Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Polymorphism and X-ray powder
diffraction: Applications
Bill David,
ISIS, Rutherford Appleton Laboratory,
Chilton, Oxfordshire, UK
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Preconceptions:
crystalline
• It doesn’t crystallise
10-1m
= I can’t see it under the microscope
= I can’t get a single crystal
= I can’t solve the structure
10-2m
1mm
10-3m
10-4m
single crystal
10-5m
10mm
10mm
10-6m
powders
10-7m
300Å
300Å
10-8m
10-9m
10-10m
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Preconceptions:
• The biggest bottleneck in structure solution is
that I can’t index my pattern
– at times it can be very difficult (e.g. pigments)
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Preconceptions:
• Powders are a fingerprint
– intensities are not reliable
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
United States Patent Application
Kind Code
20040019093
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Collecting accurate powder data for structural analysis
I. Sample preparation
The ideal
powder
sample
How
can we
make the ideal powder?
– equi-dimensioned crystals
– size ~ 1–micron
sieving
– grind (light)
– recrystallisation
– assess line sharpness
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Collecting accurate powder data for structural analysis
II. Diffractometer geometry
Bragg-Brentano (flat plate geometry)
q
2q
Advantages
– high count rate
– excellent sample environment
geometry
Disadvantages
– systematic errors in peak
intensities (preferred orientation)
and peak positions (sample
transparency)
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Collecting accurate powder data for structural analysis
II. Diffractometer geometry
Debye-Scherrer (capillary geometry)
2q
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Collecting accurate powder data for structural analysis
II. Data collection – variable counting time
7000
20
18
16
Count scheme
14
6000
12
10
8
6
5000
4
2
0
0
10
20
30
40
50
60
70
4000
3000
2000
1000
Form-factor fall-off
0
10
15
20
25
30
35
40
45
50
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
55
60
Collecting accurate powder data for structural analysis
II. Data collection – variable counting time
40000
20
18
16
35000
Count scheme
14
12
10
8
30000
6
4
2
0
25000
0
10
20
30
40
50
20000
15000
10000
5000
0
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
60
70
Collecting accurate powder data for structural analysis
II. Data collection – variable counting time
7000
6000
5000
4000
3000
2000
1000
0
10
15
20
25
30
35
40
45
50
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
55
60
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
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Line broadening: size and strain
strain
d
   q cot q
d
 2q  2 tan q
size
d
d

