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Tableting & Scale up

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Changing tableting machines and scale up

Changing tableting machines and scale up

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  • 1. Changing Tableting Machines in Scale-Up and Production: Ramifications for SUPAC FDA CDER DPQR Seminar April 3, 2000 Michael Levin, Ph.D. Metropolitan Computing Corporation (MCC), East Hanover, NJ 07936
  • 2. Page 2 MAKING A TABLET ! Die ! Upper punch ! Lower punch ! Upper compression roll ! lower compression roll ! Turret
  • 3. Page 3 MAKING A TABLET UPPER PUNCH LOWER PUNCH UPPER PUNCH LOWER PUNCH LOWER PUNCH UPPER PUNCH LOWER PUNCH UPPER PUNCH LOWER PUNCH Apparent density Tapped density Deformation Fracture, Plastic Flow Fusion
  • 4. Page 4 TABLETING PROCESS HARDNESS (bonding) DISSOLUTION (porosity) Adapted from K. Marshall (1999a) COMPACTION increase in mechanical strength (consolidation of particles) COMPRESSION reduction in bulk volume (displacement of gaseous phase)
  • 5. Page 5 COMPRESSION MECHANISMS YESPARTLYVISCO-ELASTIC (starch) NONOBRITTLE (emcompress) YESPARTLYBRITTLE-PLASTIC (lactose) YESNOPLASTIC (avicel) NOYESELASTIC (rubber) TIME DEPENDENTREVERSIBLE Adapted from K. Marshall (1999a)
  • 6. Page 6 COMPACTIBILITY PROFILE 0 2 4 6 8 0 5 10 15 20 Compaction Force (kN) Hardness(kP) starch avicel lactose emcompress Adapted from K. Marshall (1999a)
  • 7. Page 7 0 20 40 60 80 100 0 5 10 15 20 Compaction Force (kN) Porosity(%) COMPRESSIBILITY PROFILE starch avicel lactose emcompress
  • 8. Page 8 COMPACTIBILITY PROFILE 0 2 4 6 8 0 1 2 3 4 Compaction Force (kN) Hardness(kP) Avicel High speed Avicel Low speed
  • 9. Page 9 0 20 40 60 80 100 0 1 2 3 Compaction Force (kN) Porosity(%) Avicel High speed Avicel Low speed COMPRESSIBILITY PROFILE
  • 10. Page 10 0 5 10 15 20 25 30 35 40 0 2 4 6 8 10 12 14 16 18 20 22 24 26 specification specification POROSITY, HARDNESS AND DISSOLUTION Hardness (kP) t75% Dissolution (min) Porosity (%) Adapted from K. Marshall (1999a) SpeedForce
  • 11. Page 11 FACTORS IN TABLETING Press Force Press Speed Hardness Porosity Surface Area Dissolution Disintegration
  • 12. Page 12 Report and Recommendation of the USP Advisory Panel on Physical Test Methods: Compactibility Test K. Marshall (1999b) USP RECOMMENDATION ! Consolidation (Compactibility) area under hardness – log applied pressure plot ! Compressibility area under porosity – log applied pressure plot ! Compaction Rate Sensitivity area between two compactibility curves plots for two speeds that differ by a factor of 10
  • 13. Page 13 Tableting Equipment
  • 14. Page 14 Tableting Cycle
  • 15. Page 15 DIFFERENCES IN TABLET PRESSES ! Mode of die fill (SUPAC IR/MR) G gravity G force feed G centrifugal G compression coating ! Mode of Compression G To constant thickness › Variations in porosity G To constant force › Variations in thickness ! Effect of Precompression
  • 16. Page 16 DIFFERENCES IN TABLET PRESSES ! Effect of Speed G Hardness G Porosity G Temperature G Power of compaction G Lamination and capping G Disintegration time G Dissolution time
  • 17. Page 17 Contact Time and Dwell Time Force Dwell Time Contact Time Compression Event Contact Time: when punch head is in contact with the wheel Dwell Time: when flat portion of punch head is in contact with the wheel
