POLYMORPHISM OF MIZOLASTINE: DETERMINATION OF THREE MODIFICATIONS BY SINGLE CRYSTAL X-RAY DIFFRACTION

Philippe Ochsenbein¹, Michel Bonin², Kurt Schenk² & Denis Loyaux¹

¹ Synthélabo Recherche, 10 Rue des Carrieres, F-92504 Rueil Malmaison, France
² Institut de Cristallographie de l'Université de Lausanne, BSP Dorigny, CH-1015 Lausanne, Suisse.

Keywords: Polymorphism, Pharmaceutical Drug, Conformational Analysis.

Mizolastine is a non-sedating antihistaminic drug recently commercialized in several European countries by Synthélabo. Three polymorphic modifications have been observed and characterized by DSC, powder XRD, as well as various spectroscopic methods. Two optically distinct crystal morphologies have been obtained from dichloromethane, leading to two crystal structures A and B. After recrystallization in a saturated 3:2 ethanol/water mixture; one additional modification C could be isolated. Data collections were carried out on a STOE Image Plate System equipped with graphite monochromatized MoKa radiation, the structures were solved using SIR92 and refined with the help of SHELX93. All structures are triclinic and centrosymmetric. The crystal structure B with the highest melting point (ca. 225°C) has four formula units per asymmetric unit and no solvent, whereas the other two have two independent molecules and solvent molecules. In all cases, strong hydrogen bonds between two anti parallel adjacent pyrimidinone moieties are found. Crystal packing analysis of the pseudopolymorph C (mp. ca. 215°C) shows a layered pattern with intermolecular (hydrogen and weak CH...O bonds) interactions with two water molecules within one layer. The molecules in the crystals of the modification A, witch are unstable under air condition, form channels including disordered CH₂Cl₂, whereas the B crystal lattice exhibits a stacking in column of molecules along the long axis parameter, laterally maintained with A-A interactions. Molecular structure analysis shows in all three structures various dihedral angles between the fluorophenyl and benzimidazole moieties, indicating a conformational polymorphism. Melting C crystals leads after recrystallization to another modification corresponding to form B.