The Influence of PVAP on the Stability of Amorphous Solid Dispersions of Itraconazole Produced using Hot Melt Extrusion Technology

Abstract

The purpose of this study was to improve the melt extrusion processability of polyvinyl acetate phthalate (PVAP) and investigate its use as a stabilizing polymer for supersaturated solutions of itraconazole (ITZ) in neutral pH aqueous media and in the solid-state during storage over time. Polyvinyl pyrrolidone vinyl acetate (PVPVA) was incorporated into PVAP as a carrier matrix with the aim of lowering the melt viscosity and increasing the plasticity of PVAP while maintaining its high glass transition temperature (Tg). Amorphous solid dispersions of ITZ (40% w/w) in a 30:70% w/w PVAP:PVPVA mixture were produced by melt extrusion. Solid-state analyses of the composition were performed using differential scanning calorimetry and X-ray diffraction. Dissolution analysis was conducted using a pH-change method. Solid-state analyses demonstrated that the extruded composition was entirely amorphous and ITZ was largely distributed in PVAP- and PVPVA-rich portions of the ternary dispersion. Dissolution analysis revealed that PVAP functioned to prolong the release of supersaturated levels of ITZ from the dispersion following an acidic-to-neutral pH transition. In the solid state, ITZ remained in its amorphous form throughout 6 months of storage. The results of this study suggest that substantial improvements in melt extrusion with PVAP can be achieved by incorporating PVPVA and that the PVAP-PVPVA polymer combination can stabilize amorphous ITZ.