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X-ray Powder Diffraction: exposing the bare bones of solid forms Dr. Noel Hamill
Welcome <ul><li>Dr Noel Hamill,Team Leader Physical Sciences, ALMAC </li></ul><ul><li>[email_address] </li></ul><ul><li>Wi...
Contents <ul><li>Theory of powder diffraction </li></ul><ul><li>X-ray Powder Diffraction </li></ul><ul><ul><li>Instrumenta...
Theory <ul><li>A crystalline powder contains many small crystallites, ideally randomly oriented </li></ul><ul><li>Diffract...
Diffraction by crystal planes crystalline amorphous θ  ~ 20º x-rays in x-rays out top of sample θ  ~ 5º x-rays in x-rays o...
Diffraction from powders <ul><li>Rings of x-rays diffracted from a crystalline powder as captured by an area detector </li...
X-ray Powder Diffraction <ul><li>Information from a powder pattern: </li></ul><ul><ul><li>Angular position of diffraction ...
X-ray Diffractometer <ul><li>Traditional set-up </li></ul><ul><li>Prone to errors due to sample preparation </li></ul>Refl...
Transmission mode  <ul><li>Reduces preferred orientation from ‘difficult’ crystallite shapes (tiles, needles) </li></ul><u...
Instrument capabilities <ul><li>Autosampling </li></ul><ul><li>Variable temperature </li></ul><ul><li>In situ measurement ...
Sources of error <ul><li>The powder pattern can be affected by: </li></ul><ul><ul><li>Sample height displacement </li></ul...
Sample Displacement Error <ul><li>In reflection mode, if the sample height is different from the focal plane, peak positio...
Preferred Orientation <ul><li>Preferred orientation arises when there is a tendency for the crystallites in a powder to be...
Preferred Orientation calculated acetaminophen XRPD pattern  (refcode HXACAN01) XRPD pattern from the (100) face of manual...
Particle Statistics <ul><li>Theory suggests particles < 20   m are best </li></ul><ul><li>Ideally, large particles should...
Reducing measurement errors <ul><li>Spinning and oscillation </li></ul><ul><li>Reducing particle size to 1-20  m (caution...
Applications <ul><li>Degree of crystallinity </li></ul><ul><li>Phase identification </li></ul><ul><li>Unit cell indexing <...
Crystallinity
Phase identification <ul><li>Diffraction pattern is like a fingerprint for a crystal phase </li></ul><ul><li>Rarely, mater...
Polymorph detection <ul><li>As instruments become more sensitive, identification of new polymorphs possible </li></ul><ul>...
Unit cell indexing <ul><li>Searching for a space group and unit cell dimensions which match the peak positions in the obse...
Crystal structure by XRPD <ul><li>Rapid advances are being made in techniques to solve a crystal structure from an XRPD pa...
Mixture analysis Patterns are additive 5000 10000 Counts Position [°2Theta] 15 20 25 30 Position [°2Theta] 10 15 20 25 30 ...
Quantitative analysis <ul><li>Quantitative analysis of mixtures can be carried out if proper attention is paid to instrume...
Method development & validation <ul><li>Phase III API with 3 forms </li></ul><ul><li>Developed and validated transmission ...
Method validation issues <ul><li>Particle size needs to be controlled </li></ul><ul><li>Preferred orientation needs to be ...
Thank you for your time… ..any questions?
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X-ray Powder Diffraction:exposing the bare bones of solid forms

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The theory of powder diffraction
X-ray Powder Diffraction.
Instrumentation.
Sources of error.
Applications.
Case studies.

