LASENTEC Monitoring and Quantifing Polymorphic Crystallizations The Application of Raman James Ward Paul Barrett  MT AutoC...
Presentation overview <ul><li>Brief introduction of raman and overview of particle size </li></ul><ul><li>Case studies tha...
PVM Images: Particle shape and crystallization
FBRM: Lab to Production Lab to Plant installations
Introduction to Raman <ul><li>Phenomena documented in 1928 – Raman & Krishnan </li></ul><ul><li>C.V. Raman and K.S. Krishn...
FBRM/Raman in 1 probe Source: Laser Illumination Fiber Collection Fiber Probe CCD Detector Echelle Grating Mirror Probe Di...
What is Raman? “We’re not talking noodles here” <ul><li>Raman - Based on measurements of inelastic scattering of monochrom...
Raman Spectroscopy Elastically Scattered light Majority of scattered light is elastically scattered light Raman scattering...
What does Raman measure in polymorphism? => Shift in Raman spectra Polymorphs => Different intermolecular bonding Slightly...
Spectrum Comparison-Polystyrene FT-IR Transmission Spectrum FT-Raman Spectrum 20 40 60 80 %Transmittance 1 2 3 4 Raman Int...
<ul><li>Carbamazepine (CBZ)  </li></ul><ul><li>Tegretol-Xr®   Carbatrol®   Atretol®   Tegretol® </li></ul><ul><li>Indicate...
Recent References Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice...
Hydration of CBZ <ul><li>Objectives </li></ul><ul><ul><li>Follow Hydration of CBZ with FBRM & PVM </li></ul></ul>Form I Fo...
The Hydration - Particle Dynamics via FBRM & PVM Anhydrous CBZ Charged PVM Image Trended FBRM particle counts Chords Per S...
The Hydration - Particle Dynamics via FBRM & PVM Anhydrous CBZ Charged PVM Image Trended FBRM particle counts Chords Per S...
The Hydration - Particle Dynamics via FBRM & PVM Dry material disperses Increase in coarse particles as material aggregate...
The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) T...
The Hydration - Particle Dynamics via FBRM & PVM Platelets disappear (drop in coarse) Needles appear (increase in fine cou...
The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) T...
The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) T...
The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) T...
The Hydration - Particle Dynamics via FBRM & PVM Coarse increase again - Needle lengthening PVM Image Trended FBRM particl...
The Hydration - Particle Dynamics via FBRM & PVM Steady state is achieved No additional significant change in dimension, s...
How can Raman be utilized for the CBZ example?
Spectral changes during CBZ hydration <ul><li>PEAK </li></ul><ul><li>INTENSITY </li></ul><ul><li>CHANGES </li></ul>B) PEAK...
Raman & FBRM – Complementary technologies HOWEVER, We know that particle number, dimension and shape are changing over tim...
Why is Raman signal influenced by particles? Consider backscatter turbidity: Light striking a particle is  scattering in a...
Turbidity:  Time/Intensity The turbidity measurement is a convoluted function of: Solids Concentration  Particle Size Part...
Turbidity:  same reading, different particle systems Same Turbidity Measurement Same Turbidity Measurement FBRM can be uti...
What about Raman? From a theory perspective, it appears that the backscatter intensity, for a given material at a given wa...
Utilizing Raman for crystallizations Is there a relationship between particle dimension and particle concentration and the...
Example 3: The influence of Particle Dimension and Particle Number on Raman Spectra
Two model materials selected <ul><li>Mannitol and Sucrose </li></ul><ul><li>Not polymorphs, but 2 distinct Raman spectra <...
As the solids concentration of the fine sucrose increases, there is a direct linear relationship between the solids concen...
Raman is a function of the particle system The Raman measurement is a convoluted function of: A - Solids Concentration  B ...
10 g of large Sucrose,  10 g of milled Sucrose So what if size of material is changed? Chord Length Microns Chords Per Sec...
Raman Spectra Peak height of coarse 5025 Peak height of fines 4315 No change in solids concentration, but a 15% change in ...
