際際滷

際際滷Share a Scribd company logo

Paolo avalle discovery chemistry congress2012

Download as PPT, PDF
Paolo Avalle
Paolo Avalle

NIR microscopy and MRI techniques were used to image oral solid dosage forms and gain insights into dissolution mechanisms. NIR microscopy provided maps of API and excipient distributions in pellets and tablets. It was used to examine diffusion-based and erosion-based dissolution from modified release formulations in situ. For a low solubility drug, NIR showed API migrating within the hydrating gel layer and persisting for hours, while the layer eroded. Imaging insights helped elucidate the complex interplay of drug diffusion, polymer swelling and erosion dynamics over time.

1 of 55
Download to read offline
Application of imaging techniques to oral dosage forms. Examples of in-situ imaging. Paolo Avalle Merck Sharp & Dohme (UKCH)
Introduction Direction of modern formulation efforts: improve the solubility of the drugs with effective formulation tune the drug release profile to meet the desired Pharmacokinetic criteria. Focus of the talk: use of imaging techniques as a characterization tool of drug-polymers system Remit of imaging characterization techniques Provide surface and internal chemical imaging of the whole dosage form or of individual components on a macro-, micro- or nanoscale. Temporal and spatial mapping of the drug release from the tablet matrix and obtaining novel mechanistic insights into the drug liberation phenomena. Understanding the interplay between the underlying diffusion and erosion mechanism of release and how these can be related to the solubility of the drug.
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 Formulation troubleshooting CR pellets 2. In-situ NIR: Imaging the dissolution mechanism. Diffusion based systems (high solubility) Erosion based systems (low solubility) Failure mode of erosion based matrices 3. In-situ MRI: gel layer formation and drug mobilization
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 various ways: - The integrated absorbance of a specific peak - Intensity of a specific peak - PCA - PLS pixel: 25 x 25 袖m 1 2 3 4 1 2 3 4 pixel: 25 x 25 袖m 1 2 3 4 1 2 3 4
GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose Reconstructed image with background suppression Artifact. No coating present in this part of the pellet cfr. Optical Image GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose Reconstructed image with background suppression Artifact. No coating present in this part of the pellet cfr. Optical Image presented at UKICRS 2010 Distribution of API and excipients. 1. Distribution of API and excipients 1: 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 surface 8: Horizontal movement of the blade.
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 excipients presented at UKICRS 2010 Distribution of API and excipients: Co-localization
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 detected Note 1) Negative-correlation between the spatial distribution of LACTOSE and API 2) Positive-correlation between the spatial distribution of AVICEL and API 3) Negative-correlation but more noisy between GMS-900 and MK-1 1. Distribution of API and excipients presented at UKICRS 2010 Distribution of API and excipients: Co-localization
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. Avicel API Two positively correlated clusters a) White and Green, located in the centre of the picture indicates a degree of matching in the coating pixels intensities between the two maps. b) Yellow-red, located on the right side of the map indicate degree of matching intensities between the AVICEL and MK-0941 maps a b Controlled Release pellets MK-1. Spatial Co-location presented at UKICRS 2010
Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0256 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.0196 cm-1 A Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0139 -0.012 -0.010 -0.008 -0.006 -0.004 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.0278 cm-1 A 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0108 -0.008 -0.006 -0.004 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.0199 cm-1 A Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0256 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.0196 cm-1 A Date: 18/04/2006 6100.0 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 -0.02 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.140 cm-1 A Date: 18/04/2006 6100.0 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 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.0156 cm-1 A 1. Distribution of API and excipients Formulation troubleshooting CR pellets: PLS data representation FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL presented at UKICRS 2010
Scheme for tablet hydration. - swelling. - drug migration vs. dissolution - polymer dissolution within a controlled release formulation. The particle labelled A indicates the drug. While it is commonly accepted that swelling is subsequent to permeation and hydration of the tablet the extent of those event and the extent of drug migration vs. dissolution is largely dependent on the solubility of the drug and the viscosity of the polymer. Together, these parameters modulate the release profile. 2. In-situ NIR: Imaging the dissolution mechanism Basic Concepts
