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

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 buttonOpen up PDF-4 Organics 2008

* With releases before 2008, all searches shown can be run but theywould have to be graphed by a separate program

Method

• Use crystallographic, structural, chemicalor diffraction fields that are indicators ofpolymorphism (see next slide)• Plot the results• Compare the data• Use graphics interfaces to compare

diffraction patterns, entry cards, editorscomments etc.

Differences in Polymorphsin the solid state

Molecular Symmetry

Molecular Volume

Molecular Packing

Examine Crystal System, Space Group,Space Group Number, Pearson Symbols

Examine Author Cell, Crystal Cell andReduced Cells, Cell Axis Ratio’s, Cell Volumes

Examine Powder patterns for differencesin interplanar spacing, examine strong lines (d1, d2, d3) and long lines (l1, l2, l3)

Search Fields in PDF-4/Organics

Hierarchal Searchfor Polymorphs – General Method

Space Group vsVolume

Examine Groups

Within a groupExamine d-spacingsor Cell edges orStructural classes

Compare DiffractionPatterns

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 combinationof fields shownon the prior slide

Perform a Seach – Point and Click the Search Icon on the Toolbar

SearchStructureChemistryElementsReferences- 48 Searches

Perform a Search (48 Searches, 66 Fields)

- Get results and then plot

Polymorph MapGlycine –

68 Determinations, 5 SG’s

Molecular SymmetryInternational Space Group

Molecular Volume –Reduced Cell Volume

Polymorph MapGlycine – 68 Determinations

Symmetry vs Volume with inserts of the diffraction patterns forthe points in question

Glycine – Volume vs a cell edgeCompaction series (useful for tableting)

Plots two parameters in a Volume Change

GlycineReduced Cell a vs Cell c

Straight line changes in cell parameters are often due to thermalexpansion or contraction in a temperature or pressure series

AZT Polymorphs - Reduced Volume vs Cell Edge3 Forms, same space group

Need to examine molecular packing and subtledifferences in diffraction patterns

Low Temp Form

2 Room Temp FormsSubtle polymorphism - Molecular visualization (CSD)shows 2 similar configurations that vary inmethyl group rotation and close contacts

Note: The low temperatureform has a molecular configurationchange from room temperatureforms

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 Cocainesome superimpose (same polymorph)

others don’t (different polymorph)

CocainePatterns suggest at least 3 Forms

or 2 Forms & impurity

123

1 & 3

Codeine4 Determinations, 2 Forms

Famotidine – 2 PolymorphsRed 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 ?

MicrocrystallineCellulose Form I beta

+

FamotidineForm B

Heroin2 or 3 Polymorphs

Monoclinic

Orthorhombic

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

Cimetidine12 Determinations – 8 Crystal structures

Reduced cell a vs cell c

2 Major groups

Possible polymorphism with agroup

Comparison of key diffraction interplanar spacings

indicate a complex polymorphism

Strongest Diffraction Line

Largest Diffraction Line(long line, highest d)

Cimetidine

Cimetidine

Cimetidine – Strong Lines9 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 Group16 Determinations, 11 Single Crystal

in 5 different space groups

Carbamazepine – Reduced Cellsvs Cell a

GammaAlpha

Beta

Form IV

Interplanar Spacingsd1 vs l1, suggests many polymorphs

Alpha Form, R-3Form II

Author Assignments

Beta Form, P21/n, P21/cForm III

3 Determinations, Inconsistent 7 Determinations, Consistent 2 Unassigned

Gamma Form, P-1Form I

4 Determinations, Only 1 assigned by author

Form IV, C2/c

1 Determination

Note: Several lower quality determinationscan be reasonably assigned to one of these four forms.

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

Form IVBeta

Gamma

Alpha

GammaAre these the same ? (probably)

P1

P-1

To determine similarity you also need to look at expermental methods forboth data collection and specimen preparation

Note: P1 deleted because of poor Figure of merit relative to P-1

Using PDF-4+ to discover andanalyze 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 ClickJAVA interface