Application of imaging techniques tooral dosage forms.Examples of in-situ imaging.Paolo AvalleMerck Sharp & Dohme (UK’CH)
Introduction• Direction of modern formulation efforts:– improve the solubility of the drugs with effective formulation– tu...
Agenda•Mechanism of dissolution explored by imaging techniques– NIR microscopy– MRI•Conclusions & Acknowledgements
NIR microscopy• Applications & Case studies:1. Distribution of API and excipients.– Formulation development: CR pellets– F...
NIR spectroscopy• High content imaging I achieved by rasterized acquisition of spectra.• A single spectrum is acquired at ...
GMS-900PVPOptical ImagePVPAvicel Ethocel TECAPI LactoseReconstructed imagewith background suppressionArtifact.No coating p...
• The distribution of different chemicals is represented in colour-coded intensity maps.• The maps of two chemicals can be...
•Maps obtained by Least square fitting of the NIR spectra of the 7 pure components.•Maps were masked to remove the backgro...
Scatter plot• The intensity of Each pixel of the API map is used as X-coordinate.• The intensity of Each Pixel of the AVIC...
Date: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0256-0.020-0.015-0.010-0.0050.0000.0050....
Scheme for tablet hydration.- swelling.- drug migration vs. dissolution - polymerdissolution within a controlled releasefo...
TABLETS:400 mg, 8 mm, flat-faced tablets containing 125 mg dose of a low solubility drug (MK-1),IN FLOW ANALYSIS:A bespoke...
The subsequent acquisition of spectral map and their processingAllow to follow the evolution of the API signal and the HPM...
FastSlowFastSlowFastSlowThe hydration profiles exhibited several trends:1. An apparent high intensity plateau, correspondi...
The erosion, swelling and API dissolution front forboth formulation SLOW AND FAST with datamodellingThe data were modelled...
• Image Size: 6000 x 2000 µm• Pixel Size: 25 µm• Scan Time: ~ 18 min• Scan Frequency: Every 30 min•Medium: Deionised Water...
STEP by STEP processing roadmapBlack = experimental spectrum (PLS target) Blue = PLS FitLoad *.fsm inTransmittanceLoad *.f...
API Maps from PLS30’ 60’ 90’ 120’ 150’ 180’ 210’ 240’#1#2#330’ 60’ 90’ 120’ 150’ 180’ 210’ 240’HPMC Maps from PLSIn-situ N...
API depletion and hydration profiles from PLS API mapsselective enhancement8 bit BlueChannelconversionR3 240’8 bitGrayscal...
Mechanism of release: Swelling and Erosion fronts.Physical tablet boundaryPLS API mapR2 30’PLS API mapR2 240’Is it possibl...
R1 R2 R3ZOOM-IN on EROSION AND DISSOLUTION FRONTSMechanism of release:Swelling and Erosion fronts. Source of error barsPhy...
API / HPMCSpatial Co-location of API and HPMC• API and HPMC are clearly co-located•Their distribution is not mutually excl...
• This approach enables the editing of a sequence of images• The gel layer region (dark green) show low API concentration,...
1 1NIRpostPLSNIRpostPLSAPI-HPMCcorrelationAPI-HPMCcorrelation2 2 2 2 2 2API distribution time course• From the correlation...
30’ 60’ 90’ 120’150’ 180’ 210’ 240’Single particle tracking : Particle 1Presented at UKPharmSCI 2011, paper in progress
30’ 60’ 90’ 120’150’ 180’ 210’ 240’1. Aggregation2. Migration 3. DisintegrationBlue contour: indicated the particle frame ...
30’ 60’ 90’ 120’ 150’ 180’ 210’ 240’Particle -1dissolvedParticle -1 show a a dissolution behaviour, fragmentation is also ...
Ref. frameBecause of the complex aggregation and migration the perimeter is not a good descriptor of the time course as th...
•In-situ MRI- Acquisition of MRI data during the dissolution,- Hyphenation of USP-IV dissolution with MRI.
Hyphenation of USP-IV dissolution with MRI.NMR spectrometerPeristalticpump SGFUSP-IVFlow-through cellxyzImagingplaneFaSSIF...
