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 and analyze polymorphs

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

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.

Differences in Polymorphs in the solid state Molecular Symmetry Molecular Volume Molecular Packing Examine Crystal System, Space Group, Space Group Number, Pearson Symbols 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) Search Fields in PDF-4/Organics

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

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

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

Polymorph Map Glycine – 68 Determinations, 5 SG’s Molecular Symmetry International Space Group Molecular Volume – Reduced Cell Volume

Polymorph Map Glycine – 68 Determinations Symmetry vs Volume with inserts of the diffraction patterns for the points in question

Glycine – Volume vs a cell edge Compaction series (useful for tableting) Plots two parameters in a Volume Change

Glycine Reduced 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

AZT Polymorphs - Reduced Volume vs Cell Edge 3 Forms, same space group Need to examine molecular packing and subtle differences in diffraction patterns 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 Note: The low temperature form has a molecular configuration change from room temperature forms

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

5 Reference Patterns for Cocaine some superimpose (same polymorph) others don’t (different polymorph)

Cocaine Patterns suggest at least 3 Forms or 2 Forms & impurity & 3

Codeine 4 Determinations, 2 Forms

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

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

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

Heroin 2 or 3 Polymorphs Monoclinic Orthorhombic

3 Determinations Heroin – Orthorhombic Form Different Polymorphs or poor experimental technique ?

Cimetidine12 Determinations – 8 Crystal structures Reduced cell a vs cell c 2 Major groups Possible polymorphism with a group

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

Cimetidine – Strong Lines 9 possible polymorphs 4 patterns, Monoclinic A, Form I Monoclinic Z Monoclinic D Form IV Form B Not shown – Patterns for Form II and Form III, 3 patterns not identified by form

Carbamazepine - Cell vs Space Group 16 Determinations, 11 Single Crystal in 5 different space groups

Carbamazepine – Reduced Cells vs Cell a Gamma Alpha Beta Form IV

Interplanar Spacings d1 vs l1, suggests many polymorphs

Alpha Form, R-3 Form II Author Assignments Beta Form, P21/n, P21/c Form III 3 Determinations, Inconsistent7 Determinations, Consistent 2 Unassigned Gamma Form, P-1 Form I 4 Determinations, Only 1 assigned by author Form IV, C2/c 1 Determination Note: Several lower quality determinations can be reasonably assigned to one of these four forms.

Carbamazepine - Cell vs Space Group 16 Determinations, 11 Single Crystal, in 5 different space groups Note: Can assign all 5 powder patterns to one of these groups by comparing diffraction patterns Form IV Beta Gamma Alpha

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

Using PDF-4+ to discover and analyze polymorphs 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 Point and Click JAVA interface