Using PDF-4+/Organics to discover and analyze polymorphs

1. T.G. Fawcett, S. N. Kabbekodu, F. Needham, J. R. Blanton, D. M. Crane, J. Faber International Centre for Diffraction Data Using PDF-4+/Organics to discover andanalyze polymorphs

2. Indentifying Polymorphs • In this presentation we heavily use the graphics capability embedded in PDF-4/Organics. The graphics package was added with Release 2008*. From the Start button Open up PDF-4 Organics 2008 * With releases before 2008, all searches shown can be run but they would have to be graphed by a separate program

3. Method • Use crystallographic, structural, chemical or diffraction fields that are indicators of polymorphism (see next slide) • Plot the results • Compare the data • Use graphics interfaces to compare diffraction patterns, entry cards, editors comments etc.

4. Differences in Polymorphsin the solid state Search Fields in PDF-4/Organics Examine Crystal System, Space Group, Space Group Number, Pearson Symbols Molecular Symmetry Molecular Volume Molecular Packing Examine Author Cell, Crystal Cell and Reduced Cells, Cell Axis Ratio’s, Cell Volumes Examine Powder patterns for differences in interplanar spacing, examine strong lines (d1, d2, d3) and long lines (l1, l2, l3)

5. Hierarchal Searchfor Polymorphs – General Method • Similar but not identical patterns • Compare instrumental details • Compare specimen preparation • Compare physical properties • Use molecular visualization tools* • Use cluster analyses* Use any combination of fields shown on the prior slide Space Group vs Volume Examine Groups Within a group Examine d-spacings or Cell edges or Structural classes Compare Diffraction Patterns * May require additional software

6. Perform a Seach – Point and Click the Search Icon on the Toolbar Search Structure Chemistry Elements References - 48 Searches

7. Perform a Search (48 Searches, 66 Fields) - Get results and then plot

8. Polymorph MapGlycine – 68 Determinations, 5 SG’s Molecular Symmetry International Space Group Molecular Volume – Reduced Cell Volume

9. Polymorph MapGlycine – 68 Determinations Symmetry vs Volume with inserts of the diffraction patterns for the points in question

10. Glycine – Volume vs a cell edgeCompaction series (useful for tableting) Plots two parameters in a Volume Change

11. GlycineReduced Cell a vs Cell c Straight line changes in cell parameters are often due to thermal expansion or contraction in a temperature or pressure series

12. AZT Polymorphs - Reduced Volume vs Cell Edge3 Forms, same space groupNeed to examine molecular packing and subtledifferences in diffraction patterns Note: The low temperature form has a molecular configuration change from room temperature forms Low Temp Form 2 Room Temp Forms Subtle polymorphism - Molecular visualization (CSD) shows 2 similar configurations that vary in methyl group rotation and close contacts

13. 1. Dyer et al Molecular Drawings by Conquest, 2 Room Temperature Polymorphs of AZT 2. Brinbaum et. al Short C..N contact to azide

14. 5 Reference Patterns for Cocainesome superimpose (same polymorph)others don’t (different polymorph)

15. CocainePatterns suggest at least 3 Formsor 2 Forms & impurity 1 & 3 1 2 3

16. Codeine4 Determinations, 2 Forms

17. Famotidine – 2 PolymorphsRed Cell a vs Cell volume Temperature Series Polymorphs A &B – both as a temperature series

18. Polymorphs of Famotidine Tablet of Pepcid AC Same molecule, two different crystalline forms

19. What is Pepcid AC ? Microcrystalline Cellulose Form I beta + Famotidine Form B

20. Heroin2 or 3 Polymorphs Orthorhombic Monoclinic

21. 3 Determinations Heroin – Orthorhombic FormDifferent Polymorphs or poor experimental technique?

22. Cimetidine12 Determinations – 8 Crystal structuresReduced cell a vs cell c Possible polymorphism with a group 2 Major groups

23. Comparison of key diffraction interplanar spacingsindicate a complex polymorphism Cimetidine Largest Diffraction Line (long line, highest d) Strongest Diffraction Line

24. Cimetidine

25. Cimetidine – Strong Lines9 possible polymorphs Monoclinic D 4 patterns, Monoclinic A, Form I Monoclinic Z Form B Form IV Not shown – Patterns for Form II and Form III, 3 patterns not identified by form

26. Carbamazepine - Cell vs Space Group16 Determinations, 11 Single Crystalin 5 different space groups

27. Carbamazepine – Reduced Cellsvs Cell a Beta Form IV Alpha Gamma

28. Interplanar Spacingsd1 vs l1, suggests many polymorphs

29. Author Assignments Note: Several lower quality determinations can be reasonably assigned to one of these four forms. Alpha Form, R-3 Form II Beta Form, P21/n, P21/c Form III 3 Determinations, Inconsistent 7 Determinations, Consistent 2 Unassigned Gamma Form, P-1 Form I Form IV, C2/c 4 Determinations, Only 1 assigned by author 1 Determination

30. Carbamazepine - Cell vs Space Group16 Determinations, 11 Single Crystal, in 5 different space groupsNote: Can assign all 5 powder patterns to one of these groups by comparing diffraction patterns Alpha Form IV Beta Gamma

31. GammaAre these the same ? (probably) Note: P1 deleted because of poor Figure of merit relative to P-1 P1 P-1 To determine similarity you also need to look at expermental methods for both data collection and specimen preparation

32. Using PDF-4+ to discover andanalyze polymorphs Point and Click JAVA interface 48 Searches 66 Field Display Graphics Interface Use multiple measurements of symmetry, molecular size, molecular volume, packing and molecular orientation to discover and identify polymorphism