diversity amidst similarity, 25 th erice crystallography course, 9-20 june 2004

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


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


Preconceptions:

• It doesn’t crystallise= I can’t see it under the microscope

= I can’t get a single crystal

= I can’t solve the structure

10-10m

10-1m

10-2m

10-3m

10-4m

10-5m

10-6m

10-7m

10-8m

10-9m

crystalline

300Å

10m

1mm

single crystal

300Å

10m

powders


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)


Preconceptions:

• Powders are a fingerprint – intensities are not reliable


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.

AbstractOndansetron 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.


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.


Kind Code A1



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.


Kind Code A1


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.


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


Collecting accurate powder data for structural analysisII. Diffractometer geometry

Bragg-Brentano (flat plate geometry)

Advantages– high count rate– excellent sample environment

geometry

Disadvantages– systematic errors in peak

intensities (preferred orientation) and peak positions (sample transparency)


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.

Debye-Scherrer (capillary geometry)


Collecting accurate powder data for structural analysisII. Data collection – variable counting time

0

1000

2000

3000

4000

5000

6000

7000

10 15 20 25 30 35 40 45 50 55 60

0

2

4

6

8

10

12

14

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18

20

0 10 20 30 40 50 60 70

Count scheme

Form-factor fall-off


0

5000

10000

15000

20000

25000

30000

35000

40000


0

2

4

6

8

10

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14

16

18

20

0 10 20 30 40 50 60 70

Count scheme



0

1000

2000

3000

4000

5000

6000

7000

10 15 20 25 30 35 40 45 50 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


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.


Line broadening: size and strain

tan22

cot

d

d

strain size

cos2

sin2cot

eff

eff

eff

p

p

p

d

d

d


Line broadening: urea

1110.910.810.710.610.510.410.310.210.1109.99.89.79.69.59.49.39.29.198.98.88.78.68.58.48.3

60

55

50

45

40

35

30

25

20

15

10

5

0

-5

urea_295 0.00 %urea_295 0.00 %

21.421.22120.820.620.420.22019.819.619.419.21918.818.618.418.21817.817.617.417.21716.816.616.416.216

10510095908580757065605550454035302520151050-5

urea_295 0.00 %urea_295 0.00 %

as received

lightly ground

(0 0 2)(0 2 1)(2 1 0)


Bill Marshall, ISIS

P212121

P21212

P-421m


21.421.22120.820.620.420.22019.819.619.419.21918.818.618.418.21817.817.617.417.21716.816.616.416.216

10510095908580757065605550454035302520151050-5

urea_295 0.00 %urea_295 0.00 %

lightly ground

Line broadening: urea

1110.910.810.710.610.510.410.310.210.1109.99.89.79.69.59.49.39.29.198.98.88.78.68.58.48.3

60

55

50

45

40

35

30

25

20

15

10

5

0

-5

urea_295 0.00 %urea_295 0.00 %

ac plane

0.0 0.5 1.0 1.5 2.0

0.0

0.5

1.0

1.5

2.0

0.00.51.01.52.0

0.0

0.5

1.0

1.5

2.0

0

30

60

90

120

150

180

210

240

270

300

330

ab plane

0.0 0.5 1.0 1.5 2.0

0.0

0.5

1.0

1.5

2.0

0.00.51.01.52.0

0.0

0.5

1.0

1.5

2.0

0

30

60

90

120

150

180

210

240

270

300

330

as received

(0 0 2)(0 2 1)(2 1 0)

ab plane

0.0 0.5 1.0 1.5 2.0

0.0

0.5

1.0

1.5

2.0

0.00.51.01.52.0

0.0

0.5

1.0

1.5

2.0

0

30

60

90

120

150

180

210

240

270

300

330


Neutron powder diffraction finds protons


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


Two polymorphs of Zantac®,ranitidine hydrochloride

8 10 12 14 16 18 20 22 24 26 28 30Diffraction angle 2

0

10000

X-ra

y In

tens

ity (

arb.

uni

ts)

0

1000

0

Pure Form 1

1.0% Form 2 in Form 1

Pure Form 2

Detection sensitivity depends on signal intensity sharp peaks low backgroundAll are enhanced by use of synchrotron radiation

(max 12K)

(max 176K)

courtesy Peter Stephens, SUNY


X-ray powderdiffraction

Hundreds of lines … … not thousandsThere is much less information in a powder diffraction pattern than asingle crystal pattern… so why use powders?

Thealgorithm

Basic information theory ...

bits

of

info

rmat

ion

Singlecrystaldata Crystal

structurePowder data

Powder dataMoleculartopology

It’s tougher solving structures from powdersthan from single crystals.

Otherexperiments

known...

not known...

12

34

5

6

7

+ position & orientation

Simplifying the search problem

3N {xyz} + {} +

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 DASHDASH optimisation.b The ortho and meta C-atoms of ring 1 are disordered over two equally occupied sites.


A brief introduction to four examples …

Paracetamol hydrates

Zopiclone hydratesCarbamazepine

Benzamide


Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine



pure -carbamazepine

-carbamazepine (ex tablet)



pure -carbamazepine

pure -carbamazepine



1 2

3 4

Dehydration of pharmaceutical compounds

Zopiclone hydrates

C17H17ClN5O3.2H2O

hypnotic – insomnialine phases: dihydrate - anhydrous

Paracetamol hydrates

C8H9NO2.nH20pain-killer, analgesic, antipyretic

4'-hydroxyacetanilide, acetaminophen, tylenol

Zopiclone dehydration and phase transformations

TGA

DSC

-7.17ww% = 2H2O

monoclinic dihydrate

2.2 2.4 2.6 2.8 3 3.2 3.4 3.6

298 K

monoclinic anhydrous

325 K

ID31 ESRF

cryostream

chiral

+ H20hygroscopic

+ 2H20

racemate racemate

350 K

orthorhombic anhydrous

- 2H20

Zopiclone dehydration and phase transformations

2 theta

dih

ydra

te

anh

ydro

us

T(o C

)

zopiclonemonohydrate

zopiclone

zopiclonedihydrate

zopiclone

2 theta

Tem

pera

ture

(o C

)not simply line-phase behaviour (i.e. dihydrate – anhydrous)

2H2O

xH2O

no H2O

C:\Documents and Settings\bill\My Documents\My Research\W 130204\TOPAS-130204\tb.exe

TOPASzopiclone dihydratestandard line-shape (axial divergence …)

Zopiclone cell volume

Temperature (oC)

40 60 80 100

Uni

t ce

ll (A

3 )

1800

1820

1840

1860

1880

1900

1920

1940

1960

1980

Cell volume vs TLower bound volume vs T

Estimated water content

Temperature (oC)

20 40 60 80 100

Est

imat

ed w

ater

con

tent

0.0

0.5

1.0

1.5

2.0

time20oC

35oC

30oC30oC

water+amorphous

crystallisation + ice formation

ice melting

trihydrate

step-function inwater background

trihydrate – monohydratetransformation

novel phaseformation

new intermediate phase

monohydrate

time2

new intermediate phase

time22 mins

run 5

run 7

run 9

almost pure new phase

new + trihydrate + ice

pure trihydrate


Postscript: benzamide

Wohler & Liebig, 1832

First observation of polymorphism in organic materials


Postscript: benzamide

2726252423222120191817161514131211109876543

75,000

70,000

65,000

60,000

55,000

50,000

45,000

40,000

35,000

30,000

25,000

20,000

15,000

10,000

5,000

0

-5,000

Form 1 17.10 %Form II 82.90 %

Benzamide: a scientific treasure huntDavey / Pulham /DavidFeynman Room, Thursday lunchtime


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, 25 th erice crystallography course, 9-20 june 2004

Documents

xray powder diffraction

form b

accurate powder data

novel forms

melting endotherm

melting points

degree c

strong intensity peaks