Viscosity behavior of high-concentration monoclonal antibody solutions: Correlation with interaction parameter and electroviscous effects

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 (kD) 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 kD 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 kD could serve as a qualitative screening tool to predict high-concentration viscosity behavior, whereas the correlation with net charge was inconsistent. A higher negative kD generally resulted in a more viscous solution at high concentrations; however, direct quantitative assessment was not possible. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:9981011, 2012