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PrésentationGénérale-Confidentiel
1 - 26/05/2016
Co-micronization: innovative technology to enhance oral
bioavai...
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PrésentationGénérale-Confidentiel
2 - 26/05/2016
OVERVIEW
Introduction
Factors influencing solubility and dissol...
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PrésentationGénérale-Confidentiel
3 - 26/05/2016
INTRODUCTION
Formulation strategies used to enhance solubility ...
Référence
PrésentationGénérale-Confidentiel
4 - 26/05/2016
INTRODUCTION
Factors influencing solubility
Molecular structure...
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PrésentationGénérale-Confidentiel
5 - 26/05/2016
INTRODUCTION
Factors influencing dissolution
Noyes-Whitney
Para...
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PrésentationGénérale-Confidentiel
6 - 26/05/2016
MICRONIZATION
Micronization
Most straightforward approach to en...
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PrésentationGénérale-Confidentiel
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MICRONIZATION
Micronization
« Universal » formulation strategy ...
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PrésentationGénérale-Confidentiel
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MICRONIZATION
Micronization vs. oral bioavailability
For drugs ...
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MICRONIZATION
Micronization vs. oral bioavailability
A microniz...
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PrésentationGénérale-Confidentiel
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MICRONIZATION
Co-micronization vs. Micronization
Modification ...
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MICRONIZATION
Co-micronization vs. Micronization
Modification ...
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MICRONIZATION
Co-micronization vs. Micronization
Modification ...
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MICRONIZATION
Co-micronization vs. Micronization
Promote speci...
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MICRONIZATION
Co-micronization vs. Micronization
Promote speci...
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MICRONIZATION
Co-micronization vs. Micronization
Promote speci...
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MICRONIZATION
Co-micronization vs. Micronization
Promote speci...
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MICRONIZATION
Co-micronization vs. Micronization
Promote speci...
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PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Phy...
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Phy...
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Phy...
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Che...
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Sur...
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CO-MICRONIZATION
Selection of the pharmaceutical excipient
Dil...
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PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Controls on produced samples
Particle size di...
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PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Controls on produced samples
Blend uniformity...
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PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Development: from preformulation to industria...
Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Precellys®: Innovative technology and high pe...
Référence
PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Precellys®: Innovative technology and high pe...
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PrésentationGénérale-Confidentiel
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CO-MICRONIZATION
Micronization / co-micronization : available ...
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CO-MICRONIZATION
Micronization / co-micronization : available ...
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CO-MICRONIZATION
Micronization / co-micronization : available ...
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CO-MICRONIZATION
Micronization / co-micronization : available ...
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CASE STUDY(1)
Ketoprofen (BCS class 2)
Solubility: 0.2mg/ml (p...
Référence
PrésentationGénérale-Confidentiel
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CASE STUDY(1)
Ketoprofen (BCS class 2)
Particle size / morphol...
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PrésentationGénérale-Confidentiel
35 - 26/05/2016
CASE STUDY(1)
Ketoprofen (BCS class 2)
X-ray diffraction
Polox...
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PrésentationGénérale-Confidentiel
36 - 26/05/2016
CASE STUDY(2)
BP002945 (BCS class 2)
Solubility: 0.007mg/ml (p...
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PrésentationGénérale-Confidentiel
37 - 26/05/2016
CASE STUDY(2)
BP002945 (BCS class 2)
Particle size / morpholog...
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PrésentationGénérale-Confidentiel
38 - 26/05/2016
CASE STUDY(2)
BP002945 (BCS class 2)
Dissolution (pH 4.6, 0.1%...
Référence
PrésentationGénérale-Confidentiel
39 - 26/05/2016
CONCLUSION
Co-micronization: Formulation strategy defining inn...
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Conference on Co- micronization by PH.D. Jérôme Hecq

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Co-micronization: innovative technology to enhance oral
bioavailability of poorly water soluble APIs.

Jerome HECQ, Pharm.D, Ph.D.

