Crystallization of a polymorphic hydrate system

F. Tian, H. Qu, M. Louhi-Kultanen, J. Rantanen*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

8 Citations (Scopus)


Nitrofurantoin can form two monohydrates, which have the same chemical composition and molar ratio of water, but differ in the crystal arrangements. The two monohydrates (hydrates I and II) could be produced independently via evaporative crystallization, where supersaturation and solvent composition were both found to have an effect. Hydrate I showed much slower crystallization than hydrate II. During cooling crystallization, the nucleation and growth of hydrate II was again dominant, consuming all supersaturation and leading to no hydrate I formation. Seeding of hydrate I during cooling crystallization was also applied, but the hydrate I seeds were not able to initiate its nucleation rather than dissolving into crystallizing solution. Although solubility tests revealed that hydrate II is more stable than hydrate I due to its lower solubility (110±4 and 131±12 μg/mL for hydrates II and I, respectively), this difference is rather small. Therefore, the small free energy difference between the two hydrates, together with the slow crystallization of hydrate I, both lead to a hindrance of hydrate I formation. Furthermore, the crystal structure of hydrate II demonstrated a higher H-bonding extent than hydrate I, suggesting its more favorable crystallization. This is in good agreement with experimental results.

Original languageEnglish
Pages (from-to)753-763
Number of pages11
JournalJournal of Pharmaceutical Sciences
Issue number2
Publication statusPublished - Feb 2010
MoE publication typeA1 Journal article-refereed


  • Crystal structure
  • Crystallization
  • Hydrate
  • Nitrofurantoin
  • Polymorphism
  • Supersaturation


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