Pharmaceutical Research

, Volume 34, Issue 1, pp 193–207 | Cite as

Contrasting the Influence of Cationic Amino Acids on the Viscosity and Stability of a Highly Concentrated Monoclonal Antibody

  • Barton J. Dear
  • Jessica J. Hung
  • Thomas M. Truskett
  • Keith P. JohnstonEmail author
Research Paper



To explain the effects of cationic amino acids and other co-solutes on the viscosity, stability and protein-protein interactions (PPI) of highly concentrated (≥200 mg/ml) monoclonal antibody (mAb) solutions to advance subcutaneous injection.


The viscosities of ≥200 mg/ml mAb1 solutions with various co-solutes and pH were measured by capillary rheometry in some cases up to 70,000 s−1. The viscosities are analyzed in terms of dilute PPI characterized by diffusion interaction parameters (k D ) from dynamic light scattering (DLS). MAb stability was measured by turbidity and size exclusion chromatography (SEC) after 4 weeks of 40°C storage.


Viscosity reductions were achieved by reducing the pH, or adding histidine, arginine, imidazole or camphorsulfonic acid, each of which contains a hydrophobic moiety. The addition of inorganic electrolytes or neutral osmolytes only weakly affected viscosity. Systems with reduced viscosities also tended to be Newtonian, while more viscous systems were shear thinning.


Viscosity reduction down to 20 cP at 220 mg/ml mAb1 was achieved with co-solutes that are both charged and contain a hydrophobic interaction domain for sufficient binding to the protein surface. These reductions are related to the DLS diffusion interaction parameter, k D , only after normalization to remove the effect of charge screening. Shear rate profiles demonstrate that select co-solutes reduce protein network formation.


antibody arginine histidine rheology viscosity 



Centrifugal filtration


Camphorsulfonic acid


Dynamic light scattering






Diffusion interaction parameter


Lyophilization dilution


Monoclonal antibody


Isoelectric point


Protein-protein interactions




Inherent viscosity


Acknowledgments and Disclosures

We acknowledge support from AbbVie, the National Science Foundation (12474795) and the Welch Foundation (KPJ F-1319 and TMT F-1696). We thank Christian Reid for useful comments during the course of this work.

Supplementary material

11095_2016_2055_MOESM1_ESM.docx (1.7 mb)
ESM 1 (DOCX 1787 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Barton J. Dear
    • 1
  • Jessica J. Hung
    • 1
  • Thomas M. Truskett
    • 1
  • Keith P. Johnston
    • 1
    Email author
  1. 1.McKetta Department of Chemical EngineeringThe University of Texas at AustinAustinUSA

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