Enabling direct preferential crystallization in a stable racemic compound system

Lina C. Harfouche, Clément Brandel, Yohann Cartigny, Joop H. Ter Horst, Gérard Coquerel, Samuel Petit

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The preparative resolution by preferential crystallization (PC) of proxyphylline has been achieved despite the existence of a stable racemic compound. This is enabled through the careful selection of a solvent in which both the racemic compound and the metastable conglomerate possess a low nucleation rate. Induction time measurements in isobutyl alcohol show that a highly supersaturated solution (β = 2.3) remains clear for almost 1 h at 20 mL scale, revealing a slow nucleation rate. Seeding the supersaturated solution with the pure enantiomer triggered its crystallization both isothermal and polythermic modes of PC were successfully implemented. Alongside the reported case of diprophylline, this study opens opportunities to broaden the application of PC toward slowly crystallizing racemic compounds.

Original languageEnglish
Pages (from-to)4670-4676
Number of pages7
JournalMolecular Pharmaceutics
Issue number11
Early online date23 Sep 2019
Publication statusPublished - 4 Nov 2019


  • metastable conglomerate
  • nucleation inhibition
  • preferential crystallization
  • proxyphylline

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