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Open access publications by faculty, postdocs, and graduate students in the Department of Chemical and Biomolecular Engineering
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Browsing Open Access Publications by Author "Allen, David P."
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Item Surface-mediated spontaneous emulsification of the acylated peptide semaglutide(Proceedings of the National Academy of Sciences, 2024-01-16) Li, Qi; Tangry, Vasudev; Allen, David P.; Seibert, Kevin D.; Qian, Ken K.; Wagner, Norman J.Significance We identify the fundamental mechanisms of an undesired instability known as “ouzo” formation in a class of therapeutics used for treating type 2 diabetes and obesity. Spontaneous emulsification in solutions of acylated peptides in the presence of hydrophobic surfaces is elucidated as a function of physico-chemical conditions and surface hydrophobicity as characterized by Hansen solubility parameters. Quantitative prediction of the colloidal size is demonstrated using the classical Rayleigh theory, while formation rates reduce to a master curve dependent on the surface hydrophobicity and stirring rate. We demonstrate that colloidal physics and molecular thermodynamics provide quantitative predictions of the colloidal droplet size and qualitatively rank formation rates, thereby improving our understanding of this important class of therapeutic molecules. Abstract Acylated peptides composed of glucagon-like peptide-1 receptor agonists modified with a fatty acid side chain are an important class of therapeutics for type 2 diabetes and obesity but are susceptible to an unusual physical instability in the presence of hydrophobic surfaces, i.e., spontaneous emulsification, also known as ouzo formation in practice. In this work, light scattering, small-angle X-ray scattering, and circular dichroism measurements are used to characterize the physical properties of the semaglutide colloidal phase, including size distribution, shape, secondary structure, internal structure, and internal composition, as a function of solution physico-chemical conditions. The existence and size of the colloids formed are successfully predicted by a classical Rayleigh model, which identifies the parameters controlling their size and formation. Colloid formation is found to be catalyzed by hydrophobic surfaces, and formation rates are modeled as an autocatalytic reaction, enabling the formation of a master curve for various surfaces that elucidates the mechanism. Surfaces differ due to differences in surface wettability, which can be correlated with Hansen solubility parameters. This work provides insights into this unusual colloidal phenomenon and guides the peptide synthesis process and drug product formulation in the pharmaceutical industry.