The influence of the solvent and intermolecular interactions on the physical structure of spray dried amorphous solid dispersions

Abstract

It was the overall aim of this thesis to improve our comprehension of the influence of two key factors on the physical structure, phase behavior and other properties of spray dried ASDs. The effect of the organic solvent, used during spray drying, and the availability of different API and polymer H-bond donor and acceptor groups was assessed. To this end, a series of ASDs were spray dried, from either different organic solvents, or containing APIs and polymers with varying H-bonding properties. In the introduction, the use and benefits of amorphous solid dispersions were first placed against the background of the current pharmaceutical landscape. The perks, but also the challenges, of oral drug delivery were explained, especially regarding the effect of drug solubility and permeability on the oral bioavailability of the drugs. Lipinski’s rule of five and the different classification systems (like the BCS) using API solubility and permeability were introduced. Considering the increasing amount of poorly soluble compounds in the pipelines of pharmaceutical companies, the need for solubility enhancing strategies was explained. In this regard, the steps in the dissolution process were described and it was highlighted which aspects of this process were impacted by different enabling strategies. The solubility advantage of the amorphous form of an API over the crystalline state was highlighted, and amorphous solid dispersions were introduced as an approach to overcome the thermodynamic instability of pure amorphous drugs. The role of the polymer and its influence on the physical stability and drug release behavior was briefly addressed, and the importance of drug-polymer intermolecular interactions was explained. A theoretical overview of intermolecular interactions was given, followed by further elaborating on the effect of the interactions on the physical stability and dissolution characteristics. As an introduction to spray drying, an overview of the different ASD manufacturing techniques was given, leading up to an explanation of the spray drying process and the different factors that influence it. The introduction was concluded with an overview of the solid-state characterization techniques that were applied in this work, together with the methods used to characterize the stability and pharmaceutical performance of the ASDs.