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

Abstract

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, COM-PASSII), 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 calc...

Simulation-based evaluation of zeolite adsorbents for the removal of emerging contaminants

“…60,84,85 As various simplifications were made in the present work, it is quite clear that the approach could be improved in various ways. Such improvements could include (a) the use of a force field that is more specifically designed for the modelling of pharmaceutical compounds, and that provides a reliable representation of both vdW and electrostatic interactions, 86 (b) a calculation of E zg that takes into account several local minima, e.g., by using a Boltzmann averaging over different configurations, (c) the development of approximate ways to include the transfer from solution to the adsorbed phase, e.g., by taking into account the hydration free energy computed using the same force field, (d) the use of less idealised adsorbent models incorporating framework Al atoms and associated protons/cations (or other heterogeneities), (e) the inclusion of interactions with coadsorbed water molecules and/or among coadsorbed pollutants. A combination of force field methods with electronic structure calculations should be particularly helpful to develop an increasingly accurate atomic-level picture.…”

Simulation-Based Evaluation of Zeolite Adsorbents for the Removal of Emerging Contaminants

“…[59,70,71] In the light of the various simplifications made in the present work, discussed above, it is quite clear that the approach could be improved in various ways. Such improvements could include a) the use of another force field that is more specifically designed for the modelling of pharmaceutical compounds [72], b) a calculation of E zg that takes into account several local minima, e.g., by using a Boltzmann averaging over different configurations, c) the development of approximate ways to include the transfer from solution to the adsorbed phase, e.g., by taking into account the hydration free energy computed using the same force field. A combination of force field methods with electronic structure calculations should be particularly helpful to develop an increasingly accurate atomic-level picture.…”

Conformational Change Initiates Dehydration in Fluconazole Monohydrate

“…The COMPASS-II (with its own charges) forcefield was chosen for all simulations since it was specifically designed to be generally suitable for application to condensed phases 52 and has been shown to be one of the best off-the shelf forcefields for the simulation of molecular crystals. [53][54]55,56 A number of other forcefield models available in Materials Studio were also tested but COMPASS and COMPASS-II provided the best results (ESI). Deleted: The COMPASS II forcefield extends the coverage for use with polymers and pharmaceutical like molecules adding functional groups commonly found in data bases for these molecules, with particular attention being given to the parameterisation of nitrogen, sulfate and sulfonate groups.…”