Structures of two conformational polymorphs of the cholesterol-lowering drug probucol

Abstract

Two polymorphic forms of the drug probucol, (4,4′-[(1-Methylethylidene)-bis(thio)]bis-[2,6-bis (1, 1-dimethylethyl)phenol]), have been isolated and characterized by thermal analysis, X-ray powder diffraction and single crystal X-ray analyses. Form I, with onset melting point 125°C, is monoclinic, space groupP2₁ c witha=16.972(5),b=10.534(4),c=19.03(1)Å,β=113.66(3)°,Z=4. Form II, with onset melting temperature 116°C, is monoclinic, space groupP2₁/_n witha=11.226(2),b=15.981(2),c=18.800(3)Å,β=104.04(1)°,Z=4. The probucol molecule adopts different conformations in the two polymorphs. In Form II, the C-S-C-S-C chain is extended and the molecular symmetry approximates C_2v whereas in Form I, the two S-C-S-C torsion angles are approximately 80° and 165°. Molecular mechanics calculations show that the less symmetrical conformer of Form I is more stable than the conformer in Form II by approximately 26 kJ mol⁻¹. Crystal packing in both polymorphs is determined by van der Waals interactions only. X-ray powder diffraction indicates that Form II converts to Form I on grinding.