APGI Day – MERCK and GATTEFOSSE
CNAM – Paris
24th May 2016

Publié dans : Santé & Médecine
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Conference on Co- micronization by PH.D. Jérôme Hecq

  1. 1. Référence PrésentationGénérale-Confidentiel 1 - 26/05/2016 Co-micronization: innovative technology to enhance oral bioavailability of poorly water soluble APIs APGI Day – MERCK and GATTEFOSSE CNAM – Paris 24/05/2016 Jerome HECQ, Pharm.D, Ph.D.
  2. 2. Référence PrésentationGénérale-Confidentiel 2 - 26/05/2016 OVERVIEW Introduction Factors influencing solubility and dissolution Micronization / Co-micronization Benefits and drawbacks From preformulation to industrial manufacturing Case studies Conclusion
  3. 3. Référence PrésentationGénérale-Confidentiel 3 - 26/05/2016 INTRODUCTION Formulation strategies used to enhance solubility / dissolution rate / oral bioavailability Formulation strategy selection: Consider multiple variables - API - Excipients - Drug load (vs. dose) - Manufacturing process Composition Performance - Solubility - Dissolution - Bioavailability - Food effect - Chemical stability (compatibility) - Physical stability - Safety
  4. 4. Référence PrésentationGénérale-Confidentiel 4 - 26/05/2016 INTRODUCTION Factors influencing solubility Molecular structure (molecular weight / size, polarity / functional groups) Temperature pKa and GIT pH profile Surfactants Solid state (crystalline state: polymorphs, pseudopolymorphs, amorphous) Particle size (influence: size<100nm - Ostwald) Illustration of the calculated effect of particle diameter on Cs/C∞ for a particle having a molecular weight of 708, a density of 1g/ml and an interfacial surface tension of 50 (blue), 75 (green) and 100 (red) dyn cm-1. (Kipp, 2004. Int. J. Pharm., 284 (1-2), 109-122)
  5. 5. Référence PrésentationGénérale-Confidentiel 5 - 26/05/2016 INTRODUCTION Factors influencing dissolution Noyes-Whitney Parameter Definition Physicochemical characteristic in vivo factor D Diffusion coefficient (solute) Molecular size of solute particle GIT fluids viscosity A Specific surface area of dispersed particles Particle size Presence of surfactants h Thickness of diffusion layer - GIT motility S Saturation solubility of API Solid state, polarity,… pH, surfactants Cb Solute concentration in the dissolution media at time t - GIT fluids volume
  6. 6. Référence PrésentationGénérale-Confidentiel 6 - 26/05/2016 MICRONIZATION Micronization Most straightforward approach to enhance API dissolution rate: increase of the surface area of the particles in contact of the dissolution media
  7. 7. Référence PrésentationGénérale-Confidentiel 7 - 26/05/2016 MICRONIZATION Micronization « Universal » formulation strategy applicable to most APIs independently of their physicochemical properties: − Molecular weight / size / structure − Log P − pKa − Solubility in organic solvents or excipients − Chemical stability (temperature, compatibility issues) − Melting point: Low MP APIs may have a tendency to show agglomeration during the micronization process (ball milling > jet milling) => cryomilling No use of excipients, solvents
  8. 8. Référence PrésentationGénérale-Confidentiel 8 - 26/05/2016 MICRONIZATION Micronization vs. oral bioavailability For drugs showing poor oral bioavailability due to low solubility and not exclusively due to their poor dissolution behavior, micronization may have a low or no impact on bioavailability => Nanomilling (PSD: 50-500nm) => Co-micronization with pharmaceutical excipients allowing to increase solubility (i.e. surfactants, pH modifying agents)
  9. 9. Référence PrésentationGénérale-Confidentiel 9 - 26/05/2016 MICRONIZATION Micronization vs. oral bioavailability A micronized powder will generally be presenting particle surfaces that are highly cohesive (VDW interactions, electrostatic attraction) due to the high energy brought during the size reduction process and that will lead to particle agglomeration and subsequent problems: >Poor flowability >Low bulk density >Increased poor wettability characteristics >Reduced effective surface area with potential negative impact on drug dissolution rate => Co-micronization of the drug with selected pharmaceutical excipients allows to reduce these inter-particular attractions and thus agglomeration
