The structural and thermodynamic features of three polymorphic forms of the local anesthetic drug oxybuprocaine hydrochloride (OBPHC) were characterized by hot-stage microscopy, differential scanning calorimetry (DSC), pycnometry, Fourier transform infrared spectroscopy (FTIR), FT-Raman and solid-state NMR (SSNMR) spectroscopy as well as X-ray powder and single-crystal diffractometry. Mod II°crystallizes in the space group P2 1 /n, is present in commercial products, and is the thermodynamically stable form at room temperature. Mod II°shows an endothermic transformation to mod I (mp 160 °C) at about 135 °C, indicating an enantiotropic relationship between these forms. Mod I (space group I2/a) shows a high kinetic stability and does not transform back to the more stable mod II°below the thermodynamic transition temperature (∼90 °C) on storage but does so in a solution-mediated process. Cooling mod I below -30 °C results in mod III (P2 1 /a). This transition (T trs : -33 °C) is highly reversible, proving the enantiotropic relationship between mod III and mod I. OBPHC is a classic example of conformational polymorphism demonstrating the interplay of molecular interaction forces and conformational flexibility. Two basic types of conformers can be found in the different polymorphs. Only one U-type conformer is present in the asymmetric unit of mod I, whereas in mod III two U-type conformers and in mod II°a type U-and an unusually bent type I conformer can be found. Computational modeling of the isolated molecule suggests that the I-type conformer is more stable than the U-type conformers. † This is part 12 of a series of articles with the title "Polymorphic Drug Substances of the European Pharmacopoeia".

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Various forces influence the formation of a crystal structure and sometimes an unstable balance between different supramolecular interactions is the reason for polymorphism. Four crystal structures relating to the interplay between bromine contacts, aromatic interactions, hydrogen bonding and the influence of the solvent used in the crystallization process are reported. In this context 1 and 2 were synthesized as model compounds both containing two hydroxy groups and two bromophenyl substituents in a cis configuration attached at different sides to the basic 9,10-dihydroanthracene subunit. Variation in the position of the bromo substituents in 1 and 2 allows further comparison with reference to interaction modes and crystal packing. A variety of interactions (O-H … O, O-H … Br, Br … Br) are realized in two crystal modifications of 1, 1A and 1B, with similar molecular geometry but considerably different packing relationships. The balance of forces between the possible contacts and their endeavour to control the crystal packing is influenced by the solvent which is used for crystallization. Modification 1A crystallized from pure toluene, whereas for 1B toluene with a trace of chloroform was used. In pure chloroform 1 includes solvent molecules in a host lattice, forming a clathrate structure 1C [1 Á CHCl 3 (1:1)] with packing motifs similar to the structure 1B.

Keywords: Oximes / Tautomerism / X-ray diffraction / NMR spectroscopy / Density functional calculations 1 H and 13 C NMR spectroscopic investigations of 4-benzoyl-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one oxime (4) and different methylation products thereof (5−11) indicate that 4 exists predominantly as 4-enaminopyrazolone in [D 6 ]DMSO solution. Single-crystal X-ray analysis revealed that in the solid state the same tautomeric structure of 4 was present, and closely resembles that of the corresponding N-