In-situ MRIFluvastatin123Fluvastatin123pKa1 = 4.27pKa2 = 13.98pKa3 = 14.96Formulation composition- 84.24 mg Fluvastatin So...
In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XLWater Maps0 100%[H2O]IN PRESS: Journal of Controlled Release
In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XLT2 relaxation mapsT2-relxation maps shown indicate a quite...
(a) (b)In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XL19F Signals: Combining imaging with high resolution...
Conclusions• Imaging: Seeing is believing.• Current and more complex formulation dorequire more sophisticated analysistech...
Acknowledgements & Credits• Rob Saklatvalawww.linkedin.com/pub/robert-saklatvala/8/6a4/406• Brett Cooperwww.uk.linkedin.co...
BACKUP
Optical Microscopy• Widely used!– Paolo Colombo demonstrated the gel layergrowth and the evidence of– Colin Melia
Swelling rate of: HPMC K4M, HPMC K100LV, PEO301, PEO1105Correlation with in the physicochemical properties of the polymers...
Previous work findings:1. For a low solubility drug (MK-1) There is differing behaviour with respect to drugrelease from C...
original tablet boundaryRaw Image: Light intensityexpressed as a gray scale0-255 (black to white)Numerical average: each c...
PEO1105PEO301HPMC K100LVHPMC K4MHPMC K4M HPMC K100LVPEO301PEO1105•The gel layer for each polymer matrix system clearly sho...
Optical microscopy: VALIDATION
IN SITU NIR OF HIGH SOLUBILITY DRUGS• Chloropheniramine maleate• MK-2: Understanding Failure mode
ChloropheniraminemaleateCHLOROPHENIRAMINE MALEATE vs ACETYL SALICYLIC ACIDDissolution of 6.4 mm Flat Disc Tablets into Wat...
Mapping chloropheniramine maleate0’60’4175μm3250μmPLS images for HPMC Water front movementErosion –based systems: High sol...
Mapping chloropheniramine maleateTime (minutes)Position(microns)Position(microns)-800-700-600-500-400-300-200-10000 10 20 ...
Understanding Failure Mode
01020304050607080901001100 2 4 6 8 10 12 14 16 18 20Time / hours%LabelClaimUnderstanding Failure modesThe problem□ NON STR...
Understanding Failure modesApproach: replace the API with another of similar propertiesand study the dissolution0102030405...
• The stressed formulation showed a much more rapid and deeper -initial- erosion which isthen followed by a long period in...
MK-2: Rate of Water penetrationfaster in stressed tabletsPhysical tablet boundaryUnderstanding Failure modesFailure mode o...
Caffeine:Stressed vsUnstressed tabletsCaffeine was used as a control for MK-2 NIR in-situ work; data processing was applie...
-1- Significant erosion for stressed Niacin formulations-2- No gross changes in the position of dissolution and erosion fr...
Conclusion (seeing is believing)NON STRESSED MK-2 STRESSED MK-2Time lapse photography: SchematicsPharmaceutical Research,V...
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Paolo avalle discovery chemistry congress2012

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Paolo avalle discovery chemistry congress2012

  1. 1. Application of imaging techniques tooral dosage forms.Examples of in-situ imaging.Paolo AvalleMerck Sharp & Dohme (UK’CH)
  2. 2. Introduction• Direction of modern formulation efforts:– improve the solubility of the drugs with effective formulation– tune the drug release profile to meet the desired Pharmacokineticcriteria.• Focus of the talk: use of imaging techniques as a characterization tool ofdrug-polymers system• Remit of imaging characterization techniques– Provide surface and internal chemical imaging of the whole dosage form or ofindividual components on a macro-, micro- or nanoscale.– Temporal and spatial mapping of the drug release from the tablet matrix andobtaining novel mechanistic insights into the drug liberation phenomena.– Understanding the interplay between the underlying diffusion and erosionmechanism of release and how these can be related to the solubility of thedrug.
