A Molecular Perspective for the Optimization of Polymers for Amorphous Solid Dispersions
Polymers are often used to stabilize amorphous drug formulations enabling the maintenance of high drug supersaturations. However, the molecular mechanism of stabilization is unclear, making the rational design of new polymers challenging. This research has focused on understanding the effectiveness of polymers to inhibit drug crystallization using experimental and computational modeling approaches. This thesis has six sections. The first section reviews the pharmaceutical significance of amorphous solid dispersions. The second section describes a study to evaluate the phase behavior of supersaturated drug solutions of telaprevir, a compound that undergoes glass-liquid phase separation when the amorphous solubility is exceeded. The third section presents a study of the crystallization inhibition properties of commercial and newly synthesized polymers with various functional groups, as well as computational modeling to understand variations in the polymer intramolecular interactions. In the fourth section, cellulose polymers with carboxylic acids are explored for a group of nine different drugs; and drug-polymer interactions are analyzed through simulations. The fifth section describes a study of the performance of amorphous solid dispersions of telaprevir and commercial polymers by performing dissolution and diffusion measurements. The final chapter details an exploration of a group of nine newly synthesized polymers to show how variations in the functional groups and the starting cellulose material influence the performance of the amorphous formulation. Overall, this dissertation provides insight into the optimization of polymer properties such as chemical functionality and polymer solubility, using the guidance from molecular modeling to understand solution-interactions, with the end goal of contributing to the rational design of new polymers that can be employed to stabilize amorphous solid dispersions.
Taylor, Purdue University.
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