Generating Cocrystal Polymorphs with Information Entropy Driven by Molecular Dynamics-Based Enhanced Sampling

Abstract

Predicting structures of organic molecular cocrystals is a challenging task when considering the immense number of possible intermolecular orientations. Use of the Shannon information entropy, constructed from an intermolecular orientational spatial distribution function, to drive a search for crystal structures via enhanced molecular dynamics can be an efficient way to map out a landscape of putative polymorphs. Here, the Shannon entropy is used to generate a set of collective variables for differentiating polymorphs of a 1:1 cocrystal of resorcinol and urea. We show that driven adiabatic free energy dynamics, a particular enhanced-sampling approach, combined with these entropy variables, can transform the stable phase into alternate polymorphs. Density functional theory calculations confirm that a structure obtained from the enhanced molecular dynamics is stable at pressures above 1 GPa. We thus show that enhanced sampling should be considered an integral component of crystal structure searching protocols for systems with multiple independent molecules.

A Hybrid Machine Learning Approach for Structure Stability Prediction in Molecular Co-crystal Screenings

“…This is thanks to the strong physical prior that the DFTB+D4 baseline provides and the smoothness of the GAP correction. Additional improvements could be obtained by combining the current approach with more advanced structure search algorithms − and by iteratively refining the GAP correction in an active learning workflow.…”

“…In future work, we aim to combine these potentials with more advanced CSP search algorithms. 51 − 53 …”

Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy

“…The entropic effects played a role in stabilizing certain polymorphs. 60,116,117 Research suggested that the scope of polymorphs of cocrystals relies on our ability to find the right experimental conditions. Some specific methods, such as highpressure induction and polymer-induced heteronucleation, were employed as effective approaches.…”

Chasing the Co-crystal Disappearing Polymorph with Ab Initio Methods

“…As a result, the thermal effects are neglected in energy landscape assessment, which can cause the creation of many additional energy minima. To overcome these limitations, molecular dynamics methods were introduced to the studies of polymorphism. , Recently, metadynamics simulations , were used to analyze the disappearing conformational polymorph of succinic acid . In our studies, Born–Oppenheimer molecular dynamics (BOMD) calculations were used to investigate the self-assembly and stability of three urea–barbituric acid (UBA) polymorphs. , The BOMD results were compared with the analysis of H-bond propensities, coordination scores (CS), and the previous experimental data in the context of known thermodynamic stability rules. , Despite numerous experimental and theoretical trials, the “metastability” of the polar UBA polymorph is still unclear. − To our knowledge, UBA form (II) can be called one of the first known examples of disappearing co-crystal polymorphs.…”

“…To overcome these limitations, molecular dynamics methods were introduced to the studies of polymorphism. 37,38 Recently, metadynamics simulations 39,40 were used to analyze the disappearing conformational polymorph of succinic acid. 41 In our studies, Born−Oppenheimer molecular dynamics (BOMD) calculations 42 were used to investigate the selfassembly and stability of three urea−barbituric acid (UBA) polymorphs.…”