  3. 3. Agenda•Mechanism of dissolution explored by imaging techniques– NIR microscopy– MRI•Conclusions & Acknowledgements
  4. 4. NIR microscopy• Applications & Case studies:1. Distribution of API and excipients.– Formulation development: CR pellets– Formulation troubleshooting CR pellets2. In-situ NIR: Imaging the dissolution mechanism.– Diffusion – based systems (“high” solubility)– Erosion –based systems (low solubility)– Failure mode of erosion based matrices3. In-situ MRI: gel layer formation and drug mobilization
  5. 5. NIR spectroscopy• High content imaging I achieved by rasterized acquisition of spectra.• A single spectrum is acquired at each location (pixel) using a moveable stage.• From the collection of location tagged spectra a map can be generated in variousways:- The integrated absorbance of a specific peak- Intensity of a specific peak- PCA- PLSpixel: 25 x 25 µm12341234pixel: 25 x 25 µm12341234
  6. 6. GMS-900PVPOptical ImagePVPAvicel Ethocel TECAPI LactoseReconstructed imagewith background suppressionArtifact.No coating presentin this part of the pelletcfr. Optical ImageGMS-900PVPOptical ImagePVPAvicel Ethocel TECAPI LactoseGMS-900PVPOptical ImagePVPAvicel Ethocel TECAPI LactoseReconstructed imagewith background suppressionArtifact.No coating presentin this part of the pelletcfr. Optical Imagepresented at UKICRS 2010Distribution of API and excipients.1. Distribution of API and excipients1: Horizontal sample support made in-house.2: Adhesive disc.3: Microscope cover slip.4: Glue.5: Sample pellets.6: Rotating tungsten carbide blade.7: Vertical Axis of cutting: this ensures a flat surface8: Horizontal movement of the blade.
  7. 7. • The distribution of different chemicals is represented in colour-coded intensity maps.• The maps of two chemicals can be compared in a pixel-to-pixel fashion to generate a correlation chart• Avicel and API shows a positive correlation indicating potential co-location.• The association of APIand Lactose is somewhat less evident.• API and PVP appear to be anti-correlated.1. Distribution of API and excipientspresented at UKICRS 2010Distribution of API and excipients: Co-localization
  8. 8. •Maps obtained by Least square fitting of the NIR spectra of the 7 pure components.•Maps were masked to remove the background spectra from the Least square fitting of the Map.•Background of the image is showed in blue on the left side and in white on the Reconstructed image.•This maps isolated only 6 out of 7 components. TEC could not be detectedNote1) Negative-correlationbetween the spatialdistributionof LACTOSE and API2) Positive-correlationbetween the spatialdistribution of AVICEL andAPI3) Negative-correlationbut more noisy betweenGMS-900 and MK-11. Distribution of API and excipientspresented at UKICRS 2010Distribution of API and excipients: Co-localization
  9. 9. Scatter plot• The intensity of Each pixel of the API map is used as X-coordinate.• The intensity of Each Pixel of the AVICEL map is used as Y-coordinate.• Two identical maps (for example API vs. API) would generate a straight line with positive correlation.• The colour code of the points indicate their position on the map.• The position is indicated approximately by the colour key in the border of the graph.• White points are located at the centre of the original image.AvicelAPITwo positively correlated clustersa) White and Green, located inthe centre of the pictureindicates a degree ofmatching in the coatingpixels intensities betweenthe two maps.b) Yellow-red, located on theright side of the mapindicate degree of matchingintensities between theAVICEL and MK-0941 mapsabControlled Release pellets MK-1.Spatial Co-locationpresented at UKICRS 2010