  • 18. Page 18 Dwell Time Comparison for Rotary Pressesy Dwell Time, ms 0 10 20 30 40 50 60 70 80 Kilian T100 Fette PT 2090 IC Manesty Unipress Diamond Korsch PH106 Riva Piccola Manesty Betapress MCC Prester PRODUCTION PRESSES RESEARCH PRESSES Korsch PH336 Kilian TX40A Kikusui Libra2 Hata HT-AP38-SU MCC Presster
  • 19. Page 19 DIFFERENCES IN TABLET PRESSES ! Compression Roll Diameter ! Press Deformation Factor ! Tooling Geometry G porosity with tip curvature ! Instrumentation
  • 20. Page 20 What can be measured on a tablet press? ! Compression ! Precompression ! Ejection ! Speed and turret position
  • 21. Page 21 Compression Measurement FORCE SENSOR die COMPRESSION ROLL SERVO MOTOR WEIGHT ADJUSTMENT CAM TABLET THICKNESS ADJUSTMENT STRAIN GAUGES
  • 22. Page 22 Compression Transducer FORCE SENSOR die
  • 23. TABLET PRESS SIMULATION
  • 24. Page 24 Functions:Functions: •• Load ControlLoad Control •• Position ControlPosition Control Hydraulic Compaction Simulator CROSSHEADS HYDRAULIC ACTUATOR COMPRESSION LOAD CELL PUNCHES AND DIE
  • 25. Page 25 • Impossible to calculate • Pre-recorded data depends on (Force vs. Time)
  • 26. Press brand, model, tooling
  • 27. Press force and speed
  • 28. Formulation
  • 29. Instrumentation Load Control Profile Hydraulic Compaction Simulator
  • 30. Page 26 •Pre-Recorded Data •Artificial Profiles •Theoretical Profiles (Punch Displacement vs. Time) Position Control Profile Hydraulic Compaction Simulator
  • 31. Page 27 depends on
  • 32. Press brand, model, tooling
  • 33. Press force and speed
  • 34. Formulation
  • 35. Instrumentation Pre-Recorded Position Control Profile Hydraulic Compaction Simulator
  • 36. Page 28
  • 37. Sinusoid, saw-tooth, single-ended, etc.
  • 38. Useful for basic compaction research
  • 39. Useful for test standardization
  • 40. Do not simulate tablet presses Artificial Position Control Profile Hydraulic Compaction Simulator
  • 41. Page 29 Using Rippie & Danielson (1981) equation
  • 42. Does not account for flat head
  • 43. Does not account for punch deformation
  • 44. Does not account for press deformation
  • 45. In and out of an empty die Theoretical Position Control Profile Hydraulic Compaction Simulator
  • 46. Page 30 ™ PRESS 1 PRESS 2 PRESS 3 Mechanical Compaction Simulator The New Generation Tablet Press Replicator
  • 47. Page 31 ! mimic press geometry ! match press speed ! match tablet weight ! match tablet thickness ! match tooling ! control speed ! control force The Presster™
  • 48. Page 32 CASE STUDY Correlations Between a Hydraulic Compaction Simulator, Instrumented Manesty Betapress and the PressterTM G. Venkatesh et al., AAPS Meeting, 1999
  • 49. Page 33 PRODUCT QUALITY RESEARCH ! Data from G Instrumented Press G Compaction Simulator G The Presster ! Physical Tests for Submissions ! SUPAC Guidance ! Expert Systems ! Artificial Neural Networks ! Dimensional Analysis
  • 50. DIMENSIONAL ANALYSIS
  • 51. Page 35 DIMENSIONAL ANALYSIS Π-theorem Every physical relationship between n dimensional variables and constants can be reduced to a relationship between m=n-r mutually independent dimensionless groups, where r = number of dimensional units, i.e. rank of the dimensional matrix Buckingham (1914) Similarity: • Geometric • Kinematic • Dynamic For any two dynamically similar systems, all the dimensionless numbers necessary to describe the process have the same numerical value (Zlokarnik, 1998)
  • 52. Page 36 DIMENSIONAL ANALYSIS Case Study: WET GRANULATION
  • 53. Page 37
  • 54. Page 38 Granulation End Point and Product Properties
