Conformational and Synthon Polymorphism in Furosemide (Lasix)

Two polymorphs of the well-known diuretic drug Lasix, generic name furosemide, are characterized by single crystal X-ray diffraction to give a trimorphic cluster of polymorphs: known form 1 in P1 space group, and novel forms 2 and 3 in P21/n and P1 space groups. The conformationally flexible molecule 4-chloro-2-[(2-furanylmethyl)amino]-5-sulfamoylbenzoic acid has variable torsions at the sulfonamide and furyl ring portions in conformers which lie in a 6 kcal mol−1 energy window. A conformer surface map was calculated to show that the two conformations in crystal form 1 are ∼4.5 kcal mol−1 less stable than conformers present in forms 2 and 3 (0.7, 0.0 kcal mol−1). The stabilization of molecular conformations is analyzed in terms of attractive intramolecular N−H···Cl hydrogen bonds and minimization of repulsive S═O···Cl interactions. Phase stability relationships confirm the thermodynamic nature of form 1 in grinding and slurry experiments by X-ray powder diffraction and infrared spectroscopy. Despite the...