Physical mixing of water-soluble polymers with amorphous solid dispersions based on L-HPC: Supporting supersaturation and improving the kinetic solubility profile

Abstract

Amorphous solid dispersions (ASDs) are a proven strategy for enhancing the solubility and bioavailability of poorly water-soluble drugs. This study investigates the potential of hybrid systems, where ASDs composed of L-HPC were physically mixed with water-soluble polymers, including PVP K30, PVP K90, HPC, and HPMC. The objective was to evaluate how these combinations influence the kinetic-solubility profiles, precipitation inhibition, and dissolution behavior of indomethacin, a model BCS Class II drug. Additionally, direct comparisons were made with ASDs prepared solely with the respective water-soluble polymers to determine the advantages of the mixtures. Dissolution tests under non-sink conditions were conducted in 250 mL aqueous hydrochloric acid (pH 1.2) using a 20 mg drug-equivalent dose. Results demonstrated that adding water-soluble polymers significantly improved dissolution and supersaturation. Mixtures with PVPK30 exhibited rapid dissolution kinetics and prolonged supersaturation, with an AUC of 1846 ± 74 μg/mL/min, markedly higher than the 1161 ± 118 μg/mL/min for ASDs based solely on L-HPC. PVP K90 enhanced supersaturation duration but showed slower dissolution (AUC 1685 ± 65 μg/mL/min), whereas mixtures with HPMC provided sustained supersaturation (AUC 1221 ± 325 μg/mL/min) but delayed initial release due to gel formation. Direct ASDs based on PVP K90 outperformed their hybrid counterparts, while HPMC-based ASDs exhibited the slowest release profiles. These findings underscore the complementary benefits of combining L-HPC with water-soluble polymers, balancing immediate drug release with enhanced precipitation inhibition and tailored dissolution profiles. By optimizing polymer type and ratio, hybrid systems offer a promising strategy to improve bioavailability for challenging drug formulations.