STRUCTURES OF 2 CONFORMATIONAL POLYMORPHS OF THE CHOLESTEROL-LOWERING DRUG PROBUCOL

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-degrees-C, is monoclinic, space group P2(1)/c with a = 16.972(5), b = 10.534(4), c = 19.03(1) angstrom, beta = 113.66(3)-degrees, Z = 4. Form II, with onset melting temperature 116-degrees-C, is monoclinic, space group P2(1)/n with a = 11.226(2), b = 15.981(2), c = 18.800(3) angstrom, beta = 104.04(1)-degrees, 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 C2v whereas in Form I, the two S-C-S-C torsion angles are approximately 80-degrees and 165-degrees. 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.