Theoretical Calculations to Assist Experimental Crystal Form - - PowerPoint PPT Presentation

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Theoretical Calculations to Assist Experimental Crystal Form - - PowerPoint PPT Presentation

Oct 31, 2023 576 likes •843 views

Theoretical Calculations to Assist Experimental Crystal Form Screening Jacco van de Streek University of Copenhagen Department of Pharmaceutics and Analytical Chemistry Crystal Structure Prediction: Basics Free energy (p,T) energy structure

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Theoretical Calculations to Assist Experimental Crystal Form Screening

Jacco van de Streek University of Copenhagen Department of Pharmaceutics and Analytical Chemistry

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Crystal Structure Prediction: Basics

structure generation

Free energy (p,T)

energy ranking

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Why Force Fields Do not Work

energy

Typical accuracy Required accuracy (0.1 – 0.01 kcal/mol)

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Dispersion-corrected DFT (DFT-D)

Force fields... RMS = 0.497 Å Predicted Experiment

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Pure DFT... Force fields... RMS = 0.833 Å RMS = 0.497 Å Predicted Experiment

Dispersion-corrected DFT (DFT-D)

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Dispersion-corrected DFT... Pure DFT... Force fields... RMS = 0.833 Å RMS = 0.084 Å RMS = 0.497 Å Predicted Experiment

Dispersion-corrected DFT (DFT-D)

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SLIDE 7

Elattice = EDFT + EvdW

VASP

  • PAW potentials
  • Plane-wave basis set
  • GGA – PW91 / GGA – PBE
  • 520 eV enery cut-off
  • 0.07 Å-1 k-point spacing
  • Pair potentials
  • Element dependent
  • Hybridisation dependent
  • -C6  r-6

“0 K” calculations, no free energies

  • M. A. Neumann & M.-A. Perrin (2005) J. Phys. Chem. B 109, 15531-15541
  • G. Kresse & J. Hafner (1993) Phys. Rev. B 47, 558-561

Dispersion-corrected DFT (DFT-D)

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Crystal Structure Generation

Parallel tempering Monte-Carlo algorithm Tailor-made force field: accurate force field, fitted to artificial DFT-D reference data for each compound One and two independent molecules in all 230 space groups

  • M. A. Neumann (2008) J. Chem. Phys. B 112, 9810-9829
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Examples: Blind Tests

Crystal Structure Prediction Blind Tests: Blind Tests in 1999, 2001, 2004, 2007 and 2010 Good compounds for validation

  • G. M. Day et al. (2009) Acta Cryst. B65, 107-125
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:

Previous Blind Test Compounds

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Ranking Results (NOT Full Studies)

  • A. Asmadi, M. A. Neumann, J. Kendrick, P. Girard, M.-A. Perrin &
  • F. J. J. Leusen (2009) J. Phys. Chem. B 113, 16303-16313

1 & 2 2 1 1 & 2 4 1 1 1 1 1 & 2 1 1 1 2

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Previous Blind Test Compounds

Conclusion Dispersion-corrected DFT appears to work well for energy-ranking crystal structures (80% success rate)

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Efavirenz

Number of patents: 5 Number of claimed forms: 24 Number of crystal structures known: 0

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Efavirenz

Experimental polymorph screen by Dr Eva Dova (Avantium) Scan of patent literature by Dr Menno Deij (Avantium) The 24 forms boil down to eight distinct forms: A, B, C, D, E, F, H1, N

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Efavirenz (Z'=1-2)

Energy Density A B C D E F H1 N

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Energy B C F N H1 Density A B C D E F H1 N B B B

Efavirenz (Z'=1-2)

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Energy C N H1 Density A B C D E F H1 N Some patents: C most stable (@RT) Some patents: F most stable (@RT) B B B B

Efavirenz (Z'=1-2)

F

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Efavirenz

Form B is disordered, four

  • rientations of the cyclopropane

group are found in the search (ranks 20, 27, 40, 57) Disorder means that our 0 K energies are not reliable

  • S. Cuffini, R. E. Howie, E. R. T. Tiekink, J. L. Wardell &
  • S. M. S. V. Wardell (2009) Acta Cryst. E65, o3170-o3171
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  • Form N is Z'=2
  • One axial -CF3, one equatorial -CF3
  • Requires fully flexible search with Z'=2
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We can solve structures from poor quality laboratory powder patterns, scanned from a patent: low resolution, preferred orientation. Rietveld refinement with TOPAS for form N (Z'=2)

Efavirenz

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What about Forms A, D & E?

Energy C N H1 Density A B C D E F H1 N B B B B F

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Efavirenz

A Z'=3 / Z'=6 [1] B Found, Disordered [2] C Found D Solvate (from TGA) E ? F Found [3] H1 Found N Found

[1] S. Mahapatra, T. S. Thakur, S. Joseph, S. Varughese & G. R. Desiraju (2010) Cryst. Growth Des. 10, 3191-3202 [2] S. Cuffini, R. E. Howie, E. R. T. Tiekink, J. L. Wardell & S. M. S. V. Wardell (2009) Acta Cryst. E65, o3170-o3171 [3] K. Ravikumar & B. Sridhar (2009) Mol. Cryst. Liq. Cryst. 515, 190-198

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Efavirenz

Conclusions

  • Real life very complicated:
  • Z'>2
  • Disorder: entropy contribution
  • Solvates
  • Form E ambiguous
  • Crystal structures from very poor quality powder patterns:

use crystal-structure prediction

  • No more stable form found: it is unlikely that one turns up

in the future

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Current complexity limit

  • Six months on a 64 CPU quad-core Xeon or Opteron cluster
  • Quasicomplete screen for Z'=1 in 230 space groups
  • 50 – 90 % complete screen for Z'=2 in 230 space groups

Bicalutamide

F F F N H N S O HO O O F

Blind Test XX

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Acknowledgements

Marcus Neumann - Avant-garde Materials Simulation Eva Dova - Avantium Menno Deij - Avantium