Single-crystal diffuse scattering studies on polymorphs of molecular crystals. I. The room-temperature polymorphs of the drug benzocaine.

The drug benzocaine (ethyl 4-aminobenzoate), commonly used as a local anaesthetic, is a bimorphic solid at room temperature. Form (I) is monoclinic P2(1)/c, while the metastable form (II) is orthorhombic P2(1)2(1)2(1). Three-dimensional diffuse X-ray scattering data have been collected for the two forms on the 11-ID-B beamline at the Advanced Photon Source (APS). Both forms show strong and highly structured diffuse scattering. The data have been interpreted and analysed using Monte Carlo (MC) modelling on the basis that the scattering is purely thermal in origin and indicates the presence of highly correlated molecular motions. In both forms (I) and (II) broad diffuse streaks are observed in the 0kl section which indicate strong longitudinal displacement correlations between molecules in the 031 directions, extending over distances of up to 50 A. Streaks extending between Bragg peaks in the hk0 section normal to [100] correspond to correlated motions of chains of molecules extending along a that are linked by N-H...O=C hydrogen bonds and which occur together as coplanar ribbon pairs. The main difference between the two forms is in the dynamical behaviour of the ribbon pairs and in particular how they are able to slide relative to each other. While for form (I) a model involving harmonic springs is able to describe the motion satisfactorily, as simple excursions away from the average structure, there is evidence in form (II) of anharmonic effects that are precursors of a phase transition to a new low-temperature phase, form (III), that was subsequently found.

Neutron diffuse scattering in deuterated para-terphenyl, C(18)D(14).

Neutron diffuse scattering is used to explore the short-range order (SRO) in deuterated para-terphenyl, C(18)D(14). The crystal shows SRO because the central of the three phenyl groups of each molecule can twist positively or negatively and these twists are correlated over the local scale. The presence of incipient Bragg peaks at [Formula: see text] at 200 K shows that these flips are negatively correlated along the a direction (nearest neighbour correlation coefficient of ∼-0.3) and b direction (nearest neighbour correlation coefficient of ∼-0.87) and appear essentially uncorrelated along c. Diffuse peak anisotropy indicates that the range of the correlations along b is found to be ∼3 times that along a. These correlations persist, although weaker, at room temperature. A Monte Carlo simulation was used to impose a correlation structure on the population of central ring twists that was deduced from Bragg scattering. By then allowing displacive relaxation of the structure, the observed diffuse scattering was well reproduced. Modelling the displacive motions of molecules showed that the positions of nearest ab-plane neighbour molecules are strongly positively correlated, particularly for motions approximately parallel to a, while the displacive correlations are weaker between molecules stacked along c. The apparent contradiction that the displacements are most strongly correlated along a while the occupancies are most strongly correlated along b is explained in terms of the connectivity of molecular interactions.

A room-temperature X-ray diffuse scattering study of form (II) of the trimorphic molecular system p-(N-methylbenzylidene)-p-methylaniline.

Three-dimensional X-ray diffuse scattering data have been collected at room temperature for form (II) of the trimorphic molecular system p-(N-methylbenzylidene)-p-methylaniline. Although this polymorph has been reported to have a perfectly normal ordered average structure, strong and highly structured diffuse scattering was observed, indicating that substantial thermal disorder is present. A diffuse scattering analysis has been carried out using Monte Carlo simulation techniques. Narrow streaks of intensity extending between Bragg peaks in the h0l section were found to arise from planes of diffuse scattering in three dimensions. These are caused by highly correlated molecular displacements along chains of end-to-end disposed molecules running in the a-c direction, corresponding to methyl-methyl intermolecular interactions. A second significant feature--rods of diffuse scattering running in the b* direction--indicates that molecular layers normal to b have a tendency to undergo lateral displacements with little correlation between layers. Finally, the internal flexibility of the molecule is required for a best fit. Changes in the two dihedral angles are found to be strongly correlated and show large excursions (> +/- 20 degrees) from the average values. All of these features suggest possible mechanisms for the way in which form (II) might transform to other polymorphs.

The molecular conformation of Ibuprofen, C13H18O2, through X-ray diffuse scattering.

A study of the three-dimensional distribution of the X-ray diffuse scattering from the pharmaceutical Ibuprofen (2-(4-isobutylphenyl)propionic acid, C(13)H(18)O(2)) has been undertaken. The most important aspects of the molecular flexibility have been isolated, as have key correlations between variables within a single molecule. Hence, aspects of the conformational space of the molecule within a crystalline environment have been outlined. For example the correlations between torsional twists on different bonds in the molecule (corresponding to the torsional angles on atoms C3, O1 and C11) have been established. Even though the atoms are on opposite sides of the phenyl group, there is a strong negative correlation between the torsional angle on C3 and that on C11. This shows that the ability to predict the conformation a fragment of a molecule will adopt based on the conformations of the fragment found in other molecules may be limited, as aspects of molecular geometry far from the fragment itself will have impact on its conformation. Between molecules, the positional coordinate components which coincide with the direction of propagation of strong intermolecular contacts, particularly the -COOH-HOOC- dimerising interactions, are positively correlated. On the other hand, motions perpendicular to such directions, and rotations about the torsional angles, do not propagate strongly from molecule to molecule.