Conformational and synthon polymorphism in furosemide (lasix)

Babu, N. Jagadeesh ; Cherukuvada, Suryanarayan ; Thakuria, Ranjit ; Nangia, Ashwini (2010) Conformational and synthon polymorphism in furosemide (lasix) Crystal Growth & Design, 10 (4). pp. 1979-1989. ISSN 1528-7483

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Official URL: http://pubs.acs.org/doi/abs/10.1021/cg100098z?prev...

Related URL: http://dx.doi.org/10.1021/cg100098z

Abstract

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 space group, and novel forms 2 and 3 in P21/n and P 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 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 1 is ascribed to its more efficient crystal packing, higher density, and the presence of R42 (8) sulfonamide N-H···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.

Item Type:Article
Source:Copyright of this article belongs to American Chemical Society.
ID Code:24593
Deposited On:29 Nov 2010 08:47
Last Modified:04 Mar 2011 04:47

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