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Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004.

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Presentation on theme: "Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004."— Presentation transcript:

1 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004

2 Polymorphism and X-ray powder diffraction: Applications Bill David, ISIS, Rutherford Appleton Laboratory, Chilton, Oxfordshire, UK

3 Diversity amidst Similarity, 25 th 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

4 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 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 m m m m m m m m m m crystalline 300Å 10  m 1mm single crystal 300Å 10  m powders

5 Diversity amidst Similarity, 25 th 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)

6 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Preconceptions: Powders are a fingerprint –intensities are not reliable

7 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 United States Patent Application 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.

8 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 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 degree. C. 25. The crystalline form of ondansetron of claim 24 wherein the melting endotherm has a magnitude of Joules per gram. United States Patent Application Kind Code A1 Aronhime, Judith ; et al.January 29, 2004

9 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June A crystalline form of ondansetron characterized by a powder X-ray diffraction pattern having peaks at 25.4, 26.7 and 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 degrees two-theta and medium intensity peaks at 25.4 and 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, degrees two-theta. United States Patent Application Kind Code A1 Aronhime, Judith ; et al.January 29, 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.

10 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis I. 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

11 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis II. 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)  

12 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis II. 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)

13 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis II. Data collection – variable counting time Count scheme Form-factor fall-off

14 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis II. Data collection – variable counting time Count scheme

15 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Collecting accurate powder data for structural analysis II. Data collection – variable counting time

16 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 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

17 Diversity amidst Similarity, 25 th 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.

18 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Line broadening: size and strain strainsize

19 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Line broadening: urea as received lightly ground (0 0 2)(0 2 1)(2 1 0)

20 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Bill Marshall, ISIS P P P-42 1 m

21 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 lightly ground Line broadening: urea as received (0 0 2)(0 2 1)(2 1 0)

22 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Neutron powder diffraction finds protons

23 Diversity amidst Similarity, 25 th 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

24 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Two polymorphs of Zantac®, ranitidine hydrochloride (max 12K) (max 176K) courtesy Peter Stephens, SUNY

25 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004

26 X-ray powder diffraction Hundreds of lines … … not thousands There is much less information in a powder diffraction pattern than a single crystal pattern … so why use powders?

27 The algorithm Basic information theory... bits of information Single crystal data Crystal structure Powder data Molecular topology It’s tougher solving structures from powders than from single crystals. Other experiments

28 known... not known... 11 22 33 44 55 66 77 + position & orientation Simplifying the search problem 3N  {xyz} + {  } +  48  13 parameters

29 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 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 (N par ) ranges from modest (AZ I) to challenging (AZ IV, V) for global optimisation. DASH 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.

30 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 A brief introduction to four examples … Paracetamol hydrates Zopiclone hydrates Carbamazepine Benzamide

31 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine

32 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine pure  -carbamazepine  -carbamazepine (ex tablet)

33 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine pure  -carbamazepine pure  -carbamazepine

34 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine

35 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine 12 34

36 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Structure solution of polymorphs and hydrates from powder data: Example 1: carbamazepine 12 34

37 Dehydration of pharmaceutical compounds Zopiclone hydrates C 17 H 17 ClN 5 O 3.2H 2 O hypnotic – insomnia line phases: dihydrate - anhydrous Paracetamol hydrates C 8 H 9 NO 2.nH 2 0 pain-killer, analgesic, antipyretic 4'-hydroxyacetanilide, acetaminophen, tylenol

38 Zopiclone dehydration and phase transformations TGA DSC -7.17ww% = 2H 2 O

39 monoclinic dihydrate 298 K monoclinic anhydrous 325 K ID31 ESRF cryostream chiral + H 2 0 hygroscopic + 2H 2 0 racemate 350 K orthorhombic anhydrous - 2H 2 0 Zopiclone dehydration and phase transformations

40 2 theta dihydrate anhydrous T( o C)

41

42 zopiclone monohydrate zopiclone

43 dihydrate zopiclone

44 2 theta Temperature ( o C) not simply line-phase behaviour (i.e. dihydrate – anhydrous)

45 2H 2 O xH 2 O no H 2 O

46 TOPAS zopiclone dihydrate standard line-shape (axial divergence …)

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51 time 22 0oC0oC 35 o C 30 o C

52 water+amorphous crystallisation + ice formation ice melting trihydrate step-function in water background trihydrate – monohydrate transformation novel phase formation new intermediate phase monohydrate time 22

53 new intermediate phase time 22 2 mins

54 run 5 run 7 run 9 almost pure new phase new + trihydrate + ice pure trihydrate

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58 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Postscript: benzamide Wohler & Liebig, 1832 First observation of polymorphism in organic materials

59 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 Postscript: benzamide Benzamide: a scientific treasure hunt Davey / Pulham /David Feynman Room, Thursday lunchtime

60 Diversity amidst Similarity, 25 th Erice Crystallography Course, 9-20 June 2004 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.


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