Polymer-mediated solubility enhancement and supersaturation stabilization using various hydroxypropyl cellulose grades within amorphous solid dispersions

Abstract

Solubility enhancement in combination with supersaturation stabilization of poorly soluble drugs is a well-established concept to enhance oral bioavailability. One promising formulation principle to overcome low solubility issues represents the preparation of amorphous solid dispersions (ASDs). With the aid of a polymer, metastable supersaturated drug solutions are generated upon dissolution, that need to be stabilized for a sufficient dissolution time to prevent precipitation towards the equilibrium solubility of the drug. <br> As both generation and stabilization of supersaturated drug solutions highly depend on specific drug-polymer interactions in liquid-state, a supersaturation assay in pH 6.8 medium for evaluation of the precipitating effects of various polymers on eight drugs was performed, initially. The results revealed that successful drug supersaturation varied and depended on the individually selected drug-polymer system. As single polymers were not always capable of enabling satisfying precipitation inhibition, polymer mixtures of Eudragit® L 100-55 (EL 100-55) and hydroxypropyl cellulose (HPC)-SSL (50:50) were tested. Synergistic interactions between the polymers led to pronounced enhanced supersaturation of celecoxib (CXB), efavirenz (EFV), and clotrimazole (CLT). Using CXB, the liquid-state polymer-polymer interactions of EL 100-55 and HPC were further investigated, by varying the HPC grade (-L, -SSL, -UL) and the polymer mass ratios. Before designing ASD formulations, the impact of the manufacturing method on polymer mixing and polymer-polymer interactions of EL 100-55: HPC-SSL (50:50) and EL 100-55: HPC-UL (50:50) were investigated via differential scanning calorimetry (DSC), confocal Raman spectroscopy (CRS), and Fourier-transform infrared spectroscopy (FT-IR). While spray-drying (SD) and hot-melt extrusion (HME) led to homogeneous placebos with pronounced interactions, phase separated formulations with weaker interactions were obtained after vacuum compression molding (VCM). However, the lower melt viscosity of HPC-UL compared to HPC-SSL during the VCM melting process enabled higher content of partially miscible phases between EL 100-55 and HPC-UL. By processing the EL 100-55: HPC polymer mixtures with either CXB or EFV for ternary ASDs, homogeneous embedding was observed after HME and SD. In case of the phase separated ternary VCM ASDs, higher kinetic solid-state solubilities of the drugs within the HPC polymers led to preferred drug distribution within the HPC-rich phases. Since homogeneously mixed polymer phases were necessary for optimal dissolution performances, the single-phased ternary ASDs consisting of extruded EL 100-55: HPC-SSL outperformed the heterogeneous ternary ASDs that were solely prepared via VCM. However, the higher content of partially miscible phases within the ternary EL 100-55: HPC-UL VCM ASDs led to no (CXB) or only small differences (EFV) in dissolution compared to the extruded polymer ASDs.