Crystallization of D-Mannitol in Binary Mixtures with NaCl: Phase Diagram and Polymorphism

Chitra Telang, Raj Suryanarayanan, Lian Yu

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Purpose. To study the crystallization, polymorphism, and phase behavior of D-mannitol in binary mixtures with NaCl to better understand their interactions in frozen aqueous solutions. Methods. Differential scanning calorimetry, hot-stage microscopy, Raman microscopy, and variable-temperature X-ray diffractometry were used to characterize D-mannitol-NaCl mixtures. Results. NaCl and D-mannitol exhibited significant melt miscibility (up to 7.5% w/w or 0.20 mole fraction of NaCl) and a eutectic phase diagram (eutectic composition 7.5% w/w NaCl; eutectic temperature 150°C for the α and β polymorphs of D-mannitol and 139°C for the δ). The presence of NaCl did not prevent mannitol from crystallizing but, depending on sample size, affected the polymorph crystallized: below 10 mg, δ was obtained; above 100 mg, α was obtained. Pure mannitol crystallized under the same conditions first as the δ polymorph and then as the a polymorph, with the latter nucleating on the former. KCl showed similar eutectic points and melt miscibility with D-mannitol as NaCl. LiCl yielded lower eutectic melting points, inhibited the crystallization of D-mannitol during cooling, and enabled the observation of its glass transition. Conclusions. Despite their structural dissimilarity, significant melt miscibility exists between D-mannitol and NaCl. Their phase diagram has been determined and features polymorph-dependent eutectic points. NaCl influences the polymorphic behavior of mannitol, and the effect is linked to the crystallization of mannitol in two polymorphic stages.

Original languageEnglish (US)
Pages (from-to)1939-1945
Number of pages7
JournalPharmaceutical research
Issue number12
StatePublished - Dec 1 2003


  • D-mannitol
  • Eutectic
  • NaCl
  • Phase diagram
  • Polymorph


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