Phase homogeneity in ternary amorphous solid dispersions and its impact on solubility, dissolution and supersaturation - Influence of processing and hydroxypropyl cellulose grade.

ABSTRACT

As performance of ternary amorphous solid dispersions (ASDs) depends on the solid-state characteristics and polymer mixing, a comprehensive understanding of synergistic interactions between the polymers in regard of dissolution enhancement of poorly soluble drugs and subsequent supersaturation stabilization is necessary. By choosing hot-melt extrusion (HME) and vacuum compression molding (VCM) as preparation techniques, we manipulated the phase behavior of ternary efavirenz (EFV) ASDs, comprising of either hydroxypropyl cellulose (HPC)-SSL or HPC-UL in combination with Eudragit® L 100-55 (EL 100-55) (5050 polymer ratio), leading to single-phased (HME) and heterogeneous ASDs (VCM). Due to higher kinetic solid-state solubility of EFV in HPC polymers compared to EL 100-55, we visualized higher drug distribution into HPC-rich phases of the phase-separated ternary VCM ASDs via confocal Raman microscopy. Additionally, we observed differences in the extent of phase-separation in dependence on the selected HPC grade. As HPC-UL exhibited decisive lower melt viscosity than HPC-SSL, formation of partially miscible phases between HPC-UL and EL 100-55 was facilitated. Consequently, as homogeneously mixed polymer phases were required for optimal extent of solubility improvement, the manufacturing-dependent differences in dissolution performances were smaller using HPC-UL, instead of HPC-SSL, i.e. using HPC-UL was less demanding on shear stress provided by the process.