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

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

Crystallographic Structure, Intermolecular Packing Energetics, Crystal Morphology and Surface Chemistry of Salmeterol Xinafoate (Form I).

Single crystals of salmeterol xinafoate (form I), prepared from slow cooled supersaturated propan-2-ol solutions, crystallise in a triclinic P‾1 symmetry with two closely related independent salt pairs within the asymmetric unit, with an approximately double unit cell volume compared to the previously published crystal structure(1). Synthonic analysis of the bulk intermolecular packing confirms the similarity in packing energetics between the two salt pairs. The strongest synthons, as expected, are dominated by coulombic interactions. Morphological prediction reveals a plate-like morphology, dominated by the {001}, {010} and {100} surfaces, consistent with experimentally grown crystals. Though surface chemistry of the slow growing {001} face comprises of large sterically hindering phenyl groups, weaker coulombic interactions still prevail from the alcohol group present on the phenyl and hydroxymethyl groups. The surface chemistry of the faster growing {010} and {100} faces are dominated by the significantly stronger cation/anion interactions occurring between the carboxylate and protonated secondary ammonium ion groups. The importance of understanding the cohesive/adhesive nature of the crystal surfaces of an API, with respect to their interaction with other API crystals and excipients and how that may impact formulation design is highlighted

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

Three separately developed software Molecular Dynamics packages at Daresbury Laboratory, namely DL_FIELD (DL_F), DL_POLY and DL_ANALYSER, have been integrated to form an efficient computational infrastructure to investigate the detailed solution chemistry of saturated benzoic acid in hexane solutions. These software capabilities are demonstrated, in combination with the Synthonic Engineering tools and density functional theory (DFT) calculations, to assess the extent that the solute-solute intermolecular synthonic interactions in solution mirrors the synthons in the crystal structure. The results show that the majority of the COOH groups are forming OH … O H-bonds, which are a combination of classic OH … O homo-dimers and three membered H-bonding clusters. The formation of pi-pi stacking interactions is observed, but in far fewer numbers than observed for the OH … O interactions. The DFT simulations of the IR spectra of the multiple benzoic acid aggregates extracted from the MD trajectories provides further in-depth analysis of previously published IR data, by matching simulated peaks to the experimental peaks, hence identifying the exact bonding modes that are responsible for such peaks. This study demonstrates the value of a multi-scale and multi-technique approach to exploring the molecular transition pathway from solution to crystal structure

Crystal regeneration - a unique growth phenomenon observed in organic crystals post breakage

Crystal regeneration has been observed in macroscopic paracetamol crystals post breakage along their cleavage plane. High resolution imaging confirmed regeneration rates to be 3-fold faster than growth prior to breakage. Further analysis of the solute-solvent interactions is required to elucidate the process which currently lacks linearity with traditional growth theories

A Digital Workflow Supporting the Selection of Solvents for Optimizing the Crystallizability of p-Aminobenzoic Acid

We present a grid-based molecular modeling approach and software application for screening the solute–solvent and solute–solute interactions of organic molecules. This tool can provide a deeper understanding of solubilization of organic molecules, intended to guide scientists to intuitive conclusions about whether a solute/solvent pair may provide desired physical properties, such as crystallizability, solubility, and crystal polymorphism. This study focused on solutions of p-aminobenzoic acid in acetonitrile, ethanol, and water. Acetonitrile molecules are found to form the weakest interactions with the solute molecule, although they also form weak interactions with themselves. In contrast, water forms strong interactions with the solute molecule, with a strong preference to interact with the carboxylic acid group, although they also form strong self-interactions. Ethanol forms strong interactions with all of the solute molecules, along with reasonably strong interactions with itself. The looser solvation of the carboxylic acid group by acetonitrile is thought to drive the crystallization of the α polymorph, by lowering the crystallization kinetic energy barrier. In ethanol, the strong interactions of the solvent are thought to contribute to significant undercooling of ethanolic solutions observed in previous studies. Water’s strong interactions with the carboxylic acid of the solute may drive the self-assembly of the α-form by interactions of the phenyl groups and also contribute to the nucleation of the β-form from this solvent. This workflow can provide valuable guidance on the solvation properties of organic molecules and clusters, producing low-energy solvation shells of molecules and clusters to be utilized as starting points for more sophisticated simulations, such as molecular dynamics

