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Moisture-induced aggregation of lyophilized proteins in the solid state
W R Liu1, R Langer, A M Klibanov
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Biotechnology and Bioengineering
|January 20, 1991
Summary
Moisture causes pharmaceutical proteins like albumin to aggregate and lose solubility through disulfide bond formation. This solid-state aggregation can be minimized by controlling moisture and using specific formulation strategies.
Area of Science:
- Pharmaceutical Science
- Protein Chemistry
- Biochemistry
Background:
- Protein aggregation is a critical issue in the storage and delivery of pharmaceutical proteins.
- Moisture is a key factor that can induce protein aggregation in lyophilized formulations.
Purpose of the Study:
- To elucidate the mechanism of moisture-induced protein aggregation in lyophilized pharmaceutical proteins.
- To investigate factors influencing solid-state protein aggregation and identify strategies for minimization.
Main Methods:
- A model system using lyophilized bovine serum albumin (BSA) was developed to study moisture-induced aggregation.
- Investigated the effect of moisture levels, atmosphere, additives, temperature, and protein history on aggregation.
- Studied aggregation in other lyophilized proteins: ovalbumin, glucose oxidase, and beta-lactoglobulin.
Main Results:
- Lyophilized BSA rapidly loses solubility upon wetting due to intermolecular disulfide bond formation via thiol-disulfide interchange.
- Solid-state aggregation was observed in ovalbumin, glucose oxidase, and beta-lactoglobulin, primarily caused by thiol-disulfide interchange.
- Aggregation extent depends on moisture, atmosphere, additives, temperature, and protein powder history.
Conclusions:
- Moisture-induced solid-state aggregation in lyophilized proteins is primarily mediated by thiol-disulfide interchange.
- Strategies to minimize aggregation include lyophilizing from acidic solutions, adding inorganic salts or polymers, and controlling moisture content.
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