As the solids concentration of the fine sucrose and fine mannitol changes, there is a direct linear relationship between t...
The Raman intensities no longer correlate to relationship on slide 56 => Particle Dimension and Particle Concentration hav...
<ul><li>As illustrated on the previous slide, If particle concentration or particle dimension increase or decrease, intens...
Liquid Phase peaks also change with changing particle size and particle concentration The toluene peak is heavily effected...
Building calibration curve without taking into consideration effects of dimension and concentration is not advised Quantit...
<ul><li>Raman is sensitive to solids Concentration, this may be linear or non-linear depending on particle size/shape dist...
<ul><li>If two different solids are present, such as Polymorph A and Polymorph B, the Particle Size distribution and solid...
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  • THIS IS A MOVIE. There is no explaination
  • Important We used a deconvolution software called ConcIRT. It uses a simplex algorithm Possible quesiton - How do you now the algorithm works. I wll give the reason Friday
  • Monitoring and quantifing polymorphic crystallizations (james ward 111203)compressed

    1. 1. LASENTEC Monitoring and Quantifing Polymorphic Crystallizations The Application of Raman James Ward Paul Barrett MT AutoChem Polymorphism & Crystallization Forum 2003 November 12, 2003 Internet - [email_address] Phone (484) 343-5514
    2. 2. Presentation overview <ul><li>Brief introduction of raman and overview of particle size </li></ul><ul><li>Case studies that highlight the benefit and considerations of Raman </li></ul>
    3. 3. PVM Images: Particle shape and crystallization
    4. 4. FBRM: Lab to Production Lab to Plant installations
    5. 5. Introduction to Raman <ul><li>Phenomena documented in 1928 – Raman & Krishnan </li></ul><ul><li>C.V. Raman and K.S. Krishnan Nature 501 (1928), p. 3048. </li></ul><ul><li>Until relatively recently considered purely as an academic technique </li></ul><ul><li>Several key technologies changed that perspective; - compact lasers scientific CCD detectors - volume holographic element </li></ul><ul><li>- easy-to-use computing platforms </li></ul>
    6. 6. FBRM/Raman in 1 probe Source: Laser Illumination Fiber Collection Fiber Probe CCD Detector Echelle Grating Mirror Probe Diameter : 19 mm
    7. 7. What is Raman? “We’re not talking noodles here” <ul><li>Raman - Based on measurements of inelastic scattering of monochromatic light from molecules </li></ul><ul><li>Monochromatic light striking a molecule changes the electron distribution resulting in scattering (release of energy) of radiation. </li></ul>hn 0
    8. 8. Raman Spectroscopy Elastically Scattered light Majority of scattered light is elastically scattered light Raman scattering is a low probability event Approx 0.0001% of photons show a shift in frequency – i.e. Raman scattering Anti- Stokes Infrared Raman Electronic levels Vibrational levels Virtual levels Rayleigh Fluorescence Stokes Molecule of interest
    9. 9. What does Raman measure in polymorphism? => Shift in Raman spectra Polymorphs => Different intermolecular bonding Slightly different electron distributions in ‘molecular enviroment’ & ‘lattice enviroment’
    10. 10. Spectrum Comparison-Polystyrene FT-IR Transmission Spectrum FT-Raman Spectrum 20 40 60 80 %Transmittance 1 2 3 4 Raman Intensity 1000 2000 3000 4000 Wavenumbers (cm -1 )
    11. 11. <ul><li>Carbamazepine (CBZ) </li></ul><ul><li>Tegretol-Xr® Carbatrol® Atretol® Tegretol® </li></ul><ul><li>Indicated for the treatment of epilepsy, </li></ul><ul><li>trigeminal neuralgia, bipolar affective </li></ul><ul><li>disorder and acute mania </li></ul><ul><li>Four known Forms - Marketed as Form I </li></ul><ul><li>FDA recalled the product from the market for dissolution problems 5 times in the last 5 years </li></ul>Hydration of Carbamazepine (CBZ) Background
