Crystal Morphology and Interfacial Stability of RS -Ibuprofen in Relation to Its Molecular and Synthonic Structure

The key intermolecular (synthonic) interactions, crystal morphology, and surface interfacial stability of the anti-inflammatory drug RS-ibuprofen are examined in relation to its bulk crystal and surface chemistry, and to rationalize its growth behavior as a function of the crystallization environment. The OH···O H-bonding dimers between adjacent carboxylic acid groups are calculated to be the strongest bulk (intrinsic) synthons, with other important synthons arising due to interactions between the less-polar phenyl ring and aliphatic chain. Morphological prediction, using the attachment energy model, predicts a prismatic faceted shape, in good agreement with the shape of the experimentally grown crystals from the vapor phase. Crystals grown from solution are found to have higher aspect ratios, with those prepared in polar protic solvents (EtOH) producing less needle-like crystals, than those prepared in less polar and aprotic solvents (toluene, acetonitrile, and ethyl acetate). Though the anisotropy factors of the {011} and {002} forms are relatively similar (39.5% and 43.4%, respectively), examination of the surface chemistry reveals that the most important extrinsic (surface-terminated) synthons on the capping {011} surface involve H-bonding interactions, while those on the side {002} surfaces mostly involve van der Waal’s (vdW) interactions. This suggests that a polar, protic solvent is more likely to bind to the capping {011} surface and inhibit growth of the long axis of the needle, compared to apolar and/or aprotic solvents. A previously unreported re-entrant face is found to appear in the external crystal morphology at higher supersaturations (in the range of σ = 0.66–0.79), not due to twinning, which is provisionally identified as being consistent with either the {112} or {012} form. Analysis of the calculated surface entropy α-factors suggest that the capping {011} faces would be expected to be least smooth on the molecular level, with a higher degree of unsaturated extrinsic synthons, in comparison to the {002} and {100} faces. This is consistent with growth mechanism data previously published (Nguyen et al. CrystEngComm 2014, 16, 4568−4586) and with the observed re-entrant morphological instability at the capping surfaces