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X-ray Powder Diffraction:exposing the bare bones of solid forms

  1. 1. X-ray Powder Diffraction: exposing the bare bones of solid forms Dr. Noel Hamill
  2. 2. Welcome <ul><li>Dr Noel Hamill,Team Leader Physical Sciences, ALMAC </li></ul><ul><li>[email_address] </li></ul><ul><li>With nearly 10 years experience of working in the pharmaceutical industry, Noel’s current role includes; crystallisation development, solid form screening & characterisation, method development & validation. </li></ul><ul><li>Almac is privately owned, financially stable company with ~ 3,000 employees, global HQ in Northern Ireland with extensive facilities in the UK and US. </li></ul><ul><li>Almac has a comprehensive range of services from research through pharmaceutical & clinical development to commercialisation of product. </li></ul><ul><li>www.almacgroup.com </li></ul>
  3. 3. Contents <ul><li>Theory of powder diffraction </li></ul><ul><li>X-ray Powder Diffraction </li></ul><ul><ul><li>Instrumentation </li></ul></ul><ul><ul><li>Sources of error </li></ul></ul><ul><ul><li>Applications </li></ul></ul><ul><li>Case studies </li></ul>
  4. 4. Theory <ul><li>A crystalline powder contains many small crystallites, ideally randomly oriented </li></ul><ul><li>Diffraction occurs when crystallites are oriented such that specific atomic planes are in the correct relationship with the incoming x-rays </li></ul>Bragg’s law: n  =2dsin  Constructive interference is detected when the path-length difference is equal to an integer number of wavelengths
  5. 5. Diffraction by crystal planes crystalline amorphous θ ~ 20º x-rays in x-rays out top of sample θ ~ 5º x-rays in x-rays out top of sample
  6. 6. Diffraction from powders <ul><li>Rings of x-rays diffracted from a crystalline powder as captured by an area detector </li></ul><ul><li>Not uniform in intensity </li></ul><ul><ul><li>Particle statistics or preferred orientation </li></ul></ul><ul><ul><li>Need to spin the sample </li></ul></ul><ul><li>Integration of intensity along any radius (in blue) gives a plot of angle 2  vs. intensity </li></ul><ul><li>Small angle = large d spacing </li></ul>
  7. 7. X-ray Powder Diffraction <ul><li>Information from a powder pattern: </li></ul><ul><ul><li>Angular position of diffraction maxima </li></ul></ul><ul><ul><li>Peak intensities </li></ul></ul><ul><ul><li>Peak shape and width </li></ul></ul>
  8. 8. X-ray Diffractometer <ul><li>Traditional set-up </li></ul><ul><li>Prone to errors due to sample preparation </li></ul>Reflection mode (Bragg-Brentano geometry)
  9. 9. Transmission mode <ul><li>Reduces preferred orientation from ‘difficult’ crystallite shapes (tiles, needles) </li></ul><ul><li>Handles small amounts of sample (e.g. ~1mg using glass capillary) </li></ul><ul><li>Samples can be sealed from air or humidity, or kept as a suspension </li></ul><ul><li>Up to 40 º 2  , focusing mirror gives better data quality vs. reflection mode </li></ul>
  10. 10. Instrument capabilities <ul><li>Autosampling </li></ul><ul><li>Variable temperature </li></ul><ul><li>In situ measurement </li></ul><ul><ul><li>Suspensions </li></ul></ul><ul><ul><li>% RH </li></ul></ul><ul><ul><li>Radiolabelled </li></ul></ul><ul><ul><li>Potent API </li></ul></ul><ul><li>Pattern sorting software </li></ul>
  11. 11. Sources of error <ul><li>The powder pattern can be affected by: </li></ul><ul><ul><li>Sample height displacement </li></ul></ul><ul><ul><ul><li>Sample is not at the instrument focal plane </li></ul></ul></ul><ul><ul><li>Preferred orientation </li></ul></ul><ul><ul><ul><li>Particles (crystallites) are oriented relative to each other </li></ul></ul></ul><ul><ul><li>Particle statistics </li></ul></ul><ul><ul><ul><li>Too few or too large particles (crystallites) </li></ul></ul></ul><ul><li>Sample preparation is very important! </li></ul>
  12. 12. Sample Displacement Error <ul><li>In reflection mode, if the sample height is different from the focal plane, peak positions will be shifted </li></ul><ul><li>This effect is minimised in transmission mode </li></ul>sample focal plane Chen et al J. Pharm. Biomed. Analysis 2001 , 26 , 63 Incident X-rays peak shift Diffracted X-rays
  13. 13. Preferred Orientation <ul><li>Preferred orientation arises when there is a tendency for the crystallites in a powder to be oriented in one way </li></ul><ul><li>Random orientation of particles can exist only if their shape is spherical </li></ul><ul><li>In real samples, preferred orientation of particles is always present and measured intensities of diffractions are incorrect. This can result in ‘missing peaks’ </li></ul>random orientation realistic orientation