  10. 10. Date: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0256-0.020-0.015-0.010-0.0050.0000.0050.0100.0150.0196cm-1ADate: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0139-0.012-0.010-0.008-0.006-0.004-0.0020.0000.0020.0040.0060.0080.0100.0120.0140.0160.0180.0200.0220.0240.0260.0278cm-1A6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0108-0.008-0.006-0.004-0.0020.0000.0020.0040.0060.0080.0100.0120.0140.0160.0180.0199cm-1ADate: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0256-0.020-0.015-0.010-0.0050.0000.0050.0100.0150.0196cm-1ADate: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.180-0.16-0.14-0.12-0.10-0.08-0.06-0.04-0.020.000.020.040.060.080.100.120.140cm-1ADate: 18/04/20066100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0-0.0157-0.014-0.012-0.010-0.008-0.006-0.004-0.0020.0000.0020.0040.0060.0080.0100.0120.0140.0156cm-1A1. Distribution of API and excipientsFormulation troubleshooting CR pellets: PLS data representationFITACTUALFITACTUALFITACTUALFITACTUALFITACTUALFITACTUALpresented at UKICRS 2010
  11. 11. Scheme for tablet hydration.- swelling.- drug migration vs. dissolution - polymerdissolution within a controlled releaseformulation.The particle labelled ‘A’ indicates the drug.While it is commonly accepted that swelling issubsequent to permeation and hydration ofthe tablet the extent of those event and theextent of drug migration vs. dissolution islargely dependent on the solubility of the drugand the viscosity of the polymer. Together,these parameters modulate the releaseprofile.2. In-situ NIR: Imaging the dissolution mechanismBasic Concepts
  12. 12. TABLETS:400 mg, 8 mm, flat-faced tablets containing 125 mg dose of a low solubility drug (MK-1),IN FLOW ANALYSIS:A bespoke tablet hydration cell enabled the acquisition of NIR data during the dissolution process.RESULTSEXPERIMENT SET-UP• Image Size: 3000 x 1000 µm• Pixel Size: 25 µm• Scan Time: ~ 18 min• Scan Frequency: Every 30 min•Medium: Deionised Water•Temperature: 37°C•Flow Rate: 10 mL/min2. In-situ NIR: Imaging the dissolution mechanism
  13. 13. The subsequent acquisition of spectral map and their processingAllow to follow the evolution of the API signal and the HPMC signals.0’ 10’ 20’ 30’ 40’ 50’ 60’ 180’120’90’dryHPMCAPI2. In-situ NIR: Imaging the dissolution mechanismEuropean Journal of Pharmaceutical Sciences 43(5) 400-408Diffusion based systems:: comparing two diffusion-based formulation
  14. 14. FastSlowFastSlowFastSlowThe hydration profiles exhibited several trends:1. An apparent high intensity plateau, corresponding to a uniform distribution of HPMC (dry tablet core)2. A sloped region indicative of a decreasing drug/HPMC concentration across the pseudo-gel layer3. A plateau of low intensity arising from the bulk of the hydration medium.Drug and HPMC profiles from the fast and slow formulationsAs the tablet was exposed to the hydration media, polymer relaxation occurred and theHPMC began to swell and hence the increment in the intensity profile becameprogressively sloped as a consequence.2. In-situ NIR: Imaging the dissolution mechanismDiffusion based systems: comparing two diffusion-based formulationEuropean Journal of Pharmaceutical Sciences 43(5) 400-408
  15. 15. The erosion, swelling and API dissolution front forboth formulation SLOW AND FAST with datamodellingThe data were modelled using the equation firstproposed by Peppas and Sahlin to describe soluterelease from polymeric devices, where FP indicatesthe Front Position (either (i) the erosion front, (ii) theswelling front or (iii) the API front). FP is expressed inmicrons.2. In-situ NIR: Imaging the dissolution mechanismDiffusion based systems:: comparing two diffusion-based formulationEuropean Journal of Pharmaceutical Sciences 43(5) 400-408mmtktkFP 221 +=mmtktkFP 221 +=:THIN GEL LAYER: THICK GEL LAYER