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 袖m Pixel Size: 25 袖m Scan Time: ~ 18 min Scan Frequency: Every 30 min Medium: Deionised Water Temperature: 37属C Flow Rate: 10 mL/min 2. In-situ NIR: Imaging the dissolution mechanism
The subsequent acquisition of spectral map and their processing Allow to follow the evolution of the API signal and the HPMC signals. 0 10 20 30 40 50 60 18012090 dry HPMC API 2. In-situ NIR: Imaging the dissolution mechanism European Journal of Pharmaceutical Sciences 43(5) 400-408 Diffusion based systems:: comparing two diffusion-based formulation
Fast Slow Fast Slow Fast Slow The 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 layer 3. A plateau of low intensity arising from the bulk of the hydration medium. Drug and HPMC profiles from the fast and slow formulations As the tablet was exposed to the hydration media, polymer relaxation occurred and the HPMC began to swell and hence the increment in the intensity profile became progressively sloped as a consequence. 2. In-situ NIR: Imaging the dissolution mechanism Diffusion based systems: comparing two diffusion-based formulation European Journal of Pharmaceutical Sciences 43(5) 400-408
The erosion, swelling and API dissolution front for both formulation SLOW AND FAST with data modelling The data were modelled using the equation first proposed by Peppas and Sahlin to describe solute release from polymeric devices, where FP indicates the Front Position (either (i) the erosion front, (ii) the swelling front or (iii) the API front). FP is expressed in microns. 2. In-situ NIR: Imaging the dissolution mechanism Diffusion based systems:: comparing two diffusion-based formulation European Journal of Pharmaceutical Sciences 43(5) 400-408 mm tktkFP 2 21 += mm tktkFP 2 21 += :THIN GEL LAYER : THICK GEL LAYER
Image Size: 6000 x 2000 袖m Pixel Size: 25 袖m Scan Time: ~ 18 min Scan Frequency: Every 30 min Medium: Deionised Water Temperature: 37属C Flow Rate: 10 mL/min Component % API (MK-1) 31.25 HPMC K4M 20.00 Avicel PH102 47.75 Magnesium Stearate 1.00 In-situ NIR: Imaging the dissolution mechanism In-situ and in-flow imaging experiments Erosion based systems: Low solubility formulation IN-FLOW Imaging
STEP by STEP processing roadmap Black = experimental spectrum (PLS target) Blue = PLS Fit Load *.fsm in Transmittance Load *.fsm in Transmittance Reload *.fsm file Load masked .fsm in Absorbance Process / Derivative Process / PCA 20 factors Review Targets Reload masked .fsm file Process / LSQ Fit Load Target Spectra Process / Subtract Average 7800-3800 Process / Range 7800-3800 Process / Derivative Load Target Spectra Process / Subtract Average 7800-3800 Process / Range 7800-3800 Review LSQ Fit Masking PLS Fitting API HPMC AVICEL Since the fitting obtained from the PLS is very good the representation of API, HPMC, and AVICEL maps Is to be considered valid and accurate. Process / PCA 10 factors Process / Mask Process / PCA 20 factors and spatial masking ALL In-situ NIR: Imaging the dissolution mechanism Presented at UKPharmSCI 2011, paper in progress
API Maps from PLS 30 60 90 120 150 180 210 240 #1 #2 #3 30 60 90 120 150 180 210 240 HPMC Maps from PLS In-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 formulation IN-FLOW Imaging Presented at UKPharmSCI 2011, paper in progress
API depletion and hydration profiles from PLS API maps selective enhancement 8 bit Blue Channel conversion R3 240 8 bit Grayscale conversion R3 240 R1 R2 R3 R1 R2 R3 API depletionHydration In-situ NIR: Imaging the dissolution mechanism Presented at UKPharmSCI 2011, paper in progress
Mechanism of release: Swelling and Erosion fronts. Physical tablet boundary PLS API map R2 30 PLS API map R2 240 Is it possible to further explore the NIR maps and gain a better understanding at a more microscopic level of the mechanism of release? Presented at UKPharmSCI 2011, paper in progress Erosion based systems: Low solubility formulation IN-FLOW Imaging
R1 R2 R3 ZOOM-IN on EROSION AND DISSOLUTION FRONTS Mechanism of release: Swelling and Erosion fronts. Source of error bars Physical tablet boundary R2 30 EROSION FRONT SWELLING FRONT Presented at UKPharmSCI 2011, paper in progress
API / HPMC Spatial 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 contrast PLS IMAGES API HPMC http://rsbweb.nih.gov/ij/plugins/colocalization.html Contrast enhancement of PLS API/HPMC intensity maps Presented at UKPharmSCI 2011, paper in progress
This approach enables the editing of a sequence of images The gel layer region (dark green) show low API concentration, and progressive dissolution. 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 GEL erosion swelling Contrast enhancement of PLS API/HPMC intensity maps Presented at UKPharmSCI 2011, paper in progress
1 1 NIR post PLS NIR post PLS API-HPMC correlation API-HPMC correlation 2 2 2 2 2 2 API distribution time course From the correlation maps it is possible to further filter out the signal of the pure API generating 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 (or clusters of) A AB BC C 1 30 60 90 120 150 180 210 2 240 Two different particles are tracked (1) and (2) 2 Contrast enhancement of PLS API/HPMC intensity maps: Single particle tracking Presented at UKPharmSCI 2011, paper in progress
