Viscosity Behavior of High-Concentration Monoclonal Antibody Solutions: Correlation with Interaction Parameter and Electroviscous Effects

Abstract

The purpose of this work was to understand the viscosity behavior of high-concentration monoclonal antibody (mAb) solutions in a wide range of solution conditions and generate guidelines helpful to formulate products with manageable viscosity. The zeta potential and effective isoelectric point (pI) were determined from electrophoretic mobility measurements. High-frequency rheology studies characterized viscoelasticity at high concentrations. The interaction parameter (k(D) ) obtained from dynamic light scattering quantified intermolecular interactions. Circular dichroism characterized conformational stability upon change in solution pH. Except for mAb-1, all other mAb solutions were found to be more viscous at solution pHs closer to the molecular pI. For mAb-2, mAb-3, and mAb-10,the k(D) indicated intermolecular attractions at the pI, wherein the net molecular charge (Z) was zero, whereas repulsions dominated at pHs away from the pI. At the pI, Z and, hence, the charge-induced repulsions are minimal, whereas the charge distribution becomes most conspicuous. The resulting dominance of nonspecific attractive interactions at the pI increases the self-association or aggregation behavior of protein molecules, leading to a higher viscosity at the pI. mAb-1 is an exception to this general behavior. The k(D) could serve as a qualitative screening tool to predict high-concentration viscosity behavior, whereas the correlation with net charge was inconsistent. A higher negative k(D) generally resulted in a more viscous solution at high concentrations; however, direct quantitative assessment was not possible.