  • 55. Page 39 Relevance List for wet granulation: Dimensional analysis and application of the Buckingham theorem indicates that there are 4 dimensionless quantities that adequately describe the process: Ne (P) = P / (n3 d5) Newton Power Number Re = . d2 . n / Reynolds Number Fr = d2 . n / g Froude Number h/d ratio of characteristic lengths DIMENSIONAL ANALYSIS d - impeller diameter [L] h - height of granulation bed in the bowl g - gravitational constant [LT-2] η - dynamic viscosity [M L-1 T-1] ρ - specific density of particles [M L-5] n - impeller speed [T-1] P - power consumption [ML2T-5]
  • 56. Page 40 Gral300 Gral150 Gral75 Gral25 Gral10 0.00 0.50 1.00 1.50 2.00 2.50 3.00 Froude Numbers for Collete-Gral High-Shear Mixers Wet Granulation
  • 57. Page 41 PMA1800 PMA800 PMA600 PMA300 PMA150 PMA65 PMA25 PMA10 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 Froude Numbers for Fielder High-Shear Mixers Wet Granulation
  • 58. Page 42 P1250 P1000 P800 P600 P400 P250 P100 P50 P25 P10 0 0.5 1 1.5 2 Froude Numbers for Diosna High-Shear Mixers Wet Granulation
  • 59. Page 43 VG-3000 VG-2000 VG-1000 VG-800 VG-600 VG-400 VG-200 VG-100 VG-50 VG-25 VG-10 VG-5 VG-1 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 Froude Numbers for Powrex High-Shear Mixers Wet Granulation
  • 60. Page 44 VG-600 P600 PMA600 VG-200 P250 PMA300 Gral 300 VG-50 P50 PMA65 Gral 75 VG-10 P10 PMA10 Gral 10 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 Comparative Froude Numbers for High-Shear Mixers Wet Granulation
  • 61. Page 45 DIMENSIONAL ANALYSIS Tableting 1. Geometric factors d - die diameter [L] h - tablet thickness [L] 2. Physical properties c = ΔV / (Δp V) - compressibility factor [M-1LT2] where V - volume of the tablet; p - applied pressure 3. Process parameters p - Compression pressure [ML-1T-2] s - Compression speed [LT-1] t - Contact time [T]
  • 62. Page 46 DIMENSIONAL ANALYSIS Π1 = d / h Π2 = s • t / h Π3 = p • c Target quantity Predictor Equation hardness h [ML-1T-2] h • c = f(Π1, Π2, Π3) dissolution time θs [T] θs / t = f(Π1, Π2, Π3) By Buckingham’s Theorem, the Π set is These relationships are now awaiting an experimental confirmation on a range of presses and materials. The predictive power of the above relationships can have a vital role in the future of tableting scale-up.
  • 63. Page 47 CURRENT SUPAC IR/MR ! Changes in batch size G Level 1 (equipment of same design and operating principles, vary in capacity up to a factor of 10 the size of the pilot batch) G Level 2 (equipment of same design and operating principles, vary in capacity beyond a factor of 10 the size of the pilot batch) ! Manufacturing Equipment Changes G Level 1 (equipment of same design and operating principles, may vary in capacity) G Level 2 (equipment of different design and operating principles) ! Manufacturing Process Changes G Level 1 (different operating conditions, such as operating speeds within original approved application ranges) G Level 2 (different operating conditions, such as operating speeds outside of original approved application ranges)
  • 64. Page 48 ! Keith Marshall (Keith Marshall Associates) ! Gopi Venkatesh (SmithKline Beecham) ! Colleen Ruegger (Novartis) ! Marko Zlokarnik (Bayer Austria) Acknowledgements
  • 65. Page 49 Special thanks to ! Neelima Phadnis, Ph. D. (SmithKline Beecham) for her valuable insight ! Lev Tsygan (MCC) for his contribution to Mixer characterization based on Froude numbers Acknowledgements

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