    12. 12. Recent References Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder , International Journal Of Pharmaceutics, Volume 246, Issue 1-2, October 10, 2002, Pages 121-134 Murphy, D; Rodríguez-Cintrón, F; Langevin, B; Kelly, R C; Rodríguez-Hornedo, N Solid-state study of polymorphic drugs: carbamazepine , Journal Of Pharmaceutical And Biomedical Analysis, Volume 23, Issue 1, August 1, 2000, Pages 41-54 Rustichelli, C; Gamberini, G; Ferioli, V; Gamberini, M C; Ficarra, R; Tommasini, S
    13. 13. Hydration of CBZ <ul><li>Objectives </li></ul><ul><ul><li>Follow Hydration of CBZ with FBRM & PVM </li></ul></ul>Form I Form II CBZ dihydrate Slurry in Water Heat Slurry in EtOH Heat Slurry in Water Polymorphism of CBZ
    14. 14. The Hydration - Particle Dynamics via FBRM & PVM Anhydrous CBZ Charged PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    15. 15. The Hydration - Particle Dynamics via FBRM & PVM Anhydrous CBZ Charged PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    16. 16. The Hydration - Particle Dynamics via FBRM & PVM Dry material disperses Increase in coarse particles as material aggregates and dip in fines PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    17. 17. The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    18. 18. The Hydration - Particle Dynamics via FBRM & PVM Platelets disappear (drop in coarse) Needles appear (increase in fine counts) PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    19. 19. The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    20. 20. The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    21. 21. The Hydration - Particle Dynamics via FBRM & PVM PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    22. 22. The Hydration - Particle Dynamics via FBRM & PVM Coarse increase again - Needle lengthening PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    23. 23. The Hydration - Particle Dynamics via FBRM & PVM Steady state is achieved No additional significant change in dimension, shape or number of crystals PVM Image Trended FBRM particle counts Chords Per Second (not to scale) Time Microns Microns
    24. 24. How can Raman be utilized for the CBZ example?
    25. 25. Spectral changes during CBZ hydration <ul><li>PEAK </li></ul><ul><li>INTENSITY </li></ul><ul><li>CHANGES </li></ul>B) PEAK SHIFTS TIME TIME
    26. 26. Raman & FBRM – Complementary technologies HOWEVER, We know that particle number, dimension and shape are changing over time. Can this effect the Raman interpretation? Chemometrics utilized to trend ‘concentration of each form over time Form 1 Dihydrate
    27. 27. Why is Raman signal influenced by particles? Consider backscatter turbidity: Light striking a particle is scattering in all directions Vast majority of light collected coming back towards the probe has the same wavelength as the outgoing light. This phenomena is termed elastic light scattering How does light interact with a particle system?
    28. 28. Turbidity: Time/Intensity The turbidity measurement is a convoluted function of: Solids Concentration Particle Size Particle Shape Particle Size/Shape Distribution If three of these four properties are held constant, the fourth can be quantified.
    29. 29. Turbidity: same reading, different particle systems Same Turbidity Measurement Same Turbidity Measurement FBRM can be utilized to detect differences based on dimension, number and shape of particles under investigation = = = Same Projected area, different size and different solids concentration. = = = Same Projected area, different shape and possibly different solids concentration.
    30. 30. What about Raman? From a theory perspective, it appears that the backscatter intensity, for a given material at a given wavelength as measured by a bulk measurement instrument like turbidity, is directly proportional to the Raman intensity. It is evident from experimental data that particle concentration, particle dimension and particle shape can effect the Raman intensity.
