Access to Single Crystals of (±)-Form IV of Modafinil by Crystallization in Gels. Comparisons between (±)-Forms I, III, and IV and (−)-Form I

(±)-Modafinil is an active pharmaceutical ingredient
that crystallizes in several polymorphic forms. However, up to now,
only the crystal structures of (±)-Forms I and III have been
described in the literature. The crystallization in TMOS-gel with
an adapted procedure including the dissolution of an equivalent amount
of (+) and (−) enantiomers led to single crystals of (±)-Form
IV, a metastable polymorphic form at room temperature. The crystal
structure, resolved by using single crystal X-ray diffraction, reveals
that this polymorphic form crystallizes in a space group Fdd2 (occurrence ca. 0.3% in CSD version 2011). Single crystals of (±)-Form
IV could also be obtained from the racemic compound in TMOS-gel, but
prior to gelation it was necessary to heat the solution at reflux
for 3 h. These results highlight that a solvated preassembly (from
(±)-Form I or (±)-Form III) might exist in solution and
could inhibit the formation of single crystals of (±)-Form IV
in the standard conditions of crystallization in TMOS-gel. The structural
comparison between (±)-Forms I, III, and IV highlights clear
differences in terms of conformation and packing, and the same structural
comparisons between (±)-Form IV and (−)-Form I highlight
similarities both in terms of conformation and packing. (±)-Form
IV is an enantiotropic modification that is stable at high temperature
(close to the melting point) and metastable at room temperature.