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Nanobubbles in Reconstituted Lyophilized Formulations: Interaction With Proteins and Mechanism of Formation.

Authors
  • Snell, Jared R1
  • Kumar, N S Krishna2
  • Suryanarayanan, Raj2
  • Randolph, Theodore W3
  • 1 Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309.
  • 2 Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455.
  • 3 Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80309. Electronic address: [email protected]o.edu.
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jan 01, 2020
Volume
109
Issue
1
Pages
284–292
Identifiers
DOI: 10.1016/j.xphs.2019.05.005
PMID: 31095959
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Reconstitution of lyophilized disaccharide formulations results in the formation of nanosized air bubbles that persist in suspension for weeks. If proteins are present, interactions with nanobubbles may cause loss of monomeric protein and formation of subvisible particles. The goals of this work are to determine the mechanism(s) by which nanobubbles form in reconstituted lyophilized formulations and to develop strategies for reducing nanobubble generation. We hypothesize that nanobubbles are created from nanosized gas pockets within lyophilized solids, which become bubbles when the surrounding matrix is dissolved away during reconstitution. Nanosized voids may originate from small ice crystals formed within the concentrated liquid during freezing that subsequently sublime during drying. Nanobubble concentrations are correlated with the extent of mannitol crystallization during freezing. Nanosized ice crystals, induced by the release of water during mannitol crystallization, were responsible for nanobubble formation. The presence of trehalose or sucrose, in formulations with low mannitol concentrations, inhibited excipient crystallization during lyophilization and reduced nanobubble levels following reconstitution. Our results show a correlation between nanobubble formation and concentrations of insoluble IL-1ra aggregates, suggesting that minimizing nanobubble generation may be an effective strategy for reducing protein aggregation following reconstitution. Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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