Systematic Finite-Temperature Reduction of Crystal Energy Landscapes

Abstract

Crystal structure prediction methods are prone to overestimate the number of potential polymorphs of organic molecules. In this work, we aim to reduce the overprediction by systematically applying molecular dynamics simulations and biased sampling methods to cluster subsets of structures that can easily interconvert at finite temperature and pressure. Following this approach, we rationally reduce the number of predicted putative polymorphs in CSP-generated crystal energy landscapes. This uses an unsupervised clustering approach to analyze independent finite-temperature molecular dynamics trajectories and hence identify a representative structure of each cluster of distinct lattice energy minima that are effectively equivalent at finite temperature and pressure. Biased simulations are used to reduce the impact of limited sampling time and to estimate the work associated with polymorphic transformations. We demonstrate the proposed systematic approach by studying the polymorphs of urea and succinic acid, reducing an initial set of over 100 energetically plausible CSP structures to 12 and 27 respectively, including the experimentally known polymorphs. The simulations also indicate the types of disorder and stacking errors that may occur in real structures. File list (2) download file view on ChemRxiv manuscript_Francia_revised.pdf (16.99 MiB) download file view on ChemRxiv Supplementary_Information_Francia.pdf (7.35 MiB)

Reducing crystal structure overprediction of ibuprofen with large scale molecular dynamics simulations

“…In this work, we have tackled the systematic reduction of a largescale dataset of CSP_0 crystal structures, including 555 putative crystal structures of ibuprofen by systematically applying MD simulations. 15 To scale up one order of magnitude in the number of crystal structures considered, compared to previous studies, we implemented new strategies to further increase the efficiency of the clustering and analysis protocols, drastically reducing the need for manual inspection of the trajectories in different steps. In particular, through a systematic conformational analysis, we could automatically detect disorder formation in the simulation box.…”

Reducing Crystal Structure Overprediction of Ibuprofen with Large Scale Molecular Dynamics Simulations

“…In this work, we have tackled the systematic reduction of a largescale dataset of CSP 0 crystal structures, including 555 putative crystal structures of ibuprofen by systematically applying MD simulations. 15 To scale up one order of magnitude in the number of crystal structures considered, compared to previous studies, we implemented new strategies to further increase the efficiency of the clustering and analysis protocols, drastically reducing the need for manual inspection of the trajectories in different steps. In particular, through a systematic conformational analysis, we could automatically detect disorder formation in the simulation box.…”

“…In this work, we apply the approach introduced in Ref. 15 to a dataset of 555 crystal structures of ibuprofen: an application of the size and complexity typical of modern CSP studies. Ibuprofen is a conformationally flexible, chiral molecule possessing two enantiomers with different pharmacological properties.…”

Diabat method for polymorph free energies: Extension to molecular crystals

“…Additionally, stability inferred for crystals at finite temperatures from energy minimized 0 K structures depends on the value of the lattice energy at those minima, and it is common for organic molecules to have multiple lattice energy minima that correspond to the same finite temperature structure. 98,99 The experimental study provides 4!/(2! (4 − 2!))…”