30 60 90 120 150 180 210 240 Single particle tracking : Particle 1 Presented at UKPharmSCI 2011, paper in progress
30 60 90 120 150 180 210 240 1. Aggregation 2. Migration 3. Disintegration Blue 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 the whole particle will dominate for the subsequent 90 minutes before significant erosion will takes place. Single particle tracking : Particle 2 Presented at UKPharmSCI 2011, paper in progress
30 60 90 120 150 180 210 240 Particle -1 dissolved Particle -1 show a a dissolution behaviour, fragmentation is also visible. Blue line: initial particle outline. Red area: actual particle at each time point. water Single particle tracking : Particle 1 Presented at UKPharmSCI 2011, paper in progress
Ref. frame Because of the complex aggregation and migration the perimeter is not a good descriptor of the time course as the area aggregation migration disintegration Reference frame Perimeter Cluster -2 2 240 30 1. Aggregation 2. Migration 3. Disintegration water Single particle tracking : Particle 2 Presented at UKPharmSCI 2011, paper in progress
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 spectrometer Peristaltic pump SGF USP-IV Flow-through cell x y z Imaging plane FaSSIF 22.6 mm Lescol速 XL tablet In-situ MRI 0.0 0.2 0.4 0.6 0.8 1.0 0 5 10 15 20 Standard USP-IV experiment In line UV measurement UVabsorption(a.u.) Time (h) IN PRESS: Journal of Controlled Release
In-situ MRI Fluvastatin 1 2 3 Fluvastatin 1 2 3 pKa1 = 4.27 pKa2 = 13.98 pKa3 = 14.96 Formulation 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 XL IN PRESS: Journal of Controlled Release
In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL Water Maps 0 100% [H2O] IN PRESS: Journal of Controlled Release
In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL T2 relaxation maps T2-relxation maps shown indicate a quite different behaviour: - The structural integrity of the tablet remains intact, even after 42 hours. - This indicates that the gel erosion process is now slow and evenly distributed. - Collectively, figures 3 and 4 show that after 42 hours the gel matrix was highly hydrated and distributed. IN PRESS: Journal of Controlled Release
(a) (b) In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL 19 F Signals: Combining imaging with high resolution spectroscopy IN PRESS: Journal of Controlled Release
Conclusions Imaging: Seeing is believing. Current and more complex formulation do require more sophisticated analysis techniques. API dissolution need to be supported by more sophisticated test to ensure that the mechanism of drug dissolution is known and stable over time.
Acknowledgements & Credits Rob Saklatvala www.linkedin.com/pub/robert-saklatvala/8/6a4/406 Brett Cooper www.uk.linkedin.com/pub/brett-cooper/3a/759/20b Sam Pygall www.uk.linkedin.com/pub/samuel-pygall/10/139/532 Agnieszka Jamstreszka Katryn Bradley www.uk.linkedin.com/pub/kathryn-bradley/20/789/8a Nick Gower Jonathan Pritchard James Mann www.uk.linkedin.com/pub/james-mann/16/680/757 Dr. Mick Mantle www.uk.linkedin.com/pub/dr-mick-mantle/0/5a0/462 Qilei Zhang www.uk.linkedin.com/pub/qilei-zhang/1a/584/b33 Prof. Lynn Gladden www.uk.linkedin.com/pub/lynn-gladden/39/221/617
BACKUP
Optical Microscopy Widely used! Paolo Colombo demonstrated the gel layer growth and the evidence of Colin Melia
Swelling rate of: HPMC K4M, HPMC K100LV, PEO301, PEO1105 Correlation 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 Microscopy HPMC K4M HPMC K100LV PEO 301 PEO 1105 60 120 180 0 (Colombo et al, 1999) (Avalle, Pygall Pritchard, Jamstrenzka - MSD, Unpublished)
Previous work findings: 1. For a low solubility drug (MK-1) There is differing behaviour with respect to drug release from CR matrices based on PEO and HPMC 2. The mechanism and the extent of drug and polymer dissolution varies greatly upon the polymer used Evaluating the performance of poly(ethylene oxide) (PEO), hydroxyethylcellulose (HEC) and hydroxypropy methylcellulose (HPMC) in erosion-based hydrophilic matrices for low solubility drugs (Pygall et al. in preparation) Time (hours) 0 5 10 15 20 %drugrelease 0 10 20 30 40 50 PEO 1105 PEO 301 HEC 250 HPMC K4M HPMC K100LV Drug release from matrices - 125 mg of compound (MK-1 ) -40% polymer USP apparatus II dissolution test at 100 rpm, 37賊1属C. Mean values (n=3) 賊 1SD Optical Microscopy
original tablet boundary Raw Image: Light intensity expressed as a gray scale 0-255 (black to white) Numerical average: each column of pixel is averaged for each position. Each column give one point on the chart. A &B indicates swelling and erosion front positions PEO301 intensity signal as function of position -10 10 30 50 70 90 110 -300-200-1000100200300400500 position (microns) NORMALIZEDsignalintentisy Normalizedsignalintensity Physical tablet boundary @ t0 Time course: The process is repeated for each time point. From this plot we can calculate the erosion and swelling front A & B 60 0 20 40 60 80 100 120 -400-300-200-1000100200300400500600 POSITION0 min 5 min 10 min 20 min 30 min 41.2 min 49.5 min 100.5 min 149 min Series54 Series55 SWELLING FRONT EROSION FRONT Physical tablet boundary @ t0Erosion front Swelling front DISSOLUTION AND EROSION fronts fro PEO1105 as function of time -300 -200 -100 0 100 200 300 400 500 600 0 50 100 150 200 time (minutes) POSITION SWELLING FRONT EROSION FRONT Physical tablet boundary @ t0 Physical tablet boundary @ t0 0 149 49.5 (not all curves are displayed) The movement of the front position can be plotted as function of time. A B The fronts position are taken from The mean intensity of the 2 inflection points (A) and (B) Optical Microscopy
