Published on January 16, 2009
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
MAKING A TABLET ! Die ! Upper punch ! Lower punch ! Upper compression roll ! lower compression roll ! Turret Page 2
MAKING A TABLET UPPER UPPER PUNCH PUNCH LOWER LOWER LOWER PUNCH PUNCH PUNCH Apparent density Tapped density Deformation UPPER UPPER PUNCH PUNCH LOWER LOWER PUNCH PUNCH Fracture, Fusion Plastic Flow Page 3
TABLETING PROCESS COMPRESSION COMPACTION increase in mechanical strength reduction in bulk volume (consolidation of particles) (displacement of gaseous phase) DISSOLUTION HARDNESS (porosity) (bonding) Adapted from K. Marshall (1999a) Page 4
COMPRESSION TIME MECHANISMS REVERSIBLE DEPENDENT ELASTIC YES NO (rubber) PLASTIC NO YES (avicel) BRITTLE NO NO (emcompress) VISCO-ELASTIC PARTLY YES (starch) BRITTLE-PLASTIC PARTLY YES (lactose) Adapted from K. Marshall (1999a) Page 5
COMPACTIBILITY PROFILE 8 avicel 6 lactose Hardness (kP) 4 emcompress starch 2 0 0 5 10 15 20 Compaction Force (kN) Adapted from K. Marshall (1999a) Page 6
COMPRESSIBILITY PROFILE 100 80 Porosity (%) 60 avicel 40 emcompress starch 20 lactose 0 0 5 10 15 20 Compaction Force (kN) Page 7
COMPACTIBILITY PROFILE 8 6 Avicel Hardness (kP) High speed 4 Avicel Low speed 2 0 0 1 2 3 4 Compaction Force (kN) Page 8
COMPRESSIBILITY PROFILE 100 80 Porosity (%) 60 40 Avicel High speed 20 Avicel Low speed 0 0 1 2 3 Compaction Force (kN) Page 9
POROSITY, HARDNESS AND DISSOLUTION 40 t75% Dissolution (min) 35 30 specification 25 20 specification 15 10 5 Hardness (kP) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Force Speed Porosity (%) Adapted from K. Marshall (1999a) Page 10
FACTORS IN TABLETING Press Force Press Speed Hardness Porosity Surface Area Disintegration Dissolution Page 11
USP RECOMMENDATION Report and Recommendation of the USP Advisory Panel on Physical Test Methods: Compactibility Test K. Marshall (1999b) ! 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 Page 12
Tableting Equipment Page 13
Tableting Cycle Page 14
DIFFERENCES IN TABLET PRESSES ! Mode of die fill (SUPAC IR/MR) gravity G force feed G centrifugal G compression coating G ! Mode of Compression To constant thickness G › Variations in porosity To constant force G › Variations in thickness ! Effect of Precompression Page 15
DIFFERENCES IN TABLET PRESSES ! Effect of Speed Hardness G Porosity G Temperature G Power of compaction G Lamination and capping G Disintegration time G Dissolution time G Page 16
Contact Time and Dwell Time 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 Dwell Time Force Contact Time Compression Event Page 17
Dwell Time Comparison for Rotary Presses y PRODUCTION PRESSES Kikusui Libra2 Kilian TX40A Korsch PH336 Fette PT 2090 IC Hata HT-AP38-SU Manesty Unipress Diamond RESEARCH PRESSES Kilian T100 MCC Presster MCC Prester Manesty Betapress Korsch PH106 Riva Piccola 0 10 20 30 40 50 60 70 80 Dwell Time, ms Page 18
DIFFERENCES IN TABLET PRESSES ! Compression Roll Diameter ! Press Deformation Factor ! Tooling Geometry porosity with tip curvature G ! Instrumentation Page 19
What can be measured on a tablet press? ! Compression ! Precompression ! Ejection ! Speed and turret position Page 20
Compression Measurement COMPRESSION ROLL TABLET THICKNESS ADJUSTMENT FORCE SENSOR WEIGHT ADJUSTMENT STRAIN CAM GAUGES SERVO MOTOR die Page 21
Compression Transducer FORCE SENSOR die Page 22
TABLET PRESS SIMULATION
Hydraulic Compaction Simulator HYDRAULIC ACTUATOR PUNCHES AND DIE CROSSHEADS