  10. 10. Référence PrésentationGénérale-Confidentiel 10 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Modification of surface properties of the drug particles - Decrease of agglomeration phenomenon Micronization Co-micronization + Han et al., 2011. Int. J. Pharm., 415 , 185-195 Ibuprofen / silica (99/1 w/w)
  11. 11. Référence PrésentationGénérale-Confidentiel 11 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Modification of surface properties of the drug particles - Decrease of agglomeration phenomenon Micronization Co-micronization Spence et al., 2005. Pharm. Dev. Tech., 10, 451-460 Pfizer CI-1040 / MCC (90/10 w/w)Solubility < 1µg/ml Log D: 3.55 (pH 7.4) F(%) rats Micronized: 68.2 Co-micronized: 85.3
  12. 12. Référence PrésentationGénérale-Confidentiel 12 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Modification of surface properties of the drug particles - Enhancement of hydrophilic character of micronized particle surface (surfactant, water soluble excipients): Impact on wettability and solubilization properties Micronisation Co-micronisation Physical blend (µized API + exc)
  13. 13. Référence PrésentationGénérale-Confidentiel 13 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Promote specific interactions between the API and the selected pharmaceutical excipient - Impact on solubility / dissolution Povidone
  14. 14. Référence PrésentationGénérale-Confidentiel 14 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Promote specific interactions between the API and the selected pharmaceutical excipient - Amorphous form formation & stabilization Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344 Sulindac Sulindac : Neusilin 1:1 w:w →Stable > 4 months 40°C/75%RH vs. immediate crystallization (24h at 25°C/60%RH) for amorphous sulindac (no Neusilin) obtained by quench-cooling → Amorphous form of Sulindac stabilized through interactions with Neusilin
  15. 15. Référence PrésentationGénérale-Confidentiel 15 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Promote specific interactions between the API and the selected pharmaceutical excipient - Amorphous form formation & stabilization Maclean et al., 2011. J. Pharm. Sci., 100 (8), 3332-3344 Sulindac Sulindac : Neusilin 1:1 w:w Acidic drugs: reported interactions with Neusilin or other silicates: Hydrogen bonding with silanol groups / rings Ion Dipole-Dipole interactions with metal ions (Mg, Al) ⇒ Complex formation - salt formation? www.neusilin.com
  16. 16. Référence PrésentationGénérale-Confidentiel 16 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Promote specific interactions between the API and the selected pharmaceutical excipient Gupta et al., 2003. J. Pharm. Sci., 92, 536-551 Ketoprofen : Neusilin 1:5 w:w Decrease of the CO stretching peak at 1697cm-1 as function of milling time ⇒ dissociation of the ketoprofen dimer Amorphous state created during milling different than for the melt-quenched amorphous ketoprofen ⇒ Preferred interaction (H bonding) with Neusilin Hypothesis of salt formation (carboxylate formation) Free acid carboxylic CO stretch H-Bonding phenomenon with silicates reported for other acidic drugs such as indomethacin and Naproxen but also for drugs not having proton-donating groups (ex Progesterone)
