Mannitol crystallization at sub-zero temperatures: time/temperature-resolved synchrotron x-ray diffraction study and the phase diagram

Miguel A Rodrigues, Pedro Rego, Vitor Geraldes, Lauren E. Connor, Iain D. H. Oswald, Michael Sztucki, Evgenyi Shalaev

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Abstract

Mannitol, a common pharmaceutical ingredient, exhibits complex polymorphism even in simple binary mannitol/water mixtures, with four crystalline forms observed. In this investigation, time/temperature-resolved synchrotron X-ray diffraction measurements are performed during freezing and thawing of mannitol/water mixtures. Mannitol crystallization depends strongly on the cooling rate and is initiated during cooling, if the cooling rate is lower than the critical cooling rate; otherwise, mannitol remains amorphous during freezing and crystallizes during subsequent heating above -30 °C. A temperature-composition phase diagram is constructed, reflecting eutectic and peritectic points and lower-temperature equilibria involving mannitol hemihydrate, hexagonal ice, and β-mannitol. Comparison of the experimental data with the phase diagram reveals that the mannitol crystallization behavior does not follow the equilibrium but appears to obey the Ostwald crystallization rule. Novel insights on equilibrium and kinetics phase relationships in mannitol/water systems could lead to improved formulations and manufacturing processes for pharmaceuticals and biopharmaceuticals.

Original languageEnglish
Pages (from-to)1453–1460
Number of pages8
JournalJournal of Physical Chemistry Letters
Volume12
Issue number5
Early online date1 Feb 2021
DOIs
Publication statusPublished - 11 Feb 2021

Keywords

  • mannitol
  • crystallization
  • frozen solutions
  • synchrotron
  • X-ray diffraction
  • phase diagram

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