Synthonic Engineering Modelling Tools for Product and Process Design

Phys. Chem. Chem. Phys.

Pickering

Etbon

et al. 2018

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.

Section: Systsearch Of the Morphologically Important Surfacesmentioning

confidence: 99%

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

Phys. Chem. Chem. Phys.

Pickering

Etbon

et al. 2018

“…The making and breaking of covalent bonds to bring together chemicals or functional groups to build molecules is the basis of retrosynthesis in the organic synthesis community. Similarly, this concept has been expanded to view the making and breaking of intermolecular forces as the basis of bringing together the building blocks of molecular crystals, and as such the intermolecular interactions (synthons) between these building blocks are seen crucial for defining the physical properties of molecular crystals [2][3][4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

“…Molecular modelling of the intermolecular interactions (synthons) which are present in solid-state crystal structures has been utilised to rationalise the physical properties of molecular crystals [6][7][8][9][10][11][12][13] , and in addition density functional theory (DFT) has been used to probe the finer electronic structure detail and chemical robustness of the these synthons.…”

Section: Introductionmentioning

confidence: 99%

The integrated DL_POLY/DL_FIELD/DL_ANALYSER software platform for molecular dynamics simulations for exploration of the synthonic interactions in saturated benzoic acid/hexane solutions

Yong

Geatches

et al. 2019

Molecular Simulation

“…17 While experimental studies could be laborious, time consuming and expensive, molecular modelling can provide an alternative route to gain insight into the properties and propensity of formation of hydrates, minimizing the required laboratory work needed. [34][35][36][37] Synthonic modelling and computational methods can utilize atomistic force fields drawn from empirical data, to calculate the strength, directionality and dispersive nature of the intermolecular interactions (synthons) within a crystalline structure. This information can help in predicting the physiochemical properties of crystals.…”

Section: Introductionmentioning

confidence: 99%

“…This information can help in predicting the physiochemical properties of crystals. [34][35][36] In the past synthonic modelling has been used to study crystalline structures and estimate their properties, by calculating the lattice energy and identifying the dominant intermolecular interactions. [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] Synthonic modelling allows studying more complex multi-component systems, including those of hydrated structures.…”

Section: Introductionmentioning

confidence: 99%

Synthonic Modeling of Quercetin and Its Hydrates: Explaining Crystallization Behavior in Terms of Molecular Conformation and Crystal Packing

Klitou

Crystal Growth & Design

Simone

2019

Hydrated structures of a specific compound can often have different physiochemical properties compared to the anhydrous form. Therefore, being able to predict and understand these properties, especially the stability, is critical. In this study quercetin, a flavonoid molecule, is modelled in three different states of hydration to gain an understanding of the effect of water molecules on the 2 structure, packing and conformation energetics of the three forms. Conformational analysis and modelling of intermolecular interactions (synthonic modelling) have been performed. It was found that in the anhydrous form hydrogen bonding is the strongest type of interaction while in the two hydrate structures, the incorporation of water within the lattice leads to the formation of hydrogen bonds between the quercetin and water molecules. Within hydrates quercetin molecules adopt a more planar conformation which allows them to pack more closely by strongstacking interactions, thus resulting in a higher relative stability. The modelling results highlight the importance of water in the stabilization of the lattice and explain the preferential nucleation of the dihydrate form. It is further demonstrated how synthonic modelling can be a predictive tool for the product's properties, leading to more efficient product design and faster development.