Conformational and structural stability of the single molecule and hydrogen bonded clusters of para aminobenzoic acid in the gas and solution phases

The crystallographic structures of the α- and β- polymorphic forms of para aminobenzoic acid are deconstructed into their constituent hydrogen bonding molecular structural building blocks of monomers, dimers, tetramers and octamers, where they are analysed using ab initio quantum mechanical calculations of their conformation and cluster stability in solution. The molecular conformation found in the β-form is less stable than the same found in the α-form for both the gas and solution phases, suggesting that this causes a slight increase in the barrier to the crystallisation of the β-form in comparison to the α-form. The solution populations of the self-associated OH⋯O H-bonding ‘classic carboxylic acid dimer’, present in the α- and not the β-structure, is calculated to dominate in acetonitrile, dimethyl sulfoxide, ethanol, ethyl acetate, methanol, nitromethane and water. It is observed that this classic dimer is least stable in water, compared to the other PABA crystallisation solvents, with the OH⋯N H-bonding interaction present in the β-form being the second most stable dimeric interaction. These results are discussed in terms of the crystallisability and polymorphic behaviour of the α and β forms of PABA from the afore mentioned crystallisation solvents, whilst detailing how this approach could be reproducible for a range of polymorphic crystalline materials

"Particle Informatics": Advancing Our Understanding of Particle Properties through Digital Design

We introduce a combination of existing and novel approaches to the assessment and prediction of particle properties intrinsic to the formulation and manufacture of pharmaceuticals. Naturally following on from established solid form informatics methods, we return to the drug lamotrigine, re-evaluating its context in the Cambridge Structural Database (CSD). We then apply predictive digital design tools built around the CSD-System suite of software, including Synthonic Engineering methods that focus on intermolecular interaction energies, to analyze and understand important particle properties and their effects on several key stages of pharmaceutical manufacturing. We present a new, robust workflow that brings these approaches together to build on the knowledge gained from each step and explain how this knowledge can be combined to provide resolutions at decision points encountered during formulation design and manufacturing processes

Understanding the effects of a polymer on the surface dissolution of pharmaceutical cocrystals using combined experimental and molecular dynamics simulation approaches

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP) and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak interactions with the surfaces of the cocrystals, it enhanced the dissolution performance of FFA-TP. In contrast, PVP and PVP-VA reduced the dissolution rate of FFA-TP and subsequently undermined the performance of cocrystals. Taken together, the approach of combining experimental and molecular dynamics simulation provided insights into the mechanisms of cocrystal dissolution as well as the polymers acting as inhibitory excipients for precipitation/recrystallisation, making contribution to the development of novel formulations

Supersaturation and solvent dependent nucleation of carbamazepine polymorphs during rapid cooling crystallization

Polymorphic nucleation behavior of carbamazepine (CBZ) was investigated in terms of supersaturation in several solvents: nitromethane, acetonitrile, acetone, ethanol, 2-propanol and toluene. The solubility was measured and the effects of interaction between the solvent and CBZ on solubility and polymorphic nucleation were discussed. It was found that the polymorphic forms of CBZ largely depended on the solvent type and supersaturation ratio. The carbonyl group in acetone blocked the NH⋯O interaction between the dimer in form II by mimicking the same interaction with CBZ, then favored the nucleation of form III. The aromatic–aromatic interaction between CBZ and the solvent like toluene decreased the solute–solute interaction and favored the formation of form II. The nucleation domains of CBZ polymorphs (forms II and III) were separated as a function of supersaturation ratio range in each solvent, and the effects of solvents and supersaturation ratios on the induction time and transformation process were also explored. The interfacial energies of forms II and III in different solvents were calculated, and it was found that, at all investigated supersaturation ratios, the interfacial energy of form II in all solvents except acetone was always lower than that of form III, indicating that nucleation kinetics preferably favored the formation of form II. However, at lower supersaturation ratios, thermodynamics was critical and form III was obtained