Successful Application of the Derived Crystal Packing (DCP) Model in Resolving the Crystal Structure of a Metastable Polymorph of (±) Modafinil

Abstract

Polymorphic forms I and III of (() modafinil have been studied. In contrast to the structure of form I which could be solved by using conventional single crystal X-ray diffraction, the crystal structure of form III could not be elucidated due to the shape and the size of the single crystals resulting from the high supersaturation under which this phase is obtained. To bypass the problem, the derived crystal packing (DCP) model has been successfully applied by recombining the slice (002)A extracted from form I. The calculated XRPD pattern of form III fits well with the experimental data. The extensive similarities between the two crystal structures are carefully detailed. † Crystallographic data are deposited at the CCDC under number 229171.

Access to Several Polymorphic Forms of (±)-Modafinil by Using Various Solvation–Desolvation Processes

“…(±)-Modafinil (Figure ) is an API of Cephalon Inc., indicated to treat excessive sleepiness, commercialized under the name of PROVIGIL, which crystallizes in several polymorphic forms and solvates. , The crystal structure of (±)-Forms I, III, and IV have already been described in previous works. The crystal structure of (±)-Form I was determined by using single crystal X-ray diffraction, and the crystal structure of (±)-Form III was first solved by using the derived crystal packing model from (±)-Form I . Then, single crystals of (±)-Form III were harvested from crystallization in TMOS-gel .…”

“…The crystal structure of (±)-Form I was determined by using single crystal X-ray diffraction, and the crystal structure of (±)-Form III was first solved by using the derived crystal packing model 19 from (±)-Form I. 20 Then, single crystals of (±)-Form III were harvested from crystallization in TMOS-gel. 21 More recently, the crystallization in TMOS-gel with an original protocol has served to obtain single crystals of (±)-Form IV, and thus the crystal structure of this phase was resolved by using single crystal X-ray diffraction.…”

Effect of sodium chloride on the nucleation and polymorphic transformation of glycine

“…In the past decades, considerable efforts have been devoted to study the mechanism of polymorphic crystallization. Such emphases include the operational factors [4][5][6][7][8][9][10] and molecular modeling [11,12]. The crucial operational factors are temperature, solvent, agitation, supersaturation, seeding, cooling rate, pH values, and impurities/additives.…”

Pitfalls and rewards of preferential crystallization

“…No stable racemic compound exists at that temperature, but by using a combinatorial molecular modelling approach, it is possible to construct hundreds of different putative crystal lattice obtained by: (i) taking a periodic fragment of the structure of the pure enantiomer, (ii) adding a symmetry operator such as center of symmetry, glide mirror or any of the following axes ( 3,4,6) and (iii) minimizing the energy of the structure in an appropriate force field. 15 Fig. 2c depicts the complete absence of recognition between the enantiomers.…”