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 P (1) over bar space group, and novel forms 2 and 3 in P2(1)/n and P (1) over bar space groups. The conformationall, 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 similar to 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 center dot center dot center dot CI hydrogen bonds and minimization of repulsive S=O center dot center dot center dot CI 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 large difference in molecular conformer energies, crystal lattice energies of polymorphs 1-3 are very close (-41.65, 41.78, 41.53 kcal mol(-1)). These results show that the thermodynamic stability of polymorph 1 of furosemide concluded in crystallization experiments is not possible to predict through computations. Moreover, the presence of metastable conformers in the stable crystal structure reemphasizes that there is no substitute for experimental validation in polymorphic systems. The greater stability of polymorph I is ascribed to its more efficient crystal packing, higher density, and the presence of R-4(2)(8) sulfonamide N-H center dot center dot center dot O dimer synthon. Because of the differences in torsion angles and hydrogen bonding in polymorphs 1-3, they are more appropriately classified as conformational and synthon polymorphs.