Abstract: Molecular mobility has been invoked to explain physical and chemical stability of diverse pharmaceutical and biopharmaceutical systems, including, e.g., amorphous dispersions of drug molecules in polymeric matrix, various freeze-dried formulations, and frozen biological drug substances. While the molecular mobility approach has been credited with major advances in creating a scientific basis for development and stabilization of pharmaceuticals and biopharmaceuticals, it has been increasingly clear that it represents only partial description of the underlying fundamental principles. In this paper, an alternative approach is proposed to address two key questions, i.e., (a) the existence of unfrozen water (i.e., partial or complete freezing inhibition) in aqueous solutions at subzero temperatures, and (b) the role of water in the 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, whereas the chemical (in)stability is proposed to be directly related to the role of water clusters in proton transfer, which is the key elemental reaction in many chemical processes. The “inhibition of freezing by confinement” hypothesis is based on the recent studies of water structure in aqueous solutions and glasses, while also taking into account the dynamic properties. In recent studies of sorbitol / water mixtures, in particular, wide-angle neutron scattering investigation revealed the presence of nanoscaled water clusters surrounded by the sorbitol matrix. Furthermore, decoupling of mobility of the water clusters from that of the matrix was detected by terahertz spectroscopy and thermally stimulated current method. To address the water role in chemical instability of freeze-dried materials and other amorphous solids, it has been proposed that water clusters serve as a catalyst in such common degradation processes as hydrolysis and deamidation, by enabling proton transfer via the Grotthuss-like mechanism. It has also been suggested that, while proton transfer is expected to be decoupled from the global mobility, local (fast) non-cooperative processes, such as beta-relaxation and Johari-Goldstein relaxation, might be related to proton transfer and therefore to chemical degradation.

Cite: Shalaev E. , Soper A. , Zeitler J.A. , Ohtake S. , Roberts C.J. , Pikal M.J. , Wu K. , Boldyreva E.
Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals: Water Clusters Hypothesis
Journal of Pharmaceutical Sciences. 2019. V.108. N1. P.36-49. DOI: 10.1016/j.xphs.2018.07.018 WOS Scopus РИНЦ AN PMID OpenAlex

Files: Full text from publisher

Dates:

Submitted:	May 8, 2018
Accepted:	Jul 17, 2018
Published online:	Jul 25, 2018
Published print:	Jan 1, 2019

Identifiers:

Web of science:	WOS:000456898100007
Scopus:	2-s2.0-85054190771
Elibrary:	38632279
Chemical Abstracts:	2018:1856531
PMID:	30055227
OpenAlex:	W2884604545

Citing:

DB	Citing
Scopus	25
Web of science	23
Elibrary	20
OpenAlex	46

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