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Updated: Jul 15, 2026

A Microfluidic Approach for the Study of Ice and Clathrate Hydrate Crystallization
Published on: August 18, 2022
Inhibition of mannitol crystallization in frozen solutions by sodium phosphates and citrates
Ken-ichi Izutsu1, Chikako Yomota, Nobuo Aoyagi
1National Institute of Health Sciences, Tokyo, Japan. Izutsu@nihs.go.jp
Abstract:
Effects of co-solutes on the physical property of mannitol and sorbitol in frozen solutions and freeze-dried solids were studied as a model of controlling component crystallinity in pharmaceutical formulations. A frozen mannitol solution (500 mM) showed a eutectic crystallization exotherm at -22.8 degrees C, whereas sorbitol remained amorphous in the freeze-concentrated fraction in the thermal scan. Various inorganic salts reduced the eutectic mannitol crystallization peak. Trisodium and tripotassium phosphates or citrates prevented the mannitol crystallization at much lower concentrations than other salts. They also raised transition temperatures of the frozen mannitol and sorbitol solutions (T(g)': glass transition temperature of maximally freeze-concentrated amorphous phase). Crystallization of some salts (e.g., NaCl) induced crystallization of mannitol at above certain salt concentration ratios. Thermal and near-infrared analyses of cooled-melt amorphous sorbitol solids indicated increased intermolecular hydrogen-bonding in the presence of trisodium phosphate. The sodium phosphates and citrates should prevent crystallization of mannitol in frozen solutions and freeze-dried solids by the intense hydrogen-bonding and reduced molecular mobility in the amorphous phase.
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