PEO1105 PEO301 HPMC K100LV HPMC K4M HPMC K4M HPMC K100LV PEO301 PEO1105 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 with smaller 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 to the hydrophobic methoxyl group in HPMC, or to the lower compressibility index, allowing the polymer to hydrate faster. Optical microscopy RESULTS
Optical microscopy: VALIDATION
IN SITU NIR OF HIGH SOLUBILITY DRUGS Chloropheniramine maleate MK-2: Understanding Failure mode
Chloropheniramine maleate CHLOROPHENIRAMINE MALEATE vs ACETYL SALICYLIC ACID Dissolution of 6.4 mm Flat Disc Tablets into Water Using Baskets 0 20 40 60 80 100 120 0 5 10 15 20 Time (hrs) %Claim Case 2: highly soluble drug in a non-homogeneous formulations 5.5 g/L solubility in water Formulation: 10% drug loading, 20% HPMC 2. In-situ NIR: Imaging the dissolution mechanism
Mapping chloropheniramine maleate 0 60 4175亮m 3250亮m PLS images for HPMC Water front movement Erosion based systems: High solubility / non homogeneous formulation
Mapping chloropheniramine maleate Time (minutes) Position(microns) Position(microns) -800 -700 -600 -500 -400 -300 -200 -100 0 0 10 20 30 40 50 60 70 WATER FRONT MOVEMENT AREA & PERIMETER DEPLETION Time (minutes) AREA Perimeter Frame 1 Frame 1 y = 0.1143x + 98.557 R2 = 0.9951 0 20 40 60 80 100 120 -800 -600 -400 -200 0 water front movement %ofparticledepleted(perimeter) 0 10' 20' 30' 40'50' 60' PERIMETER & FRONT MOVEMENT Erosion based systems: High solubility / non homogeneous formulation
Understanding Failure Mode
0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 18 20 Time / hours %LabelClaim Understanding Failure modes The problem NON STRESSED STRESSED 1 week 40属C / 75% RH MK-2 is an erosion based controlled release formulation, with a high load of a highly soluble, but slowly dissolving molecule. Hypothesis: given the high drug loading the shift in dissolution could be caused by changes in the API. Failure mode of erosion based matrices
Understanding Failure modes Approach: replace the API with another of similar properties and study the dissolution 0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 18 20 Time / hours %LabelClaim 6 % K100M_ Niacin - Initial 6 % K100M_ Niacin - 1 week at 40/75 open 6 % K100M_Caffeine - 1 week at 40/75 open 6 % K100M_Caffeine - Initial 6 % K100M_Caffeine - 1 week at 50/75 open MK-2 NON STRESSED MK-1 STRESSED 1 w 40属C / 75% RH Caffeine STRESSED 1 w40属C / 75% RH Caffeine NON STRESSED Caffeine 1 week at 50/75 Failure mode of erosion based matrices
The stressed formulation showed a much more rapid and deeper -initial- erosion which is then followed by a long period in which the dissolution appear slower. This is confirmed by both MK-2 release signal and water penetration signal Understanding Failure modes NIACIN SIGNAL H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O TABLET CORE TABLET CORE NIACIN SIGNAL H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O TABLET CORE TABLET CORE MK-2 signal: faster tablet erosion in stressed tablets Failure mode of erosion based matrices
MK-2: Rate of Water penetration faster in stressed tablets Physical tablet boundary Understanding Failure modes Failure mode of erosion based matrices
Caffeine: Stressed vs Unstressed tablets Caffeine was used as a control for MK-2 NIR in-situ work; data processing was applied as for Niacin-based formulation (MK2) And data showed no difference in API and water penetration rates between stressed and unstressed Understanding Failure modes Failure mode of erosion based matrices
-1- Significant erosion for stressed Niacin formulations -2- No gross changes in the position of dissolution and erosion fronts for Caffeine Understanding Failure modes Failure mode of erosion based matrices
Conclusion (seeing is believing) NON STRESSED MK-2 STRESSED MK-2 Time lapse photography: Schematics Pharmaceutical Research, Vol. 17, No. 10, 2000 Sequential Layer model Siepman Peppas 2000 NON STRESSED MK-2 STRESSED MK-2 Time lapse photography: Schematics Pharmaceutical Research, Vol. 17, No. 10, 2000 Sequential Layer model Siepman Peppas 2000 Failure mode of erosion based matrices

More Related Content

Paolo avalle discovery chemistry congress2012

  • 1. Application of imaging techniques to oral dosage forms. Examples of in-situ imaging. Paolo Avalle Merck Sharp & Dohme (UKCH)
  • 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 Pharmacokinetic criteria. Focus of the talk: use of imaging techniques as a characterization tool of drug-polymers system Remit of imaging characterization techniques Provide surface and internal chemical imaging of the whole dosage form or of individual components on a macro-, micro- or nanoscale. Temporal and spatial mapping of the drug release from the tablet matrix and obtaining novel mechanistic insights into the drug liberation phenomena. Understanding the interplay between the underlying diffusion and erosion mechanism of release and how these can be related to the solubility of the drug.
