The experimental electron density in polymorphs A and B of the anti-ulcer drug famotidine.
Accurate structure factors have been measured for the two known conformational polymorphs (A and B) of famotidine up to a maximum resolution of sin(theta)/lambda = 1.2 A(-1) at 100 K using a conventional X-ray source and a CCD-based diffractometer. The experimental electron-density distribution was modelled using a multipole model and the interatomic interactions were analysed following the atoms-in-molecules theory. Excellent equivalence between most electronic and electrostatic properties in the polymorphs exists and no significant differences were found to exist across polymorphs either in the interatomic interactions (via the topological analysis) or in the atomic charges from integration of the atomic basins. Additional derived properties, such as the molecular dipole moment, similarly did not distinguish between the polymorphs. Only the molecular electrostatic potential mapped on top of the molecular surface, i.e. the isodensity contoured at 0.00675 e A(-3), was able to uncover the differences between A and B. In both conformations, the sizes of the electronegative and electropositive areas match. However, the average electrostatic potential in the electronegative area of A is -40 kJ mol(-1), while the corresponding value in B is -55 kJ mol(-1). Together with the physical shape and dimensions of A and B, this leads to a conclusion that the polymorphs are mutually exclusive at the same receptor binding site.
School of Chemistry, University of Sydney, Australia. jacobo@chem.usyd.edu.au
Jacob
J
Overgaard
David E
DE
Hibbs
D000897:Anti-Ulcer Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015738:Famotidine / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D055672:Static Electricity
D000897:Anti-Ulcer Agents; D015738:Famotidine