Prenucleation self-assembly and chiral discrimination mechanisms during solution crystallisation of racemic diprophylline

Clément Brandel, Yohann Cartigny, Gérard Coquerel, Joop H. ter Horst, Samuel Petit

Research output: Contribution to journalArticle

7 Citations (Scopus)
33 Downloads (Pure)

Abstract

The crystallisation behaviour of (RS)-diprophylline (DPL) in two different solvents is investigated to assess the incidence of solvated pre-associations on nucleation, crystal growth and chiral discrimination. In the solvated state, Raman spectroscopy shows that dimeric associations similar to those depicted in the crystalline solid solution (ssRII) predominate in isopropanol (IPA), which may account for the systematic spontaneous nucleation of this crystal form from this solvent. By contrast, spontaneous nucleation in DMF yields the stable racemic compound RI, consistently with the distinct features of the Raman spectrum collected in this solvent. A crystal growth study of ssRII in IPA reveals that the crystal habitus is impacted by the solution enantiomeric excess; this is explained by increased competition between homo- and heterochiral pre-associations. This is supported by a molecular modelling study on the enantiomeric selectivity of the DPL crystal lattices. The combination of assessment methods on solution chemistry, nucleation and chiral discrimination provides methodological tools from which the occurrence of solid solutions can be rationalised.

Original languageEnglish
Pages (from-to)16103-16112
Number of pages10
JournalChemistry - A European Journal
Volume22
Issue number45
Early online date26 Sep 2016
DOIs
Publication statusPublished - 2 Nov 2016

Keywords

  • aggregation
  • chirality
  • crystal growth
  • enantiomeric solid solutions
  • molecular modeling
  • crystallisation
  • (RS)-diprophylline
  • chiral discrimination

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