Solid Phase Behavior, Polymorphism, and Crystal Structure Features of Chiral Drug Metaxalone

Abstract

In addition to the previously known A-rac and Brac polymorphs of the chiral drug metaxalone 1, an enantiopure A-(S)-form was obtained and studied. According to X-ray analysis, the crystalline organization of this form is close to the A-rac-1 polymorph. Crystallization of metaxalone melts is accompanied by the formation of a previously unknown metastable C-phase, which in the case of both racemic and enantiomeric samples are transformed into A-rac-1 or A-(S)-1. Analysis of the PXRD and IR spectra of crystalline samples revealed a similarity of the internal structure for the A-(S)-1, Arac-1, C-(S)-1, and C-rac-1 crystalline forms and the essential difference of all of these phases from the B-rac-1 phase. According to the thermochemical data, the dependences of the change in the Gibbs free energy for all the phases studied are plotted in the interval from the melting point to 20 °C. Under standard conditions, the crystalline modifications of metaxalone, relative to ΔG 0 , form such a series: B-rac-1 < A-(S)-1 ≈ A-rac-1 < C-rac-1 < C-(S)-1. A model that describes all the experimentally revealed features of metaxalone crystallization is proposed.

Chirality, Gelation Ability and Crystal Structure: Together or Apart? Alkyl Phenyl Ethers of Glycerol as Simple LMWGs

“…The syntheses and characterization of racemic and enantiopure methyl substituted glycerol ethers 1, 10, 13 were described by us earlier [34,35]; racand (S)-3,5-dimethyl substituted ethers 14 were described in our work [36]; ortho-substituted ethers 11 and 12 were described in our work [37]. The synthesis of the racemic and (S)-para-n-alkylphenyl glycerol ethers 2-9 has been described in detail in our previous work [38].…”

Racemic Conglomerate Formation via Crystallization of Metaxalone from Volatile Deep Eutectic Solvents

“…The reciprocal 0k0 direction was not sampled and therefore the presence of a screw axis along b could not be ruled out. There are only two orthorhombic space groups consistent with this extinction features: P21221 (18) and P212121 (19). No structure solution for MTX Form A-R/S was obtained in space group P21221 (18), while a clear model was obtained ab-inito by SDM in space group P212121 (19).…”

“…14 Form B-rac can also be obtained by solvent-assisted mechanical grinding of Form A-rac or from a slurry of racemic MTX. 14,19 Both A-rac and B-rac are racemic crystals, which is expected for a chiral molecule; 90-95% of chiral molecules crystallize as racemic crystals, i.e. forming heterochiral centrosymmetric crystal structures, while only 5-10% of chiral molecules crystallize instead as homochiral conglomerates.…”

“…20 Enantiopure S-MTX was prepared by a 2-step synthesis described by Bredikhin et al. 19 Starting from enantiopure S-MTX, Form A-S was then recrystallized from a mixture of ethanol and chloroform. Moreover, in the same study, the authors also synthesized a new, metastable, racemic polymorph of MTX (Form C-rac) via crystallization of a supercooled melt of the appropriate composition.…”

“…The structure of MTX Form A-R/S was solved ab-initio by SDM in space group P212121 (19). The MTX molecule was clearly recognizable and all 16 non-hydrogen atoms of the structure were spotted by automatic routines.…”