d
peff
q cot q 
 2q 

2 peff sin q

peff cos q
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Line broadening: urea
60
urea_295 0.00 %
urea_295 0.00 %
55
as received
50
45
40
35
30
25
20
15
10
5
0
-5
8.3
8.4
8.5
8.6
8.7
8.8
8.9
9
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
9.9
10
10.1
10.2
10.3
10.4
10.5
10.6
10.7
105
10.8
10.9
11
urea_295 0.00 %
100
urea_295 0.00 %
95
lightly ground
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
(2 1 0)
5
(0 2 1)
(0 0 2)
0
-5
16
16.2
16.4
16.6
16.8
17
17.2
17.4
17.6
17.8
18
18.2
18.4
18.6
18.8
19
19.2
19.4
19.6
19.8
20
20.2
20.4
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
20.6
20.8
21
21.2
21.4
P21212
P-421m
P212121
Bill Marshall, ISIS
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Line broadening: urea
60
urea_295 0.00 %
ab plane
urea_295 0.00 %
55
as received
90
50
2.0
120
45
60
40
1.5
35
30 150
30
1.0
25
20
0.5
15
18010
5
0.0
2.0
0
0.0
0.5
1.0
1.5
0.5
1.0
1.5
2.0
0.5
0
-5
8.3
8.4
8.5
105210
8.6
1.0
8.7
8.8
8.9
9
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
9.9
10
10.1
10.2
10.3
10.4
10.5
10.6
10.7
2.0
120
lightly ground
60
90
1.5
85
80
240
2.0
75
150
1.0
270
70
65
300
30
0.5
180
60
0.0
2.0
11
urea_295 0.00 %
90
1.5
10.9
urea_295 0.00 %
100
95
10.8
330
ab
ac plane
1.5
1.0
55
0
0.0
0.5
0.5
1.0
1.5
2.0
0.5
50
1.0
210
45
40
330
1.5
35
240
30
2.0
300
270
25
20
15
10
(2 1 0)
5
(0 2 1)
(0 0 2)
0
-5
16
16.2
16.4
16.6
16.8
17
17.2
17.4
17.6
17.8
18
18.2
18.4
18.6
18.8
19
19.2
19.4
19.6
19.8
20
20.2
20.4
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
20.6
20.8
21
21.2
21.4
Neutron powder diffraction finds protons
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Detection sensitivity depends on
Two polymorphs of Zantac®,
ranitidine hydrochloride
signal intensity
sharp peaks
low background
All are enhanced by use of synchrotron radiation
Pure Form 1
X-ray Intensity (arb. units)
1000
(max 12K)
0
1.0% Form 2
in Form 1
10000
(max 176K)
0
courtesy Peter Stephens, SUNY
Pure Form 2
0
8
10
12
14
16
18
20
22
Diffraction angle 2 q
24
26
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
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30
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Hundreds of lines …
… not thousands
There is much less information in a
powder diffraction pattern than a
single crystal pattern
… so why use powders?
X-ray powder
diffraction
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
It’s tougher solving structures from powders
than from single crystals.
bits of information
Basic information theory ...
Single
crystal
Molecular
Other
Powder data
topology
experiments
data
Powder data
The
algorithm
Crystal
structure
Simplifying the search problem
t6
t4
t7
t3
t2
t1
known...
t5
+ position & orientation
not known...
3N  {xyz} + {abg} + St
48  13 parameters
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
A brief introduction to four examples …
Carbamazepine
Paracetamol hydrates
Zopiclone hydrates
Benzamide
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
pure b-carbamazepine
b-carbamazepine (ex tablet)
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
pure b-carbamazepine
pure g-carbamazepine
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
1
2
3
4
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Structure solution of polymorphs and hydrates
from powder data: Example 1: carbamazepine
1
2
3
4
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Dehydration
of pharmaceutical compounds
Paracetamol hydrates
C8H9NO2.nH20
pain-killer, analgesic, antipyretic
4'-hydroxyacetanilide,
acetaminophen, tylenol
Zopiclone hydrates
C17H17ClN5O3.2H2O
hypnotic – insomnia
line phases: dihydrate - anhydrous
Zopiclone dehydration and phase transformations
-7.17ww% = 2H2O TGA
DSC
Zopiclone dehydration and phase transformations
325 K
298 K
+ 2H20
hygroscopic
+ H 20
- 2H20
350 K
cryostream
ID31
ESRF
2.2
2.4
2.6
2.8
3
orthorhombic monoclinic
anhydrous dihydrate
chiral
racemate
3.2
3.4
monoclinic
anhydrous
racemate
3.6
2 theta
dihydrate
T(oC)
anhydrous
zopiclone
monohydrate
zopiclone
zopiclone
dihydrate
zopiclone
Temperature (oC)
not simply line-phase behaviour
(i.e. dihydrate – anhydrous)
2 theta
2H2O
xH2O
no H2O
TOPAS
zopiclone dihydrate
standard line-shape (axial divergence …)
Zopiclone cell volume
1980
1960
1940
3
Unit cell (A )
1920
1900
1880
Cell volume vs T
Lower bound volume vs T
1860
1840
1820
1800
40
60
Temperature (oC)
80
100
Estimated water content
Estimated water content
2.0
1.5
1.0
0.5
0.0
20
40
60
Temperature (oC)
80
100
35oC
30oC
2q
time
30oC
0oC
crystallisation
+ ice formation
new intermediate phase
ice melting
novel phase
formation
trihydrate
trihydrate – monohydrate
transformation
2q
time
monohydrate
step-function in
water background
water+amorphous
new intermediate phase
2 mins
2q
time
run 9
pure trihydrate
run 7
new + trihydrate + ice
run 5
almost pure new phase
Postscript: benzamide
Wohler & Liebig, 1832
First observation of polymorphism in
organic materials
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
Postscript: benzamide
Form 1 17.10 %
75,000
Form II 82.90 %
70,000
65,000
60,000
55,000
50,000
45,000
40,000
35,000
30,000
25,000
20,000
Benzamide: a scientific treasure hunt
Davey / Pulham /David
Feynman Room, Thursday lunchtime
15,000
10,000
5,000
0
-5,000
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004
24
25
26
27
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.
Diversity amidst Similarity, 25th Erice Crystallography Course, 9-20 June 2004