  16. 16. • Image Size: 6000 x 2000 µm• Pixel Size: 25 µm• Scan Time: ~ 18 min• Scan Frequency: Every 30 min•Medium: Deionised Water•Temperature: 37°C•Flow Rate: 10 mL/minComponent %API (MK-1) 31.25HPMC K4M 20.00Avicel PH102 47.75MagnesiumStearate1.00In-situ NIR: Imaging the dissolution mechanismIn-situ and in-flow imaging experimentsErosion –based systems: Low solubility formulationIN-FLOW Imaging
  17. 17. STEP by STEP processing roadmapBlack = experimental spectrum (PLS target) Blue = PLS FitLoad *.fsm inTransmittanceLoad *.fsm inTransmittanceReload*.fsm fileLoad masked .fsmin AbsorbanceProcess /DerivativeProcess / PCA“20 factors”ReviewTargetsReloadmasked .fsm fileProcess / LSQ FitLoad TargetSpectraProcess / SubtractAverage 7800-3800Process / Range7800-3800Process /DerivativeLoad TargetSpectraProcess / SubtractAverage 7800-3800Process / Range7800-3800Review LSQ FitMaskingPLSFittingAPI HPMC AVICELSince the fitting obtained from the PLS is very good the representation of API, HPMC, and AVICEL maps Is tobe considered valid and accurate.Process / PCA“10 factors”Process /MaskProcess / PCA “20 factors”and spatial masking “ALL”In-situ NIR: Imaging the dissolution mechanismPresented at UKPharmSCI 2011, paper in progress
  18. 18. API Maps from PLS30’ 60’ 90’ 120’ 150’ 180’ 210’ 240’#1#2#330’ 60’ 90’ 120’ 150’ 180’ 210’ 240’HPMC Maps from PLSIn-situ NIR: Imaging the dissolution mechanism• Undissolved API is present up to 3 hours and seems to migrate in the gel Layer• Can we zoom in and follow closely the fate of API particles?Erosion –based systems: Low solubility formulationIN-FLOW ImagingPresented at UKPharmSCI 2011, paper in progress
  19. 19. API depletion and hydration profiles from PLS API mapsselective enhancement8 bit BlueChannelconversionR3 240’8 bitGrayscaleconversionR3 240’R1R2R3R1R2R3API depletionHydrationIn-situ NIR: Imaging the dissolution mechanismPresented at UKPharmSCI 2011, paper in progress
  20. 20. Mechanism of release: Swelling and Erosion fronts.Physical tablet boundaryPLS API mapR2 30’PLS API mapR2 240’Is it possible to further explore the NIR maps and gain a better understandingat a more microscopic level of the mechanism of release?Presented at UKPharmSCI 2011, paper in progressErosion –based systems: Low solubility formulationIN-FLOW Imaging
  21. 21. R1 R2 R3ZOOM-IN on EROSION AND DISSOLUTION FRONTSMechanism of release:Swelling and Erosion fronts. Source of error barsPhysical tabletboundaryR2 30’EROSIONFRONTSWELLINGFRONTPresented at UKPharmSCI 2011, paper in progress
  22. 22. API / HPMCSpatial Co-location of API and HPMC• API and HPMC are clearly co-located•Their distribution is not mutually exclusive within the section sampled by NIR• co-location can be applied to the PLS images to create a superposition map of API and HPMC.•Thresholding can be judiciously chosen to optimize the API particles separation contrastPLS IMAGESAPIHPMChttp://rsbweb.nih.gov/ij/plugins/colocalization.htmlContrast enhancement of PLS API/HPMC intensity mapsPresented at UKPharmSCI 2011, paper in progress
  23. 23. • This approach enables the editing of a sequence of images• The gel layer region (dark green) show low API concentration, and progressivedissolution.• However larger aggregates of API (yellow) remains unchanged even when fully“immersed” in the gel Layer (240’).• This colour band discrimination makes the images amenable to further analysis.30’ 60’ 90’ 120’ 150’ 180’ 210’ 240’GELerosionswellingContrast enhancement of PLS API/HPMC intensity mapsPresented at UKPharmSCI 2011, paper in progress
