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Non-Aqueous Suspensions of Antibodies are Much Less Viscous Than Equally Concentrated Aqueous Solutions

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Abstract

Purpose

The aim of this study was to markedly lower the viscosities of highly concentrated protein, in particular antibody, formulations. An effective approach elaborated herein for γ-globulin and a monoclonal antibody is to replace aqueous solutions with equimolar suspensions in neat organic solvents.

Methods

Viscosities of aqueous solutions and non-aqueous suspensions of the model protein bovine γ-globulin and a murine monoclonal antibody were examined under a variety of experimental conditions. In addition, protein particle sizes were measured using dynamic light scattering and light microscopy.

Results

Concentrated suspensions of amorphous γ-globulin powders (up to 300 mg/mL, composed of multi-micron-sized particles) in absolute ethanol and a number of other organic solvents were found to have viscosities up to 38 times lower than the corresponding aqueous solutions. Monoclonal antibody follows the same general trend. Additionally, the higher the protein concentration and lower the temperature, the greater the viscosity benefit of a suspension over a solution.

Conclusions

The viscosities of concentrated γ-globulin and monoclonal antibody suspensions in organic solvents are drastically reduced compared to the corresponding aqueous solutions; the magnitude of this reduction depends on the solvent, particularly its hydrogen-bonding properties.

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Abbreviations

MAb:

Monoclonal antibody

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Acknowledgments and Disclosures

This study was financially supported by the Sanofi-Aventis pharmaceutical company. We also thank the MIT Biophysical Instrumentation Facility for the Study of Complex Macromolecular Systems (funded by NSF-0070319 and NIH GM68762 instrumentation grants).

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Authors and Affiliations

  1. Department of Chemistry, Massachusetts Institute of Technology, Building 56-579, Cambridge, Massachusetts, 02139, USA

    Charudharshini Srinivasan & Alisha K. Weight

  2. Biologics Center, Formulation Development, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst Bldg. H770 Room R312, 65926, Frankfurt am Main, Germany

    Till Bussemer

  3. Departments of Chemistry and Biological Engineering, Massachusetts Institute of Technology, Building 56-579, Cambridge, Massachusetts, 02139, USA

    Alexander M. Klibanov

Authors
  1. Charudharshini Srinivasan
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  2. Alisha K. Weight
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  3. Till Bussemer
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  4. Alexander M. Klibanov
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Corresponding author

Correspondence to Alexander M. Klibanov.

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Srinivasan, C., Weight, A.K., Bussemer, T. et al. Non-Aqueous Suspensions of Antibodies are Much Less Viscous Than Equally Concentrated Aqueous Solutions. Pharm Res 30, 1749–1757 (2013). https://doi.org/10.1007/s11095-013-1017-4

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  • DOI: https://doi.org/10.1007/s11095-013-1017-4

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