Polymorphism of linezolid: A combined single-crystal, powder diffraction and NMR study

Linezolid (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is one of the first commercially available (and most widely used) oxazolidinone antibiotics. It was selectively prepared as two anhydrous polymorphic forms, labelled form II and IV in accordance with preliminary reports in the patent literature. Form 11 has been characterized by single-crystal X-ray diffraction methods (orthorhombic, P2(1)2(1)2(1), a=6.536(1), b=9.949(1), c=24.807(3) angstrom, V=1613.1(3) angstrom(3), Z=4, Z'=1), while powders of form IV could be fully characterized by employing ab initio powder diffraction methods (triclinic, P1, a=6.5952(7) angstrom, b=10.9875(10) angstrom, c=12.9189(14) angstrom, alpha=110.683(4)degrees, beta=88.186(6)degrees, gamma=105.826(6)degrees, V=840.5(2) angstrom(3), Z=Z'=2). The interconversion of form II into form IV was studied by TG, DSC and thermodiffractometry, which indicated a quantitative (endothermic and irreversible) transformation (in air) just above 160 degrees C. On cooling from the melt, linezotid gives an oily material, stable at RT, which can be crystallized into form IV by controlled beating near 100 degrees C. These materials were further characterized by high-resolution H-1 and C-13 NMR studies, as well as by C-13 solid-state NMR. (C) 2007 Elsevier B.V. All rights reserved.