Prenucleation Self-Assembly and Chiral Discrimination Mechanisms during Solution Crystallisation of Racemic Diprophylline.
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.
Normandi Université, Laboratoire SMS-EA3233, Université de Rouen, 76821, Mont Saint Aignan Cedex, France. clement.brandel@univ-rouen.fr.
Clément
http://orcid.org/0000-0002-7747-0823
C
Brandel
Normandi Université, Laboratoire SMS-EA3233, Université de Rouen, 76821, Mont Saint Aignan Cedex, France.
Yohann
Y
Cartigny
Normandi Université, Laboratoire SMS-EA3233, Université de Rouen, 76821, Mont Saint Aignan Cedex, France.
Gérard
G
Coquerel
University of Strathclyde, EPSRC Centre for Innovative, Manufacturing in Continuous Manufacturing and, Crystallisation (CMAC), Strathclyde Institute of Pharmacy, and Biomedical Sciences (SIPBS), Technology and Innovation Centre, 99 George Street, Glasgow, G1 1RD, UK.
Joop H
JH
Ter Horst
Normandi Université, Laboratoire SMS-EA3233, Université de Rouen, 76821, Mont Saint Aignan Cedex, France.
Samuel
S
Petit
aggregation; chirality; crystal growth; enantiomeric solid solutions; molecular modeling