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 II has been characterized by single-crystal X-ray diffraction methods (orthorhombic, P212121, a = 6.536(1), b = 9.949(1), c = 24.807(3) Å, V = 1613.1(3) Å3, 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) Å, b = 10.9875(10) Å, c = 12.9189(14) Å, α = 110.683(4)°, β = 88.186(6)°, γ = 105.826(6)°, V = 840.5(2) Å3, 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 °C. On cooling from the melt, linezolid gives an oily material, stable at RT, which can be crystallized into form IV by controlled heating near 100 °C. These materials were further characterized by high-resolution 1H and 13C NMR studies, as well as by 13C solid-state NMR.