  24. 24. 1 1NIRpostPLSNIRpostPLSAPI-HPMCcorrelationAPI-HPMCcorrelation2 2 2 2 2 2API distribution time course• From the correlation maps it is possible to further filter out the signal of the pure APIgenerating a highly contrasted image that enable single particle tracking.• The comparison between the post-PLS (A), post Colocalization (B) and thresholding (C)shows that the signal of API distribution is retained throughout the processing.• The highly contrasted images enable the study of the evolution of single API particle (orclusters of)A AB BC C130’ 60’ 90’ 120’ 150’ 180’ 210’2240’Two different particles are tracked (1) and (2)2Contrast enhancement of PLS API/HPMC intensity maps:Single particle trackingPresented at UKPharmSCI 2011, paper in progress
  25. 25. 30’ 60’ 90’ 120’150’ 180’ 210’ 240’Single particle tracking : Particle 1Presented at UKPharmSCI 2011, paper in progress
  26. 26. 30’ 60’ 90’ 120’150’ 180’ 210’ 240’1. Aggregation2. Migration 3. DisintegrationBlue contour: indicated the particle frame at 120’ minutes chosen as reference.The aggregation process occurring in the first 90 minutes, seems to have stopped and the migration process of thewhole particle will dominate for the subsequent 90 minutes before significant erosion will takes place.Single particle tracking : Particle 2Presented at UKPharmSCI 2011, paper in progress
  27. 27. 30’ 60’ 90’ 120’ 150’ 180’ 210’ 240’Particle -1dissolvedParticle -1 show a a dissolution behaviour, fragmentation is also visible.Blue line: initial particle outline. Red area: actual particle at each time point.waterSingle particle tracking : Particle 1Presented at UKPharmSCI 2011, paper in progress
  28. 28. Ref. frameBecause of the complex aggregation and migration the perimeter is not a good descriptor of the time course as the areaaggregation migration disintegrationReferenceframePerimeterCluster -22240’30’1. Aggregation 2. Migration3.DisintegrationwaterSingle particle tracking : Particle 2Presented at UKPharmSCI 2011, paper in progress
  29. 29. •In-situ MRI- Acquisition of MRI data during the dissolution,- Hyphenation of USP-IV dissolution with MRI.
  30. 30. Hyphenation of USP-IV dissolution with MRI.NMR spectrometerPeristalticpump SGFUSP-IVFlow-through cellxyzImagingplaneFaSSIF22.6 mmLescol® XLtabletIn-situ MRI0.00.20.40.60.81.00 5 10 15 20Standard USP-IV experimentIn line UV measurementUVabsorption(a.u.)Time (h)IN PRESS: Journal of Controlled Release
  31. 31. In-situ MRIFluvastatin123Fluvastatin123pKa1 = 4.27pKa2 = 13.98pKa3 = 14.96Formulation composition- 84.24 mg Fluvastatin Sodium,- 8.42 mg Potassium Bicarbonate,- 111.26 mg Avicel, 4.88 mg Povidone,- 16.25 mg HPC (Klucel HXF),- 97.5 mg HPMC (K100 LV),- 2.44 mg MgSt,- 9.75 mg Opadry Yellow (coating)Hyphenation of USP-IV dissolution with MRI. LESCOL XLIN PRESS: Journal of Controlled Release
  32. 32. In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XLWater Maps0 100%[H2O]IN PRESS: Journal of Controlled Release
  33. 33. In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XLT2 relaxation mapsT2-relxation maps shown indicate a quitedifferent behaviour:- The structural integrity of the tabletremains intact, even after 42 hours.- This indicates that the gel erosion process isnow slow and evenly distributed.- Collectively, figures 3 and 4 show that after42 hours the gel matrix was highly hydratedand distributed.IN PRESS: Journal of Controlled Release
  34. 34. (a) (b)In-situ MRIHyphenation of USP-IV dissolution with MRI. LESCOL XL19F Signals: Combining imaging with high resolution spectroscopyIN PRESS: Journal of Controlled Release
  35. 35. Conclusions• Imaging: Seeing is believing.• Current and more complex formulation dorequire more sophisticated analysistechniques.• API dissolution need to be supported by moresophisticated test to ensure that themechanism of drug dissolution is known andstable over time.