  • 3. Agenda Mechanism of dissolution explored by imaging techniques NIR microscopy MRI Conclusions & Acknowledgements
  • 4. NIR microscopy Applications & Case studies: 1. Distribution of API and excipients. Formulation development: CR pellets Formulation troubleshooting CR pellets 2. In-situ NIR: Imaging the dissolution mechanism. Diffusion based systems (high solubility) Erosion based systems (low solubility) Failure mode of erosion based matrices 3. In-situ MRI: gel layer formation and drug mobilization
  • 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 various ways: - The integrated absorbance of a specific peak - Intensity of a specific peak - PCA - PLS pixel: 25 x 25 袖m 1 2 3 4 1 2 3 4 pixel: 25 x 25 袖m 1 2 3 4 1 2 3 4
  • 6. GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose Reconstructed image with background suppression Artifact. No coating present in this part of the pellet cfr. Optical Image GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose GMS-900 PVP Optical Image PVP Avicel Ethocel TEC API Lactose Reconstructed image with background suppression Artifact. No coating present in this part of the pellet cfr. Optical Image presented at UKICRS 2010 Distribution of API and excipients. 1. Distribution of API and excipients 1: 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 surface 8: Horizontal movement of the blade.
  • 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 excipients presented at UKICRS 2010 Distribution of API and excipients: Co-localization
  • 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 detected Note 1) Negative-correlation between the spatial distribution of LACTOSE and API 2) Positive-correlation between the spatial distribution of AVICEL and API 3) Negative-correlation but more noisy between GMS-900 and MK-1 1. Distribution of API and excipients presented at UKICRS 2010 Distribution of API and excipients: Co-localization
  • 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. Avicel API Two positively correlated clusters a) White and Green, located in the centre of the picture indicates a degree of matching in the coating pixels intensities between the two maps. b) Yellow-red, located on the right side of the map indicate degree of matching intensities between the AVICEL and MK-0941 maps a b Controlled Release pellets MK-1. Spatial Co-location presented at UKICRS 2010
  • 10. Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0256 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.0196 cm-1 A Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0139 -0.012 -0.010 -0.008 -0.006 -0.004 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.020 0.022 0.024 0.026 0.0278 cm-1 A 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0108 -0.008 -0.006 -0.004 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.016 0.018 0.0199 cm-1 A Date: 18/04/2006 6100.0 5800 5600 5400 5200 5000 4800 4600 4400 4200 4000 3800.0 -0.0256 -0.020 -0.015 -0.010 -0.005 0.000 0.005 0.010 0.015 0.0196 cm-1 A Date: 18/04/2006 6100.0 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 -0.02 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.140 cm-1 A Date: 18/04/2006 6100.0 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 -0.002 0.000 0.002 0.004 0.006 0.008 0.010 0.012 0.014 0.0156 cm-1 A 1. Distribution of API and excipients Formulation troubleshooting CR pellets: PLS data representation FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL FIT ACTUAL presented at UKICRS 2010
  • 11. Scheme for tablet hydration. - swelling. - drug migration vs. dissolution - polymer dissolution within a controlled release formulation. The particle labelled A indicates the drug. While it is commonly accepted that swelling is subsequent to permeation and hydration of the tablet the extent of those event and the extent of drug migration vs. dissolution is largely dependent on the solubility of the drug and the viscosity of the polymer. Together, these parameters modulate the release profile. 2. In-situ NIR: Imaging the dissolution mechanism Basic Concepts
  • 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 袖m Pixel Size: 25 袖m Scan Time: ~ 18 min Scan Frequency: Every 30 min Medium: Deionised Water Temperature: 37属C Flow Rate: 10 mL/min 2. In-situ NIR: Imaging the dissolution mechanism
  • 13. The subsequent acquisition of spectral map and their processing Allow to follow the evolution of the API signal and the HPMC signals. 0 10 20 30 40 50 60 18012090 dry HPMC API 2. In-situ NIR: Imaging the dissolution mechanism European Journal of Pharmaceutical Sciences 43(5) 400-408 Diffusion based systems:: comparing two diffusion-based formulation
  • 14. Fast Slow Fast Slow Fast Slow The 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 layer 3. A plateau of low intensity arising from the bulk of the hydration medium. Drug and HPMC profiles from the fast and slow formulations As the tablet was exposed to the hydration media, polymer relaxation occurred and the HPMC began to swell and hence the increment in the intensity profile became progressively sloped as a consequence. 2. In-situ NIR: Imaging the dissolution mechanism Diffusion based systems: comparing two diffusion-based formulation European Journal of Pharmaceutical Sciences 43(5) 400-408
