Surface Analysis-From Crystal Structures to Particle Properties.

Understanding the surface properties of particles is crucial for optimizing the performance of formulated products in various industries. However, acquiring this understanding often requires expensive trial-and-error studies. Here, we present advanced surface analysis tools that enable the visualization and quantification of chemical and topological information derived from crystallographic data. By employing functional group analysis, roughness calculations, and statistical interaction data, we facilitate direct comparisons of surfaces. We further demonstrate the practicality of our approach by correlating the sticking propensity of distinct ibuprofen morphologies with surface and particle descriptors calculated from a single crystal structure. Our findings support and expand upon previous work, demonstrating that the presence of a carboxylic acid group on the {011} facet leads to significant differences in particle properties and explains the higher electrostatic potential observed in the block-like morphology. While our surface analysis tools are not intended to replace the importance of chemical intuition and expertise, they provide valuable insights for formulators and particle engineers, facilitating informed, data-driven decisions to mitigate formulation risks. This research represents a significant step toward a comprehensive understanding of particle surfaces and their impact on products.

Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals.

Intermolecular (synthonic) modelling is used for a statistical analysis of crystal lattice energies, together with their contributing intermolecular interactions for the crystallographic structures selected from the CCDC's Drug Subset (https://doi.org/10.1016/j.xphs.2018.12.011). Analysis of this selected subset reveal similarities in packing compared to other organic crystals in the CSD with linear relationships between molecular weight and unit cell volume, void space, and packing coefficient. Crystal lattice energy calculations converge within a 30 Šintermolecular radius characterised by a mean lattice energy of ca. -36 kcal mol-1 with ca. 85% and 15% due to dispersive and electrostatic interactions, respectively. The distribution of the strongest synthons within the individual structures reveals an average strength of -5.79 kcal mol-1. The diversity of chemical space within the drug molecules is in agreement with the analysis of atom types across the selected subset with phenyl groups being found to contribute the highest mean energy of -11.28 kcal mol-1, highlighting the importance of aromatic interactions within pharmaceutical compounds. Despite an initial focus on Z' = 1 structures, this automated approach enables rapid and consistent quantitative analysis of lattice energy, synthon strength and functional group contributions, providing solid-form informatics for pharmaceutical R&D and a helpful basis for further investigations.

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties.

PURPOSE: Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing. METHODS: Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields. RESULTS: The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability. CONCLUSION: Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

Evaluation of Force-Field Calculations of Lattice Energies on a Large Public Dataset, Assessment of Pharmaceutical Relevance, and Comparison to Density Functional Theory.

