Viscosity and solubility are one of the most important physical properties integral to the manufacturing and use of nearly every consumer product. The formulation of materials ranging from toothpastes to therapeutic drugs must be carefully optimized to maintain the structural intactness and flow characteristics necessary for the application of interest. Therefore, accurately modeling both of these properties as a function of solution conditions can serve as a powerful method to engineer a wide range of materials. A major issue faced during the manufacturing and administration of therapeutic protein formulations is the undesirable high viscosity. Numerous models have been developed to predict the viscosity of protein solutions but many fall short of the task due to an incomplete fundamental understanding of the underlying protein-protein interactions. Can an accurate depiction of the protein-protein interactions be the missing key to successfully model the viscosity of protein solutions? It is the need for an answer to this question that led to the research presented in this dissertation. The effect of the microscopic particle-particle interactions on the macroscopic solution viscosity is understood in this work by building a simple hard sphere colloidal model. Employing a particular combination of short-ranged attractions and long-ranged repulsions (SALR interactions), the zero-shear viscosity and the osmotic second virial coefficient for a dilute colloidal suspension were computed as a function of the attractions and the repulsions strength. A major finding showed that the long-ranged repulsions (LR) had a dual action on the suspension zero-shear viscosity. The long-ranged repulsion interactions (LR) acting alone always increased the viscosity but when combined with the short-ranged attractions (SALR) reduced or lowered the viscosity of the system. The analytical approximations were written to deduce the coupling mechanism of the interactions and their effect on reducing the suspension viscosity. This new knowledge shall be very helpful for designing protein formulations with low viscosity.
With this novel insight, the simple hard sphere colloidal model with SALR interactions was applied towards predicting the viscosity of dilute to semi-dilute protein solutions. The comparison was performed for a globular shaped albumin and Y shaped therapeutic monoclonal antibody that were not explained by the previous colloidal models. The model predictions showed that it was the coupling between attractions and repulsions that gave rise to the observed experimental trends in solution viscosity as a function of pH, concentration, and ionic strength. The model was subsequently applied to assess the viscosity risk of a large panel of antibody candidates chosen for therapeutic development. Using the measurements of two high throughput in-vitro early-stage screening assays, the model acted as an attractive tool for predicting the developability assessment for antibodies.
The thesis also touches upon the influence of SALR interactions on the protein solubility. It does so by modeling the synergistic precipitation of bovine serum albumin from its solution by using a combination of two precipitants. The mechanism of synergy in the solubility-reducing action of precipitants is not clear and has been a standing problem in the field of protein purification by precipitation. The work shows that the synergy occurs due to the coupling between the microscopic protein interactions.
The belief is that this dissertation shall propel fellow scientists and engineers to think about the macromolecular solution properties in terms of the particle interactions happening at the microscopic scale.;
August 2022; School of Engineering
Dept. of Chemical and Biological Engineering;
Rensselaer Polytechnic Institute, Troy, NY
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