Dissertations and Theses

Date of Award


Document Type



Chemical Engineering

First Advisor

Raymond S. Tu

Second Advisor

Charles Maldarelli


monoclonal antibody, excipient, polysorbate 80, air/water interface, competitive adsorption, X-ray reflectivity, pendant bubble tensiometry, homology modeling, orientation


Monoclonal antibodies (mAbs) have become a leading candidate for oncological therapeutics due to their unparalleled selectivity. Monoclonal antibodies are amphiphilic, containing polar and nonpolar amino acid residues on their biomolecular surfaces. Their amphiphilic nature drives mAbs to strongly adsorb to air/water interfaces. Interfacial adsorption presents a central problem to the production and use of antibody-based pharmaceuticals. Air/water interfaces are frequently generated during the manufacture (filtration and chromatography) and production (freezing, thawing, filtration and filling) of the drug product. Moreover, air/water interfaces are present during the storage, transportation and administration of the therapeutics. When an air/water interface is created, the antibodies adsorb and expose their hydrophobic residues to the gas phase leading to irreversible adsorption, partial unfolding, interfacial aggregation, and recruitment of additional proteins from the solution phase. Depletion from solution of the therapeutically effective, native form of the mAb biologic leads inaccurate dosage and shortened shelf life. The pharmaceutical industry uses multicomponent formulations to circumvent adsorption issues, adding ‘inert’ FDA approved surfactants to the mAb solutions to populate the interface and thereby prevent the adsorption of the antibody (Fig. 1). However, the mechanism of the adsorption behavior of mAbs in the presence of surfactant is still an open scientific question and understanding the mechanism of adsorption is critical to the production and administration of the next generation mAb-based pharmaceuticals. This work elucidates the interfacial behavior of the multicomponent system at the molecular level.

This dissertation will focus on the three key aspects of mAb-surfactant adsorption. The first part is based on the transport controlled competitive dynamics between surfactant (Polysorbate 80) and two different mAbs. Pendant bubble tensiometry and X-ray reflectivity (XR) are used to quantify the rate at which the molecules “race” to the interface. The experiments show a phase space in mAb/surfactant concentration where co-adsorption of both the mAbs and surfactants occur at the air/water interface (Fig. 1a) and a phase space where surfactant dominates. A key finding is that the competitive behavior of the mAbs and the surfactants for the interface correlates with surface activity of the mAb. Additionally, this work presents a clear elucidation of the transport mechanisms underlying the armoring of the interface with the surfactants to inhibit mAb adsorption to the surface and sub-surface domain.

The second aspect of this work is to understand the dynamic orientational change in the adsorbed mAb as a function of concentration at the air/water interface using XR coupled with homology modeling (Fig. 1b,c). The confined “Y” shaped structure of mAbs, provides a contrast in the adsorption behavior of mAbs to globular proteins. The effect of the surface packing and unfolding of the mAbs at the interface will be addressed with the emphasis on how this affects the formulation of the drug product. Overall, the experiments and the homology modeling provide a complex landscape of orientational phase space during different stages of adsorption of mAbs at the air/water interface. This information about the complex phase space can be of value in designing methodologies for transferring and administrating the antibodies with maximal dosage.

Lastly, a theoretical model is developed to identify the “critical” surfactant concentration that needs to be present in therapeutic formulations to protect the air/water interface from mAb adsorption (Fig. 1d). This is based on the theoretical modeling of the kinetic adsorption mechanism for different surface-active mAbs and a diffusion-controlled adsorption for surfactants guided by our findings described above. A phase diagram that defines the surfactant dominant regime for four different hydrophobic mAbs will be presented.

In summary, this thesis develops experimental tools and a transport analysis to quantify critical parameters important to the competitive adsorption of mAbs and surfactants to the air/water interface. The work presented here constructs a general model to predict concentration regimes in which surfactant protects the interface from adsorption. Taken together, this study is intended to help the pharmaceutical industry to accelerate the stability of the therapeutics during the manufacturing, storage and delivery via intravenous injection of the drugs.


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