  36. 36. Acknowledgements & Credits• Rob Saklatvalawww.linkedin.com/pub/robert-saklatvala/8/6a4/406• Brett Cooperwww.uk.linkedin.com/pub/brett-cooper/3a/759/20b• Sam Pygallwww.uk.linkedin.com/pub/samuel-pygall/10/139/532• Agnieszka Jamstreszka• Katryn Bradleywww.uk.linkedin.com/pub/kathryn-bradley/20/789/8a• Nick Gower• Jonathan Pritchard• James Mannwww.uk.linkedin.com/pub/james-mann/16/680/757• Dr. Mick Mantlewww.uk.linkedin.com/pub/dr-mick-mantle/0/5a0/462• Qilei Zhangwww.uk.linkedin.com/pub/qilei-zhang/1a/584/b33• Prof. Lynn Gladdenwww.uk.linkedin.com/pub/lynn-gladden/39/221/617
  37. 37. BACKUP
  38. 38. Optical Microscopy• Widely used!– Paolo Colombo demonstrated the gel layergrowth and the evidence of– Colin Melia
  39. 39. Swelling rate of: HPMC K4M, HPMC K100LV, PEO301, PEO1105Correlation with in the physicochemical properties of the polymers.Based on the approach of Gao and Meury and Paolo Colombo(Colombo et al, 1999, Colombo et al, 1996, Li et al, 2005, Kiil and Dam-Johansen, 2003, Gao and Meury et al. 1996)Optical MicroscopyHPMC K4M HPMC K100LV PEO 301 PEO 110560’120’180’0’(Colombo et al, 1999) (Avalle, Pygall Pritchard, Jamstrenzka - MSD, Unpublished)
  40. 40. Previous work findings:1. For a low solubility drug (MK-1) There is differing behaviour with respect to drugrelease from CR matrices based on PEO and HPMC2. The mechanism and the extent of drug and polymer dissolution varies greatly upon thepolymer used•Evaluating the performance of poly(ethylene oxide)(PEO), hydroxyethylcellulose (HEC) and hydroxypropymethylcellulose (HPMC) in erosion-based hydrophilicmatrices for low solubility drugs –(Pygall et al. in preparation)Time (hours)0 5 10 15 20%drugrelease01020304050PEO 1105PEO 301HEC 250HPMC K4MHPMC K100LVDrug release from matrices- 125 mg of compound (MK-1 )-40% polymerUSP apparatus II dissolution test at 100rpm, 37±1°C. Mean values (n=3) ± 1SDOptical Microscopy
  41. 41. original tablet boundaryRaw Image: Light intensityexpressed as a gray scale0-255 (black to white)Numerical average: each column ofpixel is averaged for each position.Each column give one point on thechart. A &B indicates swelling anderosion front positionsPEO301 intensity signal as function of position-101030507090110-300-200-1000100200300400500position (microns)NORMALIZEDsignalintentisyNormalizedsignalintensityPhysical tabletboundary @ t0Time course: The process is repeated foreach time point.From this plot we can calculate the erosionand swelling front A & B60’020406080100120-400-300-200-1000100200300400500600POSITION0 min 5 min 10 min 20 min30 min 41.2 min 49.5 min 100.5 min149 minSeries54 Series55 SWELLING FRONT EROSION FRONTPhysical tabletboundary @ t0Erosion frontSwelling frontDISSOLUTION AND EROSION fronts fro PEO1105as function of time-300-200-10001002003004005006000 50 100 150 200time (minutes)POSITIONSWELLING FRONTEROSION FRONTPhysical tablet boundary @ t0Physical tabletboundary @ t00’149’49.5’(not all curves are displayed)The movement of the front position can beplotted as function of time.ABThe fronts position are taken fromThe mean intensity of the 2 inflection points (A) and (B)Optical Microscopy
  42. 42. PEO1105PEO301HPMC K100LVHPMC K4MHPMC K4M HPMC K100LVPEO301PEO1105•The gel layer for each polymer matrix system clearly shows the development of different gel layer morphologies•With concomitant discrimination of swelling and erosion front profiles•The PEO polymers expand rapidly and continue to expand over the next 2 hours.•The HPMC polymers expand then slows down after the first hour.•The larger particle size and lower compressibility of PEO leads to faster gel layer formation compared to HPMC withsmaller particle sizes and higher compressibility.•The fast initial wetting and swelling of PEO implies that they are more hygroscopic than HPMC. This may be due tothe hydrophobic methoxyl group in HPMC, or to the lower compressibility index, allowing the polymer to hydratefaster.Optical microscopy RESULTS
