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

Abstract

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 rationalise its growth behaviour as a function of the crystallisation 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 facetted shape, in good agreement with the shape of the experimentally grown crystals from the vapour phase. Crystals grown from solution are found to have higher aspect ratios, with t hose 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, whilst 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 = 0.66-0.79), not due to twinning, which is provisionally identified as being consistent with the {112} or {012} form. Analysis of the calculated surface entropy-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

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