Fellowship for Matt Defrese: Mechanistic Investigations of Solvent-Based Processing of Single Phase Disordered Systems from Drug Delivery

Amorphous solid dispersions (ASDs) are an increasingly utilized oral dosage formulation strategy to address poor water solubility and/or slow dissolution rates commonly encountered with new chemical entities (NMEs) in modern drug development. In an ASD, a drug compound is intimately dispersed within a polymeric carrier to form a single homogenous disordered glassy phase. Unfortunately, this amorphous solid phase is a metastable state as drug loadings frequently exceed the expected thermodynamic miscibility and/or crystalline solubility limits of the drug in the polymer matrix. It is essential that the dispersion is designed to ensure a uniform drug distribution which remains physically stable over the product shelf life to retain the desired in-vitro and in-vivo performance. Bearing in mind these concerns, it is apparent that an accounting of the interplay of formulation and processing variables on ASD attributes is necessary for the preparation of a successful dispersion drug product. The two primary mechanisms for the mixing of drug and polymer materials in the preparation of ASDs can be classified as either melt or solvent based approaches. Spray drying is solvent-based method of particular interest due to its compatibility with thermally labile materials and favorable product attributes such as particle size, porosity, and wettability when compared to alternate approaches. In brief, the spray drying of amorphous dispersions may be understood as the introduction of a liquid feed containing dissolved solids into a hot gas drying chamber, at which point the feed is atomized into droplets with a high surface area to facilitate rapid solvent removal and subsequent particle formation. Despite this apparent simplicity, spray drying is viewed as a rather complex process with many critical effects on the finished product to consider in the design of the manufacturing process. The overall goal of this thesis project is to advance the mechanistic understandings of solvent-based processing of amorphous dispersion products and to interrogate opportunities for the field of ASDs to meet the demands of modern pharmaceutical manufacturing initiatives. This project will address these objectives in the following three specific aims: Specific Aim 1: Characterize the effects of polymer conformation as controlled by solvent selection on the miscibility, physical stability, and dissolution performance of spray dried dispersions (SDDs). The hypothesis is that the extent of drug-polymer interactions in the solution state is dictated by the polymer conformation which may then be frozen into the finished SDDs due to the rapid drying process. Specific Aim 2: Characterize the effects of droplet size and solvent choice on the homogeneity, physical stability, and dissolution of SDDs, including an assessment of the tendency for particle formation and phase separation via ternary phase diagrams. The hypothesis is that differences in the solubility and diffusion of drug and polymer components within the selected solvent system, along with changes in evaporation kinetics for varying droplet size, will induce chemical heterogeneity due to competing thermodynamic and kinetic processes in the drying process. Specific Aim 3: Explore belt drying applications of film casted materials as a viable industrial alternative for the solvent-based processing of amorphous dispersion systems. The rationale for this investigation is that belt drying is a well-established low temperature solvent removal unit operation which offers ease of material access to allow the ready implementation of modern PAT approaches for the control and measurement of finished product attributes.