Crystal lattice energy is a key property affecting the ease of processing pharmaceutical materials during manufacturing, as well as product performance. We present an extensive comparison of 324 force-field protocols for calculating the lattice energies of single component, organic molecular crystals (further restricted to Z' less than or equal to one), corresponding to a wide variety of force-fields (DREIDING, Universal, CVFF, PCFF, COMPASS, COMPASSII), optimization routines, and other variations, which could be implemented as part of an automated workflow using the industry standard Materials Studio software. All calculations were validated using a large new dataset (SUB-BIG), which we make publicly available. This dataset comprises public domain sublimation data, from which estimated experimental lattice energies were derived, linked to 235 molecular crystals. Analysis of pharmaceutical relevance was performed according to two distinct methods based upon (A) public and (B) proprietary data. These identified overlapping subsets of SUB-BIG comprising (A) 172 and (B) 63 crystals, of putative pharmaceutical relevance, respectively. We recommend a protocol based on the COMPASSII force field for lattice energy calculations of general organic or pharmaceutically relevant molecular crystals. This protocol was the most highly ranked prior to subsetting and was either the top ranking or amongst the top 15 protocols (top 5%) following subsetting of the dataset according to putative pharmaceutical relevance. Further analysis identified scenarios where the lattice energies calculated using the recommended force-field protocol should either be disregarded (values greater than or equal to zero and/or the messages generated by the automated workflow indicate extraneous atoms were added to the unit cell) or treated cautiously (values less than or equal to -249 kJ/mol), as they are likely to be inaccurate. Application of the recommended force-field protocol, coupled with these heuristic filtering criteria, achieved an root mean-squared error (RMSE) around 17 kJ/mol (mean absolute deviation (MAD) around 11 kJ/mol, Spearman's rank correlation coefficient of 0.88) across all 226 SUB-BIG structures retained after removing calculation failures and applying the filtering criteria. Across these 226 structures, the estimated experimental lattice energies ranged from -60 to -269 kJ/mol, with a standard deviation around 29 kJ/mol. The performance of the recommended protocol on pharmaceutically relevant crystals could be somewhat reduced, with an RMSE around 20 kJ/mol (MAD around 13 kJ/mol, Spearman's rank correlation coefficient of 0.76) obtained on 62 structures retained following filtering according to pharmaceutical relevance method B, for which the distribution of experimental values was similar. For a diverse set of 17 SUB-BIG entries, deemed pharmaceutically relevant according to method B, this recommended force-field protocol was compared to dispersion corrected density functional theory (DFT) calculations (PBE + TS). These calculations suggest that the recommended force-field protocol (RMSE around 15 kJ/mol) outperforms PBE + TS (RMSE around 37 kJ/mol), although it may not outperform more sophisticated DFT protocols and future studies should investigate this. Finally, further work is required to compare our recommended protocol to other lattice energy calculation protocols reported in the literature, as comparisons based upon previously reported smaller datasets indicated this protocol was outperformed by a number of other methods. The SUB-BIG dataset provides a basis for these future studies and could support protocol refinement.

The CSD Drug Subset: The Changing Chemistry and Crystallography of Small Molecule Pharmaceuticals.

We report the generation and statistical analysis of the CSD drug subset: a subset of the Cambridge Structural Database (CSD) consisting of every published small-molecule crystal structure containing an approved drug molecule. By making use of InChI matching, a CSD Python API workflow to link CSD entries to the online database Drugbank.ca has been produced. This has resulted in a subset of 8632 crystal structures, representing all published solid forms of 785 unique drug molecules. We hope that this new resource will lead to improvements in targeted cheminformatics and statistical model building in a pharmaceutical setting. In addition to this, as part of the Advanced Digital Design of Pharmaceutical Therapeutics collaboration between academia and industry, we have been given the unique opportunity to run comparative analysis on the internal crystal structure databases of AstraZeneca and Pfizer, alongside comparison to the CSD as a whole.

A chiral diamine: practical implications of a three-stereoisomer cocrystallization.

A brief comparison of seven straightforward methods for molecular crystal-volume estimation revealed that their precisions are comparable. A chiral diamine, N2,N3-bis[2,6-bis(propan-2-yl)phenyl]butane-2,3-diamine, C28H44N2, has been used to illustrate the application of the methods. Three stereoisomers of the diamine cocrystallize in the centrosymmetric space group P21/c with Z' = 1.5. The molecules occupying general positions are RR and SS, whereas that residing on an inversion center is meso. This is one of only ten examples of three stereoisomers with two asymmetric atoms cocrystallizing together reported to the Cambridge Structural Database (CSD). The conformations of the SS/RR and meso molecules differ considerably and lead to statistically significantly different C(asymmetric)-C(asymmetric) bond lengths in the diastereomers. An advanced Python script-based CSD searching technique for chiral compounds is presented.

Use of the PIXEL method to investigate gas adsorption in metal-organic frameworks.

PIXEL has been used to perform calculations of adsorbate-adsorbent interaction energies between a range of metal-organic frameworks (MOFs) and simple guest molecules. Interactions have been calculated for adsorption between MOF-5 and Ar, H2, and N2; Zn2(BDC)2(TED) (BDC = 1,4-benzenedicarboxylic acid, TED = triethylenediamine) and H2; and HKUST-1 and CO2. The locations of the adsorption sites and the calculated energies, which show differences in the Coulombic or dispersion characteristic of the interaction, compare favourably to experimental data and literature energy values calculated using density functional theory.