Examination of inequivalent wetting on the crystal habit surfaces of RS-ibuprofen using grid-based molecular modelling

Abstract

Synthonic engineering tools, including grid-based searching molecular modelling, are applied to investigate the wetting interactions of the solute and four crystallisation solvents (ethanol, ethyl acetate, acetonitrile and toluene) with the {100}, {001} and {011} forms of RS-ibuprofen. The grid-based methods, in particular the construction of a crystal slab parallel to a given plane in a coordinate system with one axis perpendicular to the surface, are defined in detail. The interaction strengths and nature (dispersive, hydrogen bonding (H-bonding) or coulombic forces) are related to the crystal growth rates and morphologies. The solute is found to interact strongest with the capping {011}, then the side {001} and weakest with the top {100} habit surfaces. The solute interactions with the {100} and {001} surfaces are found to be almost solely dominated by dispersive force contributions, whilst the same with the {011} surfaces are found to have a greater contribution from H-bonding and coulombic forces. The increased surface rugosity, at the molecular level of the {011} surfaces, results in a favourable docking site in a surface 'valley', not present in the {100} and {001} surfaces. The H-bonding solvents ethanol, acetonitrile and ethyl acetate are found to strongly interact with the {011} surfaces and weakly with the {001} surfaces, with the {011} interactions having a much greater contribution from H-bonding and coulombic forces. The interaction energies of the apolar and aprotic solvent toluene, with the {011} and {001} surfaces, are found to be very close. Toluene is found having slightly stronger interactions with the {001} than the {011} surfaces, which are all dominated by dispersive interactions. The ratio of the average energy of the top 100 solvent interactions with the {001} surface divided by the average energy of the top 100 interactions with the {011} surface is compared to the ratio of the experimentally measured growth rates of the same forms. In general, the interaction energy ratio is found to have an inverse ratio with the growth rates, implying that the solvents which are calculated to interact strongly with a particular surface are impeding the growth of that surface and reducing the growth rate, in turn impacting upon the final morphology of the material.

Habit Modification of the Active Pharmaceutical Ingredient Lovastatin Through a Predictive Solvent Selection Approach

“…Nguyen 25 et al recently applied a synthonic engineering approach to understand the interfacial stability of the crystallographic faces of ibuprofen and rationalize the various aspect ratio crystals obtained from differing solution environments during crystal growth. Ros-bottom 26 et al have also used synthonic engineering by applying a grid-based surface searching methodology [27][28][29] to explain the anisotropic wettability of the crystal surfaces of ibuprofen. This article aims at using the approaches of synthonic engineering and molecular modeling discussed above to further understand the bulk crystal chemistry and surface chemistry of lovastatin in relation to its observed needle-like morphology.…”

Intermolecular Interactions in Functional Crystalline Materials: From Data to Knowledge

“…Similarly, ibuprofen [142] single crystals are faceted with (1 0 0), (0 0 2), and (0 1 1) faces, formed by hydrophobic, van der Waals and H-bonded interactions, respectively. As follows from the strength of intermolecular interactions in a crystal, and the strength of interactions between a solute and a solid [143], a polar protic solvent should bind to (0 0 2) faces to prevent the formation of needle morphology. This strategy based on the type of functional groups forming crystal faces was successfully used to optimize crystal morphology of lovastatin [144], 1-hydroxypyrene [145], isoniazid [146], tolbutamide [147] and N-benzyl-2-methyl-4-nitroaniline [148].…”

Crystallographic tomography and molecular modelling of structured organic polycrystalline powders

“…10,11 Cohesive van der Waals and electrostatic inter-particulate forces can be highly anisotropic in nature, 12 but can be modelled and manipulated using extrinsic chemical synthon force vectors. 13 Furthermore, preferential solvent interaction on particle facets 14,15 drives anisotropy of surface adhesion force response for crystals under variable relative humidity. 16 Single particle techniques provide effective measurement of anisotropic cohesion forces, [16][17][18] but direct measurement of powders is challenging.…”