High shear rheology and anisotropy in concentrated solutions of monoclonal antibodies. Issue 8 (19th July 2013)

• Record Type: Journal Article
• Authors: Zarraga, Isidro E.; Taing, Rosalynn; Zarzar, Jonathan; Luoma, Jacob; Hsiung, Jenny; Patel, Ankit; Lim, Fredric J.
• Is Part Of: Journal of pharmaceutical sciences. Volume 102:Issue 8(2013:Aug.)
• Page Start: 2538
• Page End: 2549
• Publication Date: 2013-07-19
• Subjects: proteins -- antibody -- viscosity -- injectables -- formulation -- colloid -- relaxation time -- concentrated solutions -- anisotropy -- cluster; Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.23647
• Languages: English
• ISSNs: 0022-3549

Abstract

Abstract: The high shear rheology of three concentrated solutions of immunoglobulin G1 monoclonal antibodies (mAb1, mAb2, and mAb3), differing only in their complementarity determining regions, was characterized using rotary and capillary rheometry. The more viscous solutions (mAb1 and mAb3) showed non‐Newtonian behavior at high shear rates exhibiting both shear thinning and appreciable normal stress differences (NSDs) in the shear rate range γ = 10 to 10 4 s −1 . The rheograms were retraced after γ is increased and decreased, suggesting reversible self‐associations under shear. In contrast, mAb2 solutions showed Newtonian behavior up to γ = 6 × 10 4 s −1 . The critical shear stress τ c, corresponding to the onset of the reduction in the viscosity η, is a measure of mAb equilibrium cluster strength and increased rapidly with concentration for the high viscosity mAb solutions above 100 mg/mL. In addition, decreasing the temperature from 20°C to 5°C increased η at low γ, but shear‐thinning was enhanced and its onset occurred at a lower γc . Using an Arrhenius model η = A exp( E a / kT ), the activation energy for viscous flow E a was found to decrease for mAb1 solutions as γ was increased from 10 to 10 4 s −1, suggesting mAb cluster disruption or rearrangement under shear. In contrast, for mAb2, this E a remained constant in the γ range. Finally, mAb1 and mAb3 solutions showed appreciable NSDs, with their N 1 > 0 scaling linearly with γ in the range 10 3 to 10 4 s −1, whereas their | N 2 / N 1 | was less than 0.25 in this region. These suggest anisotropy and deformation of their solution microstructure toward the extensional quadrant of the flow at high γ . In contrast, the NSDs for mAb2 were close to zero indicating that the solution microstructure under shear is practically isotropic. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2538–2549, 2013