  17. 17. Référence PrésentationGénérale-Confidentiel 17 - 26/05/2016 MICRONIZATION Co-micronization vs. Micronization Promote specific interactions between the API and the selected pharmaceutical excipient - Solid dispersion preparation could also be achieved through co- micronization using organic polymers such as Povidone (complete amorphisation) and poloxamers (partial amorphisation) Yang et al., 2012. Chem. Pharm. Bull., 60 (7), 837-845 Dipfluzine Povidone Dipfluzine PVP Dipfluzine:PVP 1:3 w:w physical blend Dipfluzine:PVP 1:3 w:w co-grinding 30 min Dipfluzine:PVP 1:3 w:w co-grinding 1 hour Dipfluzine:PVP 1:3 w:w co-grinding 2 hours Dipfluzine:PVP 1:3 w:w co-grinding 3 hours ⇒ Chemical shift of API CO stretch
  18. 18. Référence PrésentationGénérale-Confidentiel 18 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Physicochemical properties of the excipient >Melting point: Low melting point excipient may be an issue (material agglomeration → product properties / process jamming) − Difference between ball milling and jet milling: process/product temperature Pluronic F68 (poloxamer): MP: 52°C Pluronic F68 (bulk product) Pluronic F68 (Jet-mill) Pluronic F68 (Cryo Ball-mill) Saleem and Smith, 2010. AAPS PharmSciTech, 11 (4) , 1642-1649 50µm 50µm
  19. 19. Référence PrésentationGénérale-Confidentiel 19 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Physicochemical properties of the excipient >Extent of particle size reduction dependent on the mechanical properties of the material which determine the resistance to breaking and the propagation of fracture Mechanical properties (determined by nanoindentation): − Hardness: determines the resistance of a material to plastic deformation − Elasticity: determines the resistance of a material to elastic deformation. Defined by Young’s modulus. ⇒ Hard and elastic material will require more energy for particle breakage ⇒ Process energy and time may be higher/longer during co-micronization with soft materials in order to decrease API particle size (vs. micronization)
  20. 20. Référence PrésentationGénérale-Confidentiel 20 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Physicochemical properties of the excipient >Particle size distribution vs. API PSD − blend homogeneity before co-micronization >Density vs. API density − homogeneity during co-micronization (when considering jet-milling / particle acceleration (Venturi) – classification) − Particles with higher porosity may break easier
  21. 21. Référence PrésentationGénérale-Confidentiel 21 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Chemical compatibility with API >Enhanced interactions between API and excipient Toxicity (surfactants) >Dependent of API/excipient ratio selected
  22. 22. Référence PrésentationGénérale-Confidentiel 22 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Surfactants: >Sodium Lauryl sulfate >Poloxamer (polyoxyde propylene/ polyoxyde ethylene copolymer) Polymers: >Povidone (polyvinylpyrrolidone) >Copovidone (vinyl pyrrolidone / vinyl acetate copolymer) >Crospovidone (cross-linked polyvinylpyrrolidone) >Polyvinyl alcohol >Vinyl alcohol / polyethylene glycol copolymer (Kollicoat IR) >Sodium croscarmelose >Starch >Hydroxypropylmethylcellulose, hydroxyethylcellulose
  23. 23. Référence PrésentationGénérale-Confidentiel 23 - 26/05/2016 CO-MICRONIZATION Selection of the pharmaceutical excipient Diluents: >Lactose >Cellulose >Maltodextrins >Polyols (mannitol, sorbitol, isomalt,…) Others: >Buffering agents (succinic acid, fumaric acid, citric acid, phosphates,…) –Micro-environnemental pH modification (weak acid/ weak base) >Silicates
  24. 24. Référence PrésentationGénérale-Confidentiel 24 - 26/05/2016 CO-MICRONIZATION Controls on produced samples Particle size distribution analysis >Diffraction laser, scanning electronic microscopy (+ morphology / API-excipient association) Specific surface area > BET (Brunauer–Emmett–Teller) Solid state (polymorphic/ crystalline modifications) >X-ray diffraction, differential scanning calorimetry API / excipient interactions >Infra-Red (FTIR) spectroscopy, differential scanning calorimetry