    31. 31. Utilizing Raman for crystallizations Is there a relationship between particle dimension and particle concentration and the intensity of the peaks in the Raman Spectra? Raman intensities change as material dimension (and shape) are changed Some Recent Work: Ensuring Robust Polymorph Isolation Using In-Situ Raman Spectroscopy George Zhou, Ph.D., Jian Wang*, Ph.D., Zhihong Ge, Ph.D., Yongkui Sun, Ph.D Merck Research Laboratories, Merck & Co.,
    32. 32. Example 3: The influence of Particle Dimension and Particle Number on Raman Spectra
    33. 33. Two model materials selected <ul><li>Mannitol and Sucrose </li></ul><ul><li>Not polymorphs, but 2 distinct Raman spectra </li></ul>Investigate effect of Particle Concentration and Particle Dimension on Raman Spectra using this simple system Mannitol peak at 875 cm -1 Sucrose peak at 845 cm -1
    34. 34. As the solids concentration of the fine sucrose increases, there is a direct linear relationship between the solids concentration and the intensity of the Raman Sucrose peak 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000 0 2 4 6 8 10 12 Fine Sucrose concentration (g/100 ml Toluene) Raman Peak Intensities Increasing concentration of fine sucrose
    35. 35. Raman is a function of the particle system The Raman measurement is a convoluted function of: A - Solids Concentration B - Particle Size C- Particle Shape D - Particle Size/Shape Distribution Just like turbidity, if 3 of these variables are held constant the other can be quantified directly. In this case, B,C,D are constant => Directly correlate Raman to solids concentration
    36. 36. 10 g of large Sucrose, 10 g of milled Sucrose So what if size of material is changed? Chord Length Microns Chords Per Second Reduction in coarse Increase in fines Milled Large Sucrose
    37. 37. Raman Spectra Peak height of coarse 5025 Peak height of fines 4315 No change in solids concentration, but a 15% change in signal !!! Particle size changed, solids concentration held constant Intensity Change N.B. Although we have seen behavior in both directions, ( i.e. increase in signal with reduction in size at same concentration, as well as decrease for different materials) Always the same behavior for the same materials.
    38. 38. As the solids concentration of the fine sucrose and fine mannitol changes, there is a direct linear relationship between the solids concentration and the intensity of the Raman peaks of each ‘form’ Samples of 2 materials of relatively the same size, but changing their ratios Increasing Mannitol conc Decreasing Sucrose conc
    39. 39. The Raman intensities no longer correlate to relationship on slide 56 => Particle Dimension and Particle Concentration have large influence Samples of 2 materials of DIFFERENT sizes, and changing their ratios Fine material obscures the coarse
    40. 40. <ul><li>As illustrated on the previous slide, If particle concentration or particle dimension increase or decrease, intensity changes in the Raman spectra do not reflect true changes in polymorph ratios </li></ul><ul><li>Need to take into account changes in Particle Dimension and Concentration over time </li></ul><ul><li>FBRM/Raman and chemometrics </li></ul>Utilizing Raman for dynamic crystallizations
    41. 41. Liquid Phase peaks also change with changing particle size and particle concentration The toluene peak is heavily effected by the dimension and number of particle present. It is therefore difficult to use Raman to track quantitatively the liquid phase concentration in the presence of solids Solids concentration is constant, but dimension varies
    42. 42. Building calibration curve without taking into consideration effects of dimension and concentration is not advised Quantitative information from Raman We have to go back and check the reasonable assumptions we have made in the past.
    43. 43. <ul><li>Raman is sensitive to solids Concentration, this may be linear or non-linear depending on particle size/shape distribution. More work to be done. </li></ul><ul><li>Raman is intensity is a function of particle size, in some cases trends in same direction, some cases inverse, depends on the system, but most likely a constant within a system. </li></ul>Summary
    44. 44. <ul><li>If two different solids are present, such as Polymorph A and Polymorph B, the Particle Size distribution and solids concentration of each, and the change of these variables can influence NOT ONLY their own Raman Intensity response, but also the response of the other polymorph. </li></ul><ul><li>The liquid concentration measurement shown by Raman, in the presents of particles, must be tracked in relationship to the change in the particle system. </li></ul><ul><li>The Particle System is a integral part of the optical system, Raman research in particle systems must take the change in the particle system into account </li></ul>Summary

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