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.