Freezing of Aqueous Solutions and Chemical Stability of Amorphous Pharmaceuticals: Water Clusters Hypothesis | Sciact - CRIS-система Института катализа

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

Журнал

Journal of Pharmaceutical Sciences
ISSN: 0022-3549 , E-ISSN: 1520-6017

Вых. Данные

Год: 2019, Том: 108, Номер: 1, Страницы: 36-49 Страниц : 14 DOI: 10.1016/j.xphs.2018.07.018

Ключевые слова

amorphism, chemical stability, deamidation, freeze-drying, lyophilization, protein formulation(s), solid-state, stability, structure, water sorption

Авторы

Shalaev Evgenyi ¹ , Soper Alan ² , Zeitler J Axel ³ , Ohtake Satoshi ⁴ , Roberts Christopher J. ⁵ , Pikal Michael J. ⁶ , Wu Ke ¹ , Boldyreva Elena ^7,8

Организации

1	Pharmaceutical Development, Allergan plc, Irvine, CA 92612, USA
2	ISIS Facility, STFC Rutherford Appleton Laboratory, Harwell Campus, Didcot, Oxon OX11 OQX, United Kingdom
3	Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS
4	Pfizer BioTherapeutics Pharmaceutical Sciences, Chesterfield, MO, USA
5	Department of Chemical Engineering, University of Delaware, Newark, DE 19716, USA
6	Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, CT 06269 USA
7	Novosibirsk State University, Pirogova Street 2, Novosibirsk, 630090, Russian Federation
8	Boreskov Institute of Catalysis SB RAS, Novosibirsk, 630090, Russian Federation

Информация о финансировании (1)

Engineering and Physical Sciences Research Council

EP/N022769/1

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.

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 CAPlus PMID OpenAlex

Полный текст от издателя

Поступила в редакцию:	8 мая 2018 г.
Принята к публикации:	17 июл. 2018 г.
Опубликована online:	25 июл. 2018 г.
Опубликована в печати:	1 янв. 2019 г.

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

БД	Цитирований
Scopus	25
Web of science	23
РИНЦ	20
OpenAlex	46