Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals: Water Clusters Hypothesis

Evgenyi Shalaev, Alan Soper, J. Axel Zeitler, Satoshi Ohtake, Christopher J. Roberts, Michael J. Pikal, Ke Wu, Elena Boldyreva

Research output: Contribution to journalShort surveypeer-review

6 Citations (Scopus)

Abstract

Molecular mobility has been traditionally invoked to explain physical and chemical stability of diverse pharmaceutical systems. Although the molecular mobility concept has been credited with creating a scientific basis for stabilization of amorphous pharmaceuticals and biopharmaceuticals, it has become increasingly clear that this approach represents only a partial description of the underlying fundamental principles. An additional mechanism is proposed herein to address 2 key questions: (1) the existence of unfrozen water (i.e., partial or complete freezing inhibition) in aqueous solutions at subzero temperatures and (2) the role of water in the chemical stability of amorphous pharmaceuticals. These apparently distant phenomena are linked via the concept of water clusters. In particular, freezing inhibition is associated with the confinement of water clusters in a solidified matrix of an amorphous solute, with nanoscaled water clusters being observed in aqueous glasses using wide-angle neutron scattering. The chemical instability is suggested to be directly related to the catalysis of proton transfer by water clusters, considering that proton transfer is the key elementary reaction in many chemical processes, including such common reactions as hydrolysis and deamidation.

Original languageEnglish
Pages (from-to)36-49
Number of pages14
JournalJournal of Pharmaceutical Sciences
Volume108
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • amorphism
  • chemical stability
  • deamidation
  • freeze-drying
  • lyophilization
  • protein formulation(s)
  • solid-state
  • stability
  • structure
  • water sorption
  • GLASS TRANSITIONS
  • LYOPHILIZED SOLIDS
  • LIQUID TRANSITION
  • PROTEIN-STRUCTURE
  • MOLECULAR MOBILITY
  • X-RAY-DIFFRACTION
  • HYDROGEN/DEUTERIUM EXCHANGE
  • MONOCLONAL-ANTIBODY
  • GLUCOSE SOLUTIONS
  • HYDROGEN-DEUTERIUM EXCHANGE
  • Temperature
  • Freezing
  • Chemical Phenomena
  • Solutions/chemistry
  • Freeze Drying/methods
  • Drug Stability
  • Water/chemistry
  • Hydrolysis
  • Chemistry, Pharmaceutical/methods

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