Counteracting the loss of release for indomethacin-copovidone ASDs.

Abstract

This work revisits the changing release behavior of indomethacin(IND)-copovidone amorphous solid dispersions (ASDs) when increasing their drug load (DL). While showing congruent release behavior at DL 0.1, ASDs with DLs of 0.3 and higher show incongruent release finally resulting in a complete loss of release. To study and explain this phenomenon, we modeled the release kinetics of these ASDs and looked into their phase behavior both experimentally and theoretically. We applied a diffusion model to accurately describe experimental release profiles for congruent release, incongruent release as well as for loss of release. Predicted concentration profiles for IND, copovidone, and water within the ASD revealed the formation of an ASD layer that almost exclusively contains amorphous IND. Our phase-diagram predictions and experimental data explain this phenomenon by water-induced phase separation in those parts of the ASD which did absorb water from the dissolution medium. Whereas the evolving copovidone-rich phase dissolved, the IND-rich phase remained undissolved and formed a super-hydrophobic cover of the remaining inner core of the ASD, thus finally completely preventing its dissolution. Higher DLs promote phase separation. This leads to the counterintuitive effect that the higher the DL, the lower the absolute amount of IND released. While the ASD containing 6 mg IND (DL 0.1) released 6 mg IND, the one containing 42 mg IND (DL 0.7) released only 1 mg IND. The theoretical approach applied in this work is for the first time able to quantitatively predict that reducing DL or tablet size could be used to overcome this problem.