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

Using PDF‐4+/Organics to discover and
analyze polymorphs
T.G. Fawcett, S. N. Kabbekodu, F. Needham, J. R. Blanton, D. M. Crane, J. Faber
International Centre for Diffraction Data
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
Search Fields in PDF-4/Organics
Molecular Symmetry
Examine Crystal System, Space Group,
Space Group Number, Pearson Symbols
Molecular Volume
Examine Author Cell, Crystal Cell and
Reduced Cells, Cell Axis Ratio’s, Cell
Volumes
Molecular Packing
Examine Powder patterns for differences
in interplanar spacing, examine strong
lines (d1, d2, d3) and long lines (l1, l2, l3)
Hierarchal Search
for Polymorphs – General Method
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
Similar but not identical patterns
• Compare instrumental details
• Compare specimen preparation
• Compare physical properties
•Use molecular visualization tools*
•Use cluster analyses*
Compare Diffraction
Patterns
* May require additional software
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
Note: The low temperature
form has a molecular configuration
change from room temperature
forms
Low Temp Form
Subtle polymorphism Molecular visualization (CSD)
shows 2 similar configurations that vary in
methyl group rotation and close contacts
2 Room Temp Forms
1.
Dyer et al
Molecular Drawings by Conquest, 2 Room Temperature Polymorphs of AZT
2.
Brinbaum et. al
Short C..N contact to azide
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
1&3
1
2
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
Orthorhombic
Monoclinic
3 Determinations Heroin – Orthorhombic Form
Different Polymorphs or poor experimental technique?
Cimetidine12 Determinations –
8 Crystal structures
Reduced cell a vs cell c
Possible polymorphism with a
group
2 Major groups
Comparison of key diffraction interplanar spacings
indicate a complex polymorphism
Cimetidine
Largest Diffraction Line
(long line, highest d)
Strongest Diffraction Line
Cimetidine Cimetidine – Strong Lines
9 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
Carbamazepine ‐ Cell vs Space Group
16 Determinations, 11 Single Crystal
in 5 different space groups
Carbamazepine – Reduced Cells
vs Cell a
Beta
Form IV
Alpha
Gamma
Interplanar Spacings
d1 vs l1, suggests many polymorphs
Author Assignments
Alpha Form,
R-3
Form II
3 Determinations, Inconsistent
Note: Several lower quality determinations
can be reasonably assigned to one of these
four forms.
Beta Form, P21/n,
P21/c
Form III
7 Determinations, Consistent 2 Unassigned
Gamma Form, P-1
Form I
4 Determinations, Only 1 assigned by author
Form IV, C2/c
1 Determination
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
Alpha
Beta
Form IV
Gamma
Gamma
Are 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
Using PDF‐4+ to discover and
analyze polymorphs
• 48 Searches
• 66 Field Display
• Graphics Interface
Point and Click
JAVA interface
• Use multiple measurements of symmetry, molecular size, molecular volume, packing and molecular orientation to discover and identify polymorphism