title: 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.
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
authors: Sandeep
authors: S
authors: Yadav
authors: Steven J
authors: SJ
authors: Shire
authors: Devendra S
authors: DS
authors: Kalonia
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002942:Circular Dichroism; D004586:Electrophoresis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000737:chemistry*; D007526:Isoelectric Point; D008027:Light; D012212:Rheology; D012542:Scattering, Radiation; D014783:Viscosity
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G