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Taming Tautomerism in Organic Crystal Structure Prediction.

Cody J Perry1, Sebastian A Ramos1, Maria C Phelps1

  • 1Department of Chemistry, University of California Riverside, Riverside, California 92521, United States.

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|July 18, 2025
PubMed
Summary
This summary is machine-generated.

Density functional theory (DFT) models poorly predict tautomeric crystal polymorph energetics, impacting drug formulation development. A new hybrid DFT method combined with coupled-cluster theory corrections improves accuracy, revealing errors in existing mebendazole crystal structure analysis.

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Area of Science:

  • Computational chemistry
  • Solid-state chemistry
  • Pharmaceutical sciences

Background:

  • Tautomerism significantly affects drug properties like solubility, stability, efficacy, and toxicity.
  • Computational solid-form screening aids in identifying optimal drug formulations and mitigating risks from undesirable crystal forms.
  • Accurate prediction of tautomeric crystal polymorph energetics is crucial for reliable drug development.

Purpose of the Study:

  • To evaluate the accuracy of widely used density functionals in predicting tautomeric crystal polymorph energetics.
  • To investigate the impact of density-driven delocalization error on DFT predictions.
  • To develop an improved computational method for accurate prediction of tautomeric polymorphs.

Main Methods:

  • Application of various density functionals (DFT) to model tautomeric crystal polymorphs.
  • Analysis of density-driven delocalization error in DFT calculations.
  • Development and application of a hybrid DFT approach combined with intramolecular coupled-cluster (CC) theory corrections.
  • Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy for experimental validation.

Main Results:

  • Standard DFT models exhibit significant errors in predicting tautomeric polymorph energetics, underestimating solid-state tautomerization barriers.
  • Tautomeric polymorph energy differences can exceed 10 kJ/mol in ~40% of cases, with DFT errors reaching tens of kJ/mol.
  • The refined hybrid DFT-CC method shows substantially improved agreement with experimental data.
  • The study identified an incorrect tautomer in the experimentally reported crystal structure of mebendazole form B, confirmed by solid-state NMR.

Conclusions:

  • Widely used DFT functionals are unreliable for predicting tautomeric crystal polymorph energetics due to delocalization errors.
  • Accurate prediction of tautomeric polymorphs requires advanced computational methods, such as hybrid DFT with CC corrections.
  • The findings necessitate re-evaluation of computational predictions for drug formulations involving tautomerism and highlight potential errors in existing crystal structure assignments.