TY - JOUR

T1 - Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals

T2 - Water Clusters Hypothesis

AU - Shalaev, Evgenyi

AU - Soper, Alan

AU - Zeitler, J. Axel

AU - Ohtake, Satoshi

AU - Roberts, Christopher J.

AU - Pikal, Michael J.

AU - Wu, Ke

AU - Boldyreva, Elena

N1 - Copyright © 2019 Allergan, PLC. Published by Elsevier Inc. All rights reserved.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - amorphism

KW - chemical stability

KW - deamidation

KW - freeze-drying

KW - lyophilization

KW - protein formulation(s)

KW - solid-state

KW - stability

KW - structure

KW - water sorption

KW - GLASS TRANSITIONS

KW - LYOPHILIZED SOLIDS

KW - LIQUID TRANSITION

KW - PROTEIN-STRUCTURE

KW - MOLECULAR MOBILITY

KW - X-RAY-DIFFRACTION

KW - HYDROGEN/DEUTERIUM EXCHANGE

KW - MONOCLONAL-ANTIBODY

KW - GLUCOSE SOLUTIONS

KW - HYDROGEN-DEUTERIUM EXCHANGE

KW - Temperature

KW - Freezing

KW - Chemical Phenomena

KW - Solutions/chemistry

KW - Freeze Drying/methods

KW - Drug Stability

KW - Water/chemistry

KW - Hydrolysis

KW - Chemistry, Pharmaceutical/methods

UR - http://www.scopus.com/inward/record.url?scp=85054190771&partnerID=8YFLogxK

U2 - 10.1016/j.xphs.2018.07.018

DO - 10.1016/j.xphs.2018.07.018

M3 - Short survey

C2 - 30055227

AN - SCOPUS:85054190771

VL - 108

SP - 36

EP - 49

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 1

ER -