However, stability testing
(50 °C, closed container, 50 °C/30% RH, open conditions)
showed lower oxidative degradation impurities in ASD tablets prepared
at higher barrel temperatures, likely due to greater peroxide degradation.
Plasdone S630 is suitable for ASDs with drugs prone to oxidative degradation,
while standard purity grades may benefit drugs susceptible to free
radical degradation, as they generate fewer free radicals post-HME.
ASD tablets exhibited greater physical stability than milled extrudate
samples, likely due to reduced exposure to stability conditions within
the tablet matrix. Including SiO2 in the extrudate composition
resulted in greater physical stability of the ASD system in the tablet;
however, it negatively affected chemical stability, promoting greater
oxidative degradation and hydroxylation of the drug substance. No
impact of the distribution of SiO2 on drug release was
observed. The study also confirmed the congruent release of copovidone,
the drug substance, and Tween 80 using flow NMR coupled with in-line
UV/vis. This research highlights the critical roles of peroxide levels
and SiO2 in influencing the dissolution and physical and
chemical stability of ASDs. The findings provide valuable insights
for developing stable and effective pharmaceutical formulations, emphasizing
the importance of controlling reactive impurities and excipient characteristics
in ASD products prepared by using HME.