Effect of molecular interactions on properties of amorphous solid dispersions




Meng, Fan

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Amorphous solid dispersions have been widely applied to improve the oral bioavailability of BCS Class II and Class IV compounds by increasing their kinetic solubility and dissolution rate. However, maintaining the amorphous state of drug substances in amorphous solid dispersions is a challenge, whereby intermolecular interactions formed between the drug molecule and the polymer are thought to be of critical importance. A number of studies have been published to demonstrate the effect of drug-polymer intermolecular interaction on physicochemical properties of amorphous solid dispersions. In most of the cases, stronger drug-polymer interactions can more effectively disrupt molecular self-assembly of the drug in the dispersion and therefore lead to a relatively more stable amorphous solid dispersion system with a higher drug loading. Despite their success, there are still essential needs to mechanistically understand the role of all kinds of molecular interactions in amorphous solid dispersion systems. Within the scope of this dissertation, three types of molecular interactions including drug-drug interaction, drug-polymer interaction and polymer-polymer interaction in amorphous solid dispersion systems were studied. In Chapter 1, the molecular interactions in amorphous solid dispersions were discussed from thermodynamic perspective. The current understanding of the impact of molecular interactions on process conditions and amorphous solid dispersion properties was also reviewed. In Chapter 2, we demonstrated the molecular level mechanism of rafoxanide self- association in aqueous media. The effect of self-association on physichochemical properties of rafoxanide was thoroughly investigated. In Chapter 3, we studied the molecular interactions between rafoxanide and povidone in different co-solvents. The difference in molecular interaction in different co-solvents is critical to the solvent selection of spray drying process. We also illustrated the impact of rafoxanide self-association on rafoxanide-povidone interaction in different environments. In Chapter 4, we compared the solid-state properties, dissolution behavior and physical stability of rafoxanide-povidone amorphous solid dispersions with different level of molecular interactions. The differences were further explained. In Chapter 5, we claimed a novel pH mediated control-precipitation method based on interpolymer complexation. The effect of interpolymer complexation on properties of itraconazole amorphous solid dispersions was also investigated. In Appendix A, we studied the effect of surfactant on drug-polymer miscibility, drug dissolution and physical stability of celecoxib amorphous solid dispersion. This study provides supplemental information on surfactant self-association during dissolution and its impact on drug release


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