  25. 25. Référence PrésentationGénérale-Confidentiel 25 - 26/05/2016 CO-MICRONIZATION Controls on produced samples Blend uniformity (API) >Before and after co-micronization In vitro dissolution (SINK conditions) and dynamic solubility test (non SINK conditions – evaluation of supersaturation/precipitation phenomenon) Pharmacokinetic study - oral bioavailability study (rodent/ non rodent species)
  26. 26. Référence PrésentationGénérale-Confidentiel 26 - 26/05/2016 CO-MICRONIZATION Development: from preformulation to industrial manufacturing
  27. 27. Référence PrésentationGénérale-Confidentiel 27 - 26/05/2016 CO-MICRONIZATION Precellys®: Innovative technology and high performance preformulation tool High throughput ball milling technology developed and patented by Bertin Technologies allowing to produce a specific 3D (precession) movement of tubes and beads Stainless steel or ceramic (stabilized zirconium oxyde) beads
  28. 28. Référence PrésentationGénérale-Confidentiel 28 - 26/05/2016 CO-MICRONIZATION Precellys®: Innovative technology and high performance preformulation tool 4 available tube size: 0,5ml / 2ml / 7ml / 15ml >Allowing to work on very small sample size (20mg - 1000mg) Small milling time: 30 to 90 seconds cycles (hold time of 20 to 120 seconds between cycles) High milling speed: 4500rpm – 10000rpm Milling chamber temperature monitoring and control possible (range 10-20°C) in order to limit product temperature increase during the milling operation – patented cooling system (Cryolis®)
  29. 29. Référence PrésentationGénérale-Confidentiel 29 - 26/05/2016 CO-MICRONIZATION Micronization / co-micronization : available industrial manufacturing equipment and process Mechanical milling: >Ball milling − Stainless steel (316L), ceramic (ZrO2),… − Particle size reduction by friction and attrition (bead/bead or bead/wall) and little or no impact of particle/particle collision − Non negligible risk of product contamination (bead/wall and abrasive API) − Batch size (few grams – 100kg) − Long milling process time (product temperature increase vs. API stability and particle agglomeration for soft materials ><cryomilling) − Process parameters influencing particle size distribution: bead type, bead number, milling time, rotation/milling speed
  30. 30. Référence PrésentationGénérale-Confidentiel 30 - 26/05/2016 CO-MICRONIZATION Micronization / co-micronization : available industrial manufacturing equipment and process Air jet milling: >Characteristics: − Particle size reduction through particle/particle collisions (particle speed : 300-500m/s) − Particle classification system as function of size − Low risk of product contamination − Batch size (10g – tons) – continuous manufacturing process − Short milling process time (limited product temperature increase: product temperature ∼ process gas temperature) − Particle size distribution span: jet-mill < ball mill
  31. 31. Référence PrésentationGénérale-Confidentiel 31 - 26/05/2016 CO-MICRONIZATION Micronization / co-micronization : available industrial manufacturing equipment and process Air jet milling: >Equipments: − Spiral jet mill (fluid energy mill) - Particle acceleration by Venturi effect - Classification (size) par centrifugal force - Process parameters influencing particle size distribution: Feed size, Feeding pressure, Grinding pressure, Feed rate (⇒ specific energy J/g) ⇒ Possibility to align the discharging point of 2 screw feeders in the center of the Venturi feeding cone http://www.sreenex.com/html/bulk_airjetmill.htm
  32. 32. Référence PrésentationGénérale-Confidentiel 32 - 26/05/2016 CO-MICRONIZATION Micronization / co-micronization : available industrial manufacturing equipment and process Air jet milling: >Equipments: − Fluidized-bed jet mill - Particle acceleration by radial fluidized air jets - Classification (size) par centrifugal force and dynamic rotors - No limitations in feed size (vs spiral jet-mill: blockage of feed hopper) www.hmicronpowder.com/products/product/alpine- afg-fluidized-bed-jet-mill
