Influence of the manufacturing process on the physiochemical characteristics of amorphous solid dispersions with high drug loading

Drug discovery pipelines consist for 75% out of new chemical entities that are poorly water-soluble, leading to insufficient oral bioavailability. A successful formulation strategy to overcome these solubility issues is the formulation of Amorphous Solid Dispersions (ASDs), where an Active Pharmaceutical Ingredient (API) is molecularly dispersed in a carrier matrix at solid state. In this PhD project, supersaturated solid dispersions are manufactured under different conditions. To generate a supersaturated state, the API has to be dissolved in the polymer matrix above its thermodynamic solubility limit, thereby forming a thermodynamically unstable mixture. The supersaturated state can however be kinetically stabilized under the right circumstances. Accordingly, the overall aim of this project is to investigate the influence of several formulation and process parameters on the kinetic stabilization of supersaturated solid dispersions. In a first part of the project, three ASD manufacturing techniques, i.e., spray drying, hot melt extrusion and cryo-milling, are compared for their capability to generate highly drug loaded ASDs. The ASDs will be prepared using four different polymers, thereby allowing to simultaneously study the effect of the manufacturing method and the carrier on the kinetic stabilization of supersaturated ASDs. The second part of the project is about the impact of the solvent on the phase behavior of (supersaturated) ASDs prepared by either spray drying or film casting. To gain insight in the contribution of the solvent to the physical state, solubility experiments will be performed, and evaporation kinetics and the presence of interactions in solution will be investigated. Additionally, the physical stability of ASDs spray dried with different organic solvents will be studied as well. As the solid-state characterization of the supersaturated systems can be challenging, the complementary nature of modulated Differential Scanning Calorimetry (mDSC) and X-Ray Powder Diffraction (XRPD) will be another point of interest throughout the project.