  • 15. The erosion, swelling and API dissolution front for both formulation SLOW AND FAST with data modelling The data were modelled using the equation first proposed by Peppas and Sahlin to describe solute release from polymeric devices, where FP indicates the Front Position (either (i) the erosion front, (ii) the swelling front or (iii) the API front). FP is expressed in microns. 2. In-situ NIR: Imaging the dissolution mechanism Diffusion based systems:: comparing two diffusion-based formulation European Journal of Pharmaceutical Sciences 43(5) 400-408 mm tktkFP 2 21 += mm tktkFP 2 21 += :THIN GEL LAYER : THICK GEL LAYER
  • 16. Image Size: 6000 x 2000 袖m Pixel Size: 25 袖m Scan Time: ~ 18 min Scan Frequency: Every 30 min Medium: Deionised Water Temperature: 37属C Flow Rate: 10 mL/min Component % API (MK-1) 31.25 HPMC K4M 20.00 Avicel PH102 47.75 Magnesium Stearate 1.00 In-situ NIR: Imaging the dissolution mechanism In-situ and in-flow imaging experiments Erosion based systems: Low solubility formulation IN-FLOW Imaging
  • 17. STEP by STEP processing roadmap Black = experimental spectrum (PLS target) Blue = PLS Fit Load *.fsm in Transmittance Load *.fsm in Transmittance Reload *.fsm file Load masked .fsm in Absorbance Process / Derivative Process / PCA 20 factors Review Targets Reload masked .fsm file Process / LSQ Fit Load Target Spectra Process / Subtract Average 7800-3800 Process / Range 7800-3800 Process / Derivative Load Target Spectra Process / Subtract Average 7800-3800 Process / Range 7800-3800 Review LSQ Fit Masking PLS Fitting API HPMC AVICEL Since the fitting obtained from the PLS is very good the representation of API, HPMC, and AVICEL maps Is to be considered valid and accurate. Process / PCA 10 factors Process / Mask Process / PCA 20 factors and spatial masking ALL In-situ NIR: Imaging the dissolution mechanism Presented at UKPharmSCI 2011, paper in progress
  • 18. API Maps from PLS 30 60 90 120 150 180 210 240 #1 #2 #3 30 60 90 120 150 180 210 240 HPMC Maps from PLS In-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 formulation IN-FLOW Imaging Presented at UKPharmSCI 2011, paper in progress
  • 19. API depletion and hydration profiles from PLS API maps selective enhancement 8 bit Blue Channel conversion R3 240 8 bit Grayscale conversion R3 240 R1 R2 R3 R1 R2 R3 API depletionHydration In-situ NIR: Imaging the dissolution mechanism Presented at UKPharmSCI 2011, paper in progress
  • 20. Mechanism of release: Swelling and Erosion fronts. Physical tablet boundary PLS API map R2 30 PLS API map R2 240 Is it possible to further explore the NIR maps and gain a better understanding at a more microscopic level of the mechanism of release? Presented at UKPharmSCI 2011, paper in progress Erosion based systems: Low solubility formulation IN-FLOW Imaging
  • 21. R1 R2 R3 ZOOM-IN on EROSION AND DISSOLUTION FRONTS Mechanism of release: Swelling and Erosion fronts. Source of error bars Physical tablet boundary R2 30 EROSION FRONT SWELLING FRONT Presented at UKPharmSCI 2011, paper in progress
  • 22. API / HPMC Spatial 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 contrast PLS IMAGES API HPMC http://rsbweb.nih.gov/ij/plugins/colocalization.html Contrast enhancement of PLS API/HPMC intensity maps Presented at UKPharmSCI 2011, paper in progress
  • 23. This approach enables the editing of a sequence of images The gel layer region (dark green) show low API concentration, and progressive dissolution. 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 GEL erosion swelling Contrast enhancement of PLS API/HPMC intensity maps Presented at UKPharmSCI 2011, paper in progress
  • 24. 1 1 NIR post PLS NIR post PLS API-HPMC correlation API-HPMC correlation 2 2 2 2 2 2 API distribution time course From the correlation maps it is possible to further filter out the signal of the pure API generating 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 (or clusters of) A AB BC C 1 30 60 90 120 150 180 210 2 240 Two different particles are tracked (1) and (2) 2 Contrast enhancement of PLS API/HPMC intensity maps: Single particle tracking Presented at UKPharmSCI 2011, paper in progress
  • 25. 30 60 90 120 150 180 210 240 Single particle tracking : Particle 1 Presented at UKPharmSCI 2011, paper in progress
  • 26. 30 60 90 120 150 180 210 240 1. Aggregation 2. Migration 3. Disintegration Blue 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 the whole particle will dominate for the subsequent 90 minutes before significant erosion will takes place. Single particle tracking : Particle 2 Presented at UKPharmSCI 2011, paper in progress
  • 27. 30 60 90 120 150 180 210 240 Particle -1 dissolved Particle -1 show a a dissolution behaviour, fragmentation is also visible. Blue line: initial particle outline. Red area: actual particle at each time point. water Single particle tracking : Particle 1 Presented at UKPharmSCI 2011, paper in progress
  • 28. Ref. frame Because of the complex aggregation and migration the perimeter is not a good descriptor of the time course as the area aggregation migration disintegration Reference frame Perimeter Cluster -2 2 240 30 1. Aggregation 2. Migration 3. Disintegration water Single particle tracking : Particle 2 Presented at UKPharmSCI 2011, paper in progress
  • 29. In-situ MRI - Acquisition of MRI data during the dissolution, - Hyphenation of USP-IV dissolution with MRI.