  33. 33. Référence PrésentationGénérale-Confidentiel 33 - 26/05/2016 CASE STUDY(1) Ketoprofen (BCS class 2) Solubility: 0.2mg/ml (pH2.0) LogP: 3.12 Initial particle size: d(v,0.5): 50µm Tested pharmaceutical excipients: SLS, poloxamer (Kolliphor ® P407), crospovidone (Kollidon® CLF), PVP co-PEG (Kollicoat ® IR) >Ratio Ketoprofen / excipient: 7/3 w/w Precellys® milling protocol: 3 cycles of 60 sec at 5500rpm (10 sec pause between cycles)
  34. 34. Référence PrésentationGénérale-Confidentiel 34 - 26/05/2016 CASE STUDY(1) Ketoprofen (BCS class 2) Particle size / morphology Dissolution (HCl 0.1N) d(v,0.5): 50 µm d(v,0.5): 2-10 µm SLS - Ketoprofen Poloxamer - Ketoprofen Crospovidone - Ketoprofen PVP co-PEG - Ketoprofen 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 0 20 40 60 80 100 120 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 0 20 40 60 80 100 120 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 0 20 40 60 80 100 120 0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 0 20 40 60 80 100 120
  35. 35. Référence PrésentationGénérale-Confidentiel 35 - 26/05/2016 CASE STUDY(1) Ketoprofen (BCS class 2) X-ray diffraction Poloxamer 0 10000 20000 30000 40000 50000 60000 8.02 9.34 10.7 12 13.3 14.6 15.9 17.3 18.6 19.9 21.2 22.5 23.9 25.2 26.5 27.8 29.1 30.5 31.8 33.1 34.4 35.7 2 Theta (°) Intensity(a.u)Crospovidone 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 8.02 9.34 10.7 12 13.3 14.6 15.9 17.3 18.6 19.9 21.2 22.5 23.9 25.2 26.5 27.8 29.1 30.5 31.8 33.1 34.4 35.7 2 Theta (°) Intensity(a.u) PVP co-PEG 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 8.02 9.32 10.6 11.9 13.2 14.5 15.8 17.1 18.4 19.7 21 22.3 23.6 24.9 26.2 27.5 28.8 30.1 31.4 32.7 34 35.3 36.6 2 Theta (°) Intensity(a.u) Sodium lauryl sulfate 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 8.02 9.36 10.7 12 13.4 14.7 16.1 17.4 18.7 20.1 21.4 22.8 24.1 25.4 26.8 28.1 29.5 30.8 32.1 33.5 34.8 36.2 2 Theta (°) Intensity(a.u) Non micronisé Co-micronisat Mélange physique
  36. 36. Référence PrésentationGénérale-Confidentiel 36 - 26/05/2016 CASE STUDY(2) BP002945 (BCS class 2) Solubility: 0.007mg/ml (pH4.6) – 1.8mg/ml (pH2.0) Initial particle size: d(v,0.5): 150µm Tested pharmaceutical excipient: surfactant >Ratio BP002945 / excipient: 5/5 w/w Milling protocol >Precellys® : 3 cycles of 60 sec at 6500 rpm (120 sec pause between cycles) >Spiral jet mill: Feeding pressure: 8 bar / Grinding pressure: 8 bar / Feed rate: 1,2 kg/h (theoretical energy: 2900J/g)
  37. 37. Référence PrésentationGénérale-Confidentiel 37 - 26/05/2016 CASE STUDY(2) BP002945 (BCS class 2) Particle size / morphology Non micronized API: d(v,0.5): 150 µm Precellys® : d(v,0.5): 10 µm Jet-Mill: d(v,0.5): 2 µm
  38. 38. Référence PrésentationGénérale-Confidentiel 38 - 26/05/2016 CASE STUDY(2) BP002945 (BCS class 2) Dissolution (pH 4.6, 0.1% SLS) Oral bioavailability (rat) >BP002945 micronized (F 43,1%) / co-micronized (F 58.6%)
  39. 39. Référence PrésentationGénérale-Confidentiel 39 - 26/05/2016 CONCLUSION Co-micronization: Formulation strategy defining innovative API/excipient associations in order to enhance oral bioavailability of poorly water soluble APIs Impact on physical properties of API (particle surface modification ⇒ flowability, agglomeration, wettability, dissolution) + creation of specific API/excipient interactions Allows to work in favorable API / excipient ratio (highly dosed APIs – final dosage form development) Easily accessible at industrial manufacturing scale using well established manufacturing process Precellys®: High performance innovative preformulation tool to evaluate the potential benefits of co-micronization Work on very low amount of API (NCE) High throughput screening capabilities: test of diverse range of pharmaceutical excipients in one single run Results predictive of prototypes obtained using conventional micronization equipments (ball milling, jet milling)

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