Crystal structure, interaction energies and experimental electron density of the popular drug ketoprophen

The crystal and molecular structure of the pure (S)-enantiomer of the popular analgesic and anti-inflammatory drug ketoprophen (alpha-ket) is reported. A detailed aspherical charge-density model based on high-resolution X-ray diffraction data has been refined, yielding a high-precision geometric description and classification of the O-H center dot center dot center dot O interactions as medium strength hydrogen bonds. The crystal structure of the racemic form of ketoprophen (beta-ket) was also redetermined at 100 K, at 0.5 angstrom resolution. A previously unreported disorder (10% occupancy) was discovered. In contrast to the racemic beta-ket case, the (S)-enantiomer crystallizes with two independent molecules in the asymmetric unit with two distinct conformations. The major difference between the beta-ket and alpha-ket crystal forms lies in the formation of distinct hydrogen-bonded motifs: a closed ring motif in beta-ket versus infinite chains of hydrogen bonds in the chiral alpha-ket structure. However, the overall crystal packing of both forms is surprisingly similar, with close-packed layers of antiparallel-oriented benzophenone moieties bound by C-H center dot center dot center dot pi interactions. Notably, the most important stabilizing term in the total lattice energies in both instances proved to be the dispersion related to these interactions. Both forms of the title compound (alpha- and beta-ket) were additionally characterized by differential scanning calorimetry and thermogravimetric analysis.