  43. 43. Optical microscopy: VALIDATION
  44. 44. IN SITU NIR OF HIGH SOLUBILITY DRUGS• Chloropheniramine maleate• MK-2: Understanding Failure mode
  45. 45. ChloropheniraminemaleateCHLOROPHENIRAMINE MALEATE vs ACETYL SALICYLIC ACIDDissolution of 6.4 mm Flat Disc Tablets into Water Using Baskets0204060801001200 5 10 15 20Time (hrs)%ClaimCase 2: highly soluble drug in a non-homogeneous formulations5.5 g/L solubility in waterFormulation:10% drug loading, 20% HPMC2. In-situ NIR: Imaging the dissolution mechanism
  46. 46. Mapping chloropheniramine maleate0’60’4175μm3250μmPLS images for HPMC Water front movementErosion –based systems: High solubility / non homogeneous formulation
  47. 47. Mapping chloropheniramine maleateTime (minutes)Position(microns)Position(microns)-800-700-600-500-400-300-200-10000 10 20 30 40 50 60 70WATER FRONT MOVEMENT AREA & PERIMETER DEPLETIONTime (minutes)AREAPerimeterFrame 1Frame 1y = 0.1143x + 98.557R2= 0.9951020406080100120-800 -600 -400 -200 0water front movement%ofparticledepleted(perimeter)0102030405060PERIMETER & FRONT MOVEMENTErosion –based systems: High solubility / non homogeneous formulation
  48. 48. Understanding Failure Mode
  49. 49. 01020304050607080901001100 2 4 6 8 10 12 14 16 18 20Time / hours%LabelClaimUnderstanding Failure modesThe problem□ NON STRESSED● STRESSED 1 week 40°C / 75% RH• MK-2 is an erosion based controlled release formulation, with a high load of a highlysoluble, but slowly dissolving molecule.• Hypothesis: given the high drug loading the shift in dissolution could be caused bychanges in the API.Failure mode of erosion based matrices
  50. 50. Understanding Failure modesApproach: replace the API with another of similar propertiesand study the dissolution01020304050607080901001100 2 4 6 8 10 12 14 16 18 20Time / hours%LabelClaim6 % K100M_ Niacin - Initial6 % K100M_ Niacin - 1 week at 40/75 open6 % K100M_Caffeine - 1 week at 40/75 open6 % K100M_Caffeine - Initial6 % K100M_Caffeine - 1 week at 50/75 openMK-2 NON STRESSEDMK-1 STRESSED 1 w 40°C / 75% RHCaffeine STRESSED 1 w40°C / 75% RHCaffeine NON STRESSEDCaffeine 1 week at 50/75Failure mode of erosion based matrices
  51. 51. • The stressed formulation showed a much more rapid and deeper -initial- erosion which isthen followed by a long period in which the dissolution appear slower.• This is confirmed by both MK-2 release signal and water penetration signalUnderstanding Failure modesNIACIN SIGNALH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OTABLET CORETABLET CORENIACIN SIGNALH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OH2OTABLET CORETABLET COREMK-2 signal: faster tablet erosionin stressed tabletsFailure mode of erosion based matrices
  52. 52. MK-2: Rate of Water penetrationfaster in stressed tabletsPhysical tablet boundaryUnderstanding Failure modesFailure mode of erosion based matrices
  53. 53. Caffeine:Stressed vsUnstressed tabletsCaffeine was used as a control for MK-2 NIR in-situ work; data processing was applied as forNiacin-based formulation (MK2) And data showed no difference in API and water penetrationrates between stressed and unstressedUnderstanding Failure modesFailure mode of erosion based matrices
  54. 54. -1- Significant erosion for stressed Niacin formulations-2- No gross changes in the position of dissolution and erosion fronts for CaffeineUnderstanding Failure modesFailure mode of erosion based matrices
  55. 55. Conclusion (seeing is believing)NON STRESSED MK-2 STRESSED MK-2Time lapse photography: SchematicsPharmaceutical Research,Vol. 17, No. 10, 2000Sequential Layer modelSiepman Peppas 2000NON STRESSED MK-2 STRESSED MK-2Time lapse photography: SchematicsPharmaceutical Research,Vol. 17, No. 10, 2000Sequential Layer modelSiepman Peppas 2000Failure mode of erosion based matrices

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