  • 30. Hyphenation of USP-IV dissolution with MRI. NMR spectrometer Peristaltic pump SGF USP-IV Flow-through cell x y z Imaging plane FaSSIF 22.6 mm Lescol速 XL tablet In-situ MRI 0.0 0.2 0.4 0.6 0.8 1.0 0 5 10 15 20 Standard USP-IV experiment In line UV measurement UVabsorption(a.u.) Time (h) IN PRESS: Journal of Controlled Release
  • 31. In-situ MRI Fluvastatin 1 2 3 Fluvastatin 1 2 3 pKa1 = 4.27 pKa2 = 13.98 pKa3 = 14.96 Formulation 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 XL IN PRESS: Journal of Controlled Release
  • 32. In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL Water Maps 0 100% [H2O] IN PRESS: Journal of Controlled Release
  • 33. In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL T2 relaxation maps T2-relxation maps shown indicate a quite different behaviour: - The structural integrity of the tablet remains intact, even after 42 hours. - This indicates that the gel erosion process is now slow and evenly distributed. - Collectively, figures 3 and 4 show that after 42 hours the gel matrix was highly hydrated and distributed. IN PRESS: Journal of Controlled Release
  • 34. (a) (b) In-situ MRI Hyphenation of USP-IV dissolution with MRI. LESCOL XL 19 F Signals: Combining imaging with high resolution spectroscopy IN PRESS: Journal of Controlled Release
  • 35. Conclusions Imaging: Seeing is believing. Current and more complex formulation do require more sophisticated analysis techniques. API dissolution need to be supported by more sophisticated test to ensure that the mechanism of drug dissolution is known and stable over time.
  • 36. Acknowledgements & Credits Rob Saklatvala www.linkedin.com/pub/robert-saklatvala/8/6a4/406 Brett Cooper www.uk.linkedin.com/pub/brett-cooper/3a/759/20b Sam Pygall www.uk.linkedin.com/pub/samuel-pygall/10/139/532 Agnieszka Jamstreszka Katryn Bradley www.uk.linkedin.com/pub/kathryn-bradley/20/789/8a Nick Gower Jonathan Pritchard James Mann www.uk.linkedin.com/pub/james-mann/16/680/757 Dr. Mick Mantle www.uk.linkedin.com/pub/dr-mick-mantle/0/5a0/462 Qilei Zhang www.uk.linkedin.com/pub/qilei-zhang/1a/584/b33 Prof. Lynn Gladden www.uk.linkedin.com/pub/lynn-gladden/39/221/617
  • 38. Optical Microscopy Widely used! Paolo Colombo demonstrated the gel layer growth and the evidence of Colin Melia
  • 39. Swelling rate of: HPMC K4M, HPMC K100LV, PEO301, PEO1105 Correlation 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 Microscopy HPMC K4M HPMC K100LV PEO 301 PEO 1105 60 120 180 0 (Colombo et al, 1999) (Avalle, Pygall Pritchard, Jamstrenzka - MSD, Unpublished)
  • 40. Previous work findings: 1. For a low solubility drug (MK-1) There is differing behaviour with respect to drug release from CR matrices based on PEO and HPMC 2. The mechanism and the extent of drug and polymer dissolution varies greatly upon the polymer used Evaluating the performance of poly(ethylene oxide) (PEO), hydroxyethylcellulose (HEC) and hydroxypropy methylcellulose (HPMC) in erosion-based hydrophilic matrices for low solubility drugs (Pygall et al. in preparation) Time (hours) 0 5 10 15 20 %drugrelease 0 10 20 30 40 50 PEO 1105 PEO 301 HEC 250 HPMC K4M HPMC K100LV Drug release from matrices - 125 mg of compound (MK-1 ) -40% polymer USP apparatus II dissolution test at 100 rpm, 37賊1属C. Mean values (n=3) 賊 1SD Optical Microscopy
  • 41. original tablet boundary Raw Image: Light intensity expressed as a gray scale 0-255 (black to white) Numerical average: each column of pixel is averaged for each position. Each column give one point on the chart. A &B indicates swelling and erosion front positions PEO301 intensity signal as function of position -10 10 30 50 70 90 110 -300-200-1000100200300400500 position (microns) NORMALIZEDsignalintentisy Normalizedsignalintensity Physical tablet boundary @ t0 Time course: The process is repeated for each time point. From this plot we can calculate the erosion and swelling front A & B 60 0 20 40 60 80 100 120 -400-300-200-1000100200300400500600 POSITION0 min 5 min 10 min 20 min 30 min 41.2 min 49.5 min 100.5 min 149 min Series54 Series55 SWELLING FRONT EROSION FRONT Physical tablet boundary @ t0Erosion front Swelling front DISSOLUTION AND EROSION fronts fro PEO1105 as function of time -300 -200 -100 0 100 200 300 400 500 600 0 50 100 150 200 time (minutes) POSITION SWELLING FRONT EROSION FRONT Physical tablet boundary @ t0 Physical tablet boundary @ t0 0 149 49.5 (not all curves are displayed) The movement of the front position can be plotted as function of time. A B The fronts position are taken from The mean intensity of the 2 inflection points (A) and (B) Optical Microscopy
