Molecular Modeling Study Of Chiral Drug Crystals: Lattice Energy Calculations

Li, Z. Jane; Ojala, William H.; Grant, David J.W.

doi:10.1002/jps.1103

Cited by 54 publications

(5 citation statements)

References 19 publications

(34 reference statements)

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“…At the time this work was submitted for publication, the SUB-BIG dataset was, to the best of our knowledge, larger than all previously reported datasets integrating experimental sublimation enthalpies (or experimentally estimated lattice energies) and crystal structures. ,,,− ,− ,,− (Larger datasets were previously reported for molecular QSPR studies of sublimation enthalpies, but those datasets were not integrated with crystal structures. , ) However, in the course of revising our manuscript for publication, Gavezzotti and Chickos reported an even larger dataset than SUB-BIG…”

Section: Methods and Datamentioning

confidence: 99%

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

Robinson

Geatches

Morris

et al. 2019

J. Chem. Inf. Model.

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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...

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Section: Methods and Datamentioning

confidence: 99%

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

Robinson

Geatches

Morris

et al. 2019

J. Chem. Inf. Model.

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“…Computed lattice energies have been used to calculate intrinsic solubilities from energies of the crystal structure . Lattice energy calculations have also been shown to be able to resolve energy differences between crystals of the crystallized pure enantiomer and the racemate . These lattice energy differences can be calculated accurately enough to be able to predict relative solubilities and thus the eutectic composition of a compound‐forming system in solution .…”

Section: Introductionmentioning

confidence: 99%

Accurate lattice energies of organic molecular crystals from periodic turbomole calculations

Buchholz

Stein

2018

J Comput Chem

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Accurate lattice energies of organic crystals are important i.e. for the pharmaceutical industry. Periodic DFT calculations with atom-centered Gaussian basis functions with the Turbomole program are used to calculate lattice energies for several non-covalently bound organic molecular crystals. The accuracy and convergence of results with basis set size and k-space sampling from periodic calculations is evaluated for the two reference molecules benzoic acid and naphthalene. For the X23 benchmark set of small molecular crystals accurate lattice energies are obtained using the PBE-D3 functional. In particular for hydrogen-bonded systems, a sufficiently large basis set is required. The calculated lattice energy differences between enantiopure and racemic crystal forms for a prototype set of chiral molecules are in good agreement with experimental results and allow the rationalization and computer-aided design of chiral separation processes. © 2018 Wiley Periodicals, Inc.

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“…Moreover, a comparison of chiral and racemic crystals can facilitate the development of innovative applications in diverse fields, such as optoelectronics, 5,6 actuators, 7,8 and pharmaceuticals. 9 This comparative analysis may also lead to the discovery of novel materials with tailored characteristics, enabling the design of advanced materials with enhanced performance and versatility.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Elucidating the disparities between chiral and racemic crystals is essential, as it can offer valuable insights into the underlying principles governing their behavior and properties. Moreover, a comparison of chiral and racemic crystals can facilitate the development of innovative applications in diverse fields, such as optoelectronics, , actuators, , and pharmaceuticals . This comparative analysis may also lead to the discovery of novel materials with tailored characteristics, enabling the design of advanced materials with enhanced performance and versatility.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Structural and Property Differences between Highly Similar Chiral and Racemic Crystals Composed of Analogous Molecules

Ishizaki

Takagi

Asahi

et al. 2023

Crystal Growth & Design

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The structural differences between chiral and racemic crystals of enantiomers have piqued interest, as exemplified by classical Wallach’s rule. However, the mechanical and thermal disparities between these materials have not been thoroughly investigated. This study reports the structural and mechanical differences between chiral and racemic crystals of two analogous molecules. The similarity of molecular and crystal structures between the two analogues was validated through comparison with known chiral–racemic crystal pairs. Young’s moduli of the four crystals revealed larger values for racemic crystals than their chiral counterparts, consistent with the intermolecular interaction energies projected along the loading direction. The thermal response of crystals plays a significant role in their elastic behavior, and the temperature dependence of interaction energies along the [001] direction was found to agree with the temperature dependence of lattice dynamics for all four crystals.

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Molecular Modeling Study Of Chiral Drug Crystals: Lattice Energy Calculations

Cited by 54 publications

References 19 publications

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

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

Accurate lattice energies of organic molecular crystals from periodic turbomole calculations

Unraveling the Structural and Property Differences between Highly Similar Chiral and Racemic Crystals Composed of Analogous Molecules

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