Polymorphism and X-ray powder diffraction: Applications

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Polymorphism and X-ray powder diffraction
Applications

• Bill David,
• ISIS, Rutherford Appleton Laboratory,
• Chilton, Oxfordshire, UK

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Outline of talk

• Powder diffraction
• limits and preconceptions
• Powder diffraction
• a precise, quantitative technique for real
  materials
• Solving structures from powders
• developing into a routine tool
• Concomitant polymorphism
• watching the action
• Conclusions and acknowledgements

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Preconceptions
crystalline

• It doesnt crystallise
• I cant see it under the microscope
• I cant get a single crystal
• I cant solve the structure

single crystal
powders
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Preconceptions

• The biggest bottleneck in structure solution is
  that I cant index my pattern
• at times it can be very difficult (e.g. pigments)

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Preconceptions

• Powders are a fingerprint
• intensities are not reliable

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United States Patent Application 20040019093
Kind Code A1
Aronhime, Judith   et al. January 29, 2004
Novel crystal forms of ondansetron , processes
for their preparation, pharmaceutical
compositions containing the novel forms and
methods for treating nausea using
them. Abstract Ondansetron crystalline Forms A
and B are useful in the treatment of nausea and
vomiting. Form B has a uniquely high melting
point of about 244 degree C and both forms are
stable against thermally induced polymorphic
transition from 30.degree. C. up to their melting
points.
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United States Patent Application 20040019093
Kind Code A1
Aronhime, Judith   et al. January 29, 2004
24. The crystalline form of ondansetron of claim
23 wherein the thermal analysis result is a
differential scanning calorimetry thermogram
taken at a heating rate of 10.degree. C.
min.sup.-1 in a closed pan that exhibits a
melting endotherm with a maximum at
230.-.2.degree. C. 25. The crystalline form of
ondansetron of claim 24 wherein the melting
endotherm has a magnitude of 324.26 Joules per
gram.
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United States Patent Application 20040019093
Kind Code A1
Aronhime, Judith   et al. January 29, 2004
18. A crystalline form of ondansetron
characterized by a powder X-ray diffraction
pattern having peaks at 25.4, 26.7 and
27.8.-.1.0 degrees two-theta. 19. The
crystalline form of ondansetron of claim 18
further characterized by strong intensity peaks
in the powder X-ray diffraction pattern at 23.2,
25.9 and 27.8.-.1.0 degrees two-theta and medium
intensity peaks at 25.4 and 26.7.-.1.0 degrees
2-theta. 20. The crystalline form of
ondansetron of claim 18 further characterized by
peaks in the powder X-ray diffraction pattern at
11.0, 14.8, 15.5, 16.4, 20.6, 21.4, 24.2.-.1.0
degrees two-theta.
21. The crystalline form of ondansetron of
claim 18 containing less than or equal to about
5 other crystalline forms of ondansetron. 22.
The crystalline form of ondansetron of claim 21
containing less than or equal to about 1 other
crystalline forms of ondansetron.
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Collecting accurate powder data for structural
analysisI. Sample preparation

• How can we make the ideal powder?
• sieving
• grind (light)
• recrystallisation
• assess line sharpness

• The ideal powder sample
• equi-dimensioned crystals
• size 1 micron

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Collecting accurate powder data for structural
analysisII. Diffractometer geometry

• Advantages
• high count rate
• excellent sample environment geometry
• Disadvantages
• systematic errors in peak intensities (preferred
  orientation) and peak positions (sample
  transparency)

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Collecting accurate powder data for structural
analysisII. Diffractometer geometry

• Advantages
• reduced systematic errors in peak intensities
  (preferred orientation) and minimisation of peak
  position errors
• Disadvantages
• lower count rate
• peak asymmetry

DS is the preferred geometry for accurate powder
diffraction studies.
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Collecting accurate powder data for structural
analysisII. Data collection variable counting
time
Form-factor fall-off
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Collecting accurate powder data for structural
analysisII. Data collection variable counting
time
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Collecting accurate powder data for structural
analysisII. Data collection variable counting
time
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The most important thing for accurate
powder data

• get the best data
• sample preparation
• Debye-Scherrer geometry
• variable counting time
• lab data are excellent for many applications but
  synchrotron radiationo offers higher resolution
  and count rate

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Anatomy of a powder diffraction pattern

• A powder diffraction pattern of carbamazepine
  (form III) collected using a Bruker D8
  diffractometer. Bragg peak positions, areas and
  shape give information about (i) unit cell, (ii)
  crystal structure and phase amount and (iii)
  crystallite size and strain respectively. The
  pattern has been fitted using the structure
  solution program DASH. (courtesy of A. Florence,
  University of Strathclyde)
• In general, all peak positions should be assigned
  Miller indices belonging to a refined crystal
  lattice.

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Line broadening size and strain
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Line broadening urea
as received
lightly ground
(0 0 2)
(0 2 1)
(2 1 0)
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Bill Marshall, ISIS
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Line broadening urea
as received
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Neutron powder diffraction finds protons
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III Peak intensities

• Quantitative phase analysis
• How much and how many polymorphs are there?
• Structure solution
• Global optimisation using the fact that we know
  the molecular topology
• Structure refinement
• Getting the best structural coordinates from
  powder data

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Two polymorphs of Zantac, ranitidine
hydrochloride
(max 12K)
(max 176K)
courtesy Peter Stephens, SUNY
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Hundreds of lines not thousands There is
much less information in a powder diffraction
pattern than asingle crystal pattern so why
use powders?
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Its tougher solving structures from powders than
from single crystals.
Single crystal data
Powder data
Moleculartopology
Other experiments
Crystal structure
Powder data
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Simplifying the search problem
position orientation
3N ? xyz abg St
48 ? 13 parameters
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Structure solution from powder data
Compounds AZ I-V are related to target actives
developed by AstraZeneca for the treatment of
chronic obstructive pulmonary disease. The
structural complexity (Npar) ranges from modest
(AZ I) to challenging (AZ IV, V) for global
optimisation.
a Number of torsion position orientation
parameters in DASH optimisation. b The ortho and
meta C-atoms of ring 1 are disordered over two
equally occupied sites.
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A brief introduction to four examples
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
pure b-carbamazepine
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
pure b-carbamazepine
pure g-carbamazepine
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
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Structure solution of polymorphs and hydrates
from powder data Example 1 carbamazepine
1
2
3
4
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Dehydration of pharmaceutical compounds
Zopiclone hydrates
C17H17ClN5O3.2H2O hypnotic insomnia line
phases dihydrate - anhydrous
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Zopiclone dehydration and phase transformations
TGA
-7.17ww 2H2O
DSC
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Zopiclone dehydration and phase transformations
racemate
racemate
chiral
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T(oC)
2 theta
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zopiclone monohydrate
zopiclone
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zopiclone dihydrate
zopiclone
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not simply line-phase behaviour (i.e. dihydrate
anhydrous)
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TOPAS zopiclone dihydrate standard line-shape
(axial divergence )
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crystallisation ice formation
new intermediate phase
ice melting
novel phase formation
trihydrate
trihydrate monohydrate transformation
step-function in water background
monohydrate
wateramorphous
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2 mins
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pure trihydrate
run 9
run 7
new trihydrate ice
almost pure new phase
run 5
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Postscript benzamide
Wohler Liebig, 1832 First observation of
polymorphism in organic materials
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Postscript benzamide
Benzamide a scientific treasure hunt Davey /
Pulham /David Feynman Room, Thursday lunchtime
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Acknowledgments

• Urea
• Andy Fitch (ESRF)
• Alan Coelho (Bruker)
• Carbamazepine/Zopiclone
• Kenneth Shankland (ISIS)
• Norman Shankland (Strathclyde)
• Alastair Florence (Strathclyde)
• Philippe Fernandes (Strathclyde)

• Paracetamol (ESRF)
• Colin Pulham (Edinburgh)
• Benzamide
• Colin Pulham (Edinburgh)
• Charlie Broder (ISIS)
• Kenneth Shankland (ISIS)
• Philippe Fernandes (Strathclyde)
• Roger Davey (UMIST)

Conclusions

• Powder diffraction is a very powerful tool for
  the structural study of real materials.
• The hardest thing is getting good data!
• The programs are available for you all to solve
  structures from powders.