  • 42. PEO1105 PEO301 HPMC K100LV HPMC K4M HPMC K4M HPMC K100LV PEO301 PEO1105 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 with smaller 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 to the hydrophobic methoxyl group in HPMC, or to the lower compressibility index, allowing the polymer to hydrate faster. Optical microscopy RESULTS
  • 44. IN SITU NIR OF HIGH SOLUBILITY DRUGS Chloropheniramine maleate MK-2: Understanding Failure mode
  • 45. Chloropheniramine maleate CHLOROPHENIRAMINE MALEATE vs ACETYL SALICYLIC ACID Dissolution of 6.4 mm Flat Disc Tablets into Water Using Baskets 0 20 40 60 80 100 120 0 5 10 15 20 Time (hrs) %Claim Case 2: highly soluble drug in a non-homogeneous formulations 5.5 g/L solubility in water Formulation: 10% drug loading, 20% HPMC 2. In-situ NIR: Imaging the dissolution mechanism
  • 46. Mapping chloropheniramine maleate 0 60 4175亮m 3250亮m PLS images for HPMC Water front movement Erosion based systems: High solubility / non homogeneous formulation
  • 47. Mapping chloropheniramine maleate Time (minutes) Position(microns) Position(microns) -800 -700 -600 -500 -400 -300 -200 -100 0 0 10 20 30 40 50 60 70 WATER FRONT MOVEMENT AREA & PERIMETER DEPLETION Time (minutes) AREA Perimeter Frame 1 Frame 1 y = 0.1143x + 98.557 R2 = 0.9951 0 20 40 60 80 100 120 -800 -600 -400 -200 0 water front movement %ofparticledepleted(perimeter) 0 10' 20' 30' 40'50' 60' PERIMETER & FRONT MOVEMENT Erosion based systems: High solubility / non homogeneous formulation
  • 49. 0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 18 20 Time / hours %LabelClaim Understanding Failure modes The problem NON STRESSED STRESSED 1 week 40属C / 75% RH MK-2 is an erosion based controlled release formulation, with a high load of a highly soluble, but slowly dissolving molecule. Hypothesis: given the high drug loading the shift in dissolution could be caused by changes in the API. Failure mode of erosion based matrices
  • 50. Understanding Failure modes Approach: replace the API with another of similar properties and study the dissolution 0 10 20 30 40 50 60 70 80 90 100 110 0 2 4 6 8 10 12 14 16 18 20 Time / hours %LabelClaim 6 % K100M_ Niacin - Initial 6 % K100M_ Niacin - 1 week at 40/75 open 6 % K100M_Caffeine - 1 week at 40/75 open 6 % K100M_Caffeine - Initial 6 % K100M_Caffeine - 1 week at 50/75 open MK-2 NON STRESSED MK-1 STRESSED 1 w 40属C / 75% RH Caffeine STRESSED 1 w40属C / 75% RH Caffeine NON STRESSED Caffeine 1 week at 50/75 Failure mode of erosion based matrices
  • 51. The stressed formulation showed a much more rapid and deeper -initial- erosion which is then followed by a long period in which the dissolution appear slower. This is confirmed by both MK-2 release signal and water penetration signal Understanding Failure modes NIACIN SIGNAL H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O TABLET CORE TABLET CORE NIACIN SIGNAL H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O TABLET CORE TABLET CORE MK-2 signal: faster tablet erosion in stressed tablets Failure mode of erosion based matrices
  • 52. MK-2: Rate of Water penetration faster in stressed tablets Physical tablet boundary Understanding Failure modes Failure mode of erosion based matrices
  • 53. Caffeine: Stressed vs Unstressed tablets Caffeine was used as a control for MK-2 NIR in-situ work; data processing was applied as for Niacin-based formulation (MK2) And data showed no difference in API and water penetration rates between stressed and unstressed Understanding Failure modes Failure mode of erosion based matrices
  • 54. -1- Significant erosion for stressed Niacin formulations -2- No gross changes in the position of dissolution and erosion fronts for Caffeine Understanding Failure modes Failure mode of erosion based matrices
  • 55. Conclusion (seeing is believing) NON STRESSED MK-2 STRESSED MK-2 Time lapse photography: Schematics Pharmaceutical Research, Vol. 17, No. 10, 2000 Sequential Layer model Siepman Peppas 2000 NON STRESSED MK-2 STRESSED MK-2 Time lapse photography: Schematics Pharmaceutical Research, Vol. 17, No. 10, 2000 Sequential Layer model Siepman Peppas 2000 Failure mode of erosion based matrices