Dissolution of Multi-Component Single Phase Disordered Systems

Improving oral delivery of poorly soluble and poorly permeable molecules is very challenging and most often requires the use of metastable multi-component amorphous dispersions. Unique to amorphous solid dispersion systems is the fact that several polymers, multiple surfactants, and selection of drug loading (among other factors) makes optimization of a formulation exceedingly difficult. Innovator companies resort to screening solid dispersion systems with traditional solubility measurements of the active pharmaceutical ingredient (API) and via stability measurements in the solid state. For instance, dispersions of various compositions may be cast as films into well plates and the solid state analyzed via x-ray powder diffraction while, after introduction of aqueous media, the supernatent is assayed with HPLC. Despite universal recognition that dissolution of multi-component single phase systems and the structures which exist in solution (micelles, aggregates, precipitate originating from spinodal decomposition or crystallization, etc.) can significantly influence the performance of the API in vivo, approaches to measure said structures simply don’t exist in a formulation optimization environment. Further, although the literature is rich with information on the solid state stability of multi-component single phase systems, very little work has been done to understand the solution state behavior and, specifically, the influence that polymers, surfactants, and materials indogenous to the GI track may have on solution state concentration, partitioning of the API, and ultimately absorption. This work will aim to develop novel approaches to link solution state behavior to bioperformance. Specifically, approaches will be developed which enable a fundamental understanding of the thermodynamics and kinetics of dissolution in multicomponent systems, the resulting solution state structures, and ultimately the corresponding impact on the absorption process.