  14. 14. Preferred Orientation calculated acetaminophen XRPD pattern (refcode HXACAN01) XRPD pattern from the (100) face of manually oriented acetaminophen single crystals (Wen et al J. Phys. Chem. B 2004 , 108 , 11219)
  15. 15. Particle Statistics <ul><li>Theory suggests particles < 20  m are best </li></ul><ul><li>Ideally, large particles should be ground </li></ul><ul><ul><li>Beware of possible phase changes upon grinding </li></ul></ul><ul><li>Sieving may help </li></ul><ul><ul><li>Beware of separating different Forms! </li></ul></ul><ul><li>Line broadening occurs for particles <1  m </li></ul>
  16. 16. Reducing measurement errors <ul><li>Spinning and oscillation </li></ul><ul><li>Reducing particle size to 1-20  m (caution!) </li></ul><ul><li>Transmission mode (esp. using capillaries) </li></ul>
  17. 17. Applications <ul><li>Degree of crystallinity </li></ul><ul><li>Phase identification </li></ul><ul><li>Unit cell indexing </li></ul><ul><li>Crystal structure solution </li></ul><ul><li>Mixture analysis </li></ul>
  18. 18. Crystallinity
  19. 19. Phase identification <ul><li>Diffraction pattern is like a fingerprint for a crystal phase </li></ul><ul><li>Rarely, materials will yield matching XRPD patterns </li></ul><ul><ul><li>Other analytical techniques used to distinguish isostructural materials </li></ul></ul><ul><li>One extra peak at low angle is common in isostructural solvates </li></ul>erythromycin A R = OH erythromycin B R = H Stephenson et al J. Pharm. Sci. 1997 , 86 , 1239
  20. 20. Polymorph detection <ul><li>As instruments become more sensitive, identification of new polymorphs possible </li></ul><ul><li>Detection limits also decrease – caution with term ‘none detected’ </li></ul>A D E
  21. 21. Unit cell indexing <ul><li>Searching for a space group and unit cell dimensions which match the peak positions in the observed pattern. </li></ul><ul><li>To be successful, the pattern must </li></ul><ul><ul><li>Represent one crystalline phase </li></ul></ul><ul><ul><li>Have very accurate peak positions </li></ul></ul><ul><li>Indexing a pattern from an unknown sample is compelling evidence that the pattern represents a pure crystalline phase </li></ul><ul><li>Useful for comparison of cell volume (e.g. solvates) </li></ul>
  22. 22. Crystal structure by XRPD <ul><li>Rapid advances are being made in techniques to solve a crystal structure from an XRPD pattern alone </li></ul><ul><li>However, currently the structure of crystals containing only relatively rigid molecules have the best chance of being solved in this way </li></ul><ul><li>It is currently difficult or impossible to solve structures of molecules having many degrees of conformational freedom </li></ul><ul><li>Almac/UCC research partnership underway </li></ul>
  23. 23. Mixture analysis Patterns are additive 5000 10000 Counts Position [°2Theta] 15 20 25 30 Position [°2Theta] 10 15 20 25 30 Counts 2000 4000 Crystalline Form A Crystalline Form B Amorphous Resulting XRD pattern Multi-phase sample
  24. 24. Quantitative analysis <ul><li>Quantitative analysis of mixtures can be carried out if proper attention is paid to instrument configuration and sample preparation </li></ul><ul><ul><li>Be particularly conscious of preferred orientation </li></ul></ul><ul><li>Mixtures of crystalline phases </li></ul><ul><ul><li>Ratios of peak areas or intensities </li></ul></ul><ul><ul><li>Whole-pattern methods </li></ul></ul><ul><li>Mixtures of crystalline and non-crystalline phases </li></ul><ul><ul><li>Integrated intensities of crystalline and non-crystalline regions </li></ul></ul><ul><ul><li>Whole-pattern methods </li></ul></ul>
  25. 25. Method development & validation <ul><li>Phase III API with 3 forms </li></ul><ul><li>Developed and validated transmission XRPD method </li></ul><ul><ul><li>Quantify Form III in Form I </li></ul></ul><ul><ul><li>LOQ: 3% Form III </li></ul></ul><ul><ul><li>Limit test Form II (LOD 0.5%) </li></ul></ul><ul><ul><li>22 min run time </li></ul></ul><ul><li>Challenges </li></ul><ul><ul><li>Mixing: effect of milling </li></ul></ul><ul><ul><li>API potency </li></ul></ul>Transmission
  26. 26. Method validation issues <ul><li>Particle size needs to be controlled </li></ul><ul><li>Preferred orientation needs to be eliminated </li></ul><ul><li>Standards need to be pure physical forms (e.g. can they be indexed?) </li></ul><ul><li>Robustness of instrument and sample preparation parameters should be tested routinely </li></ul>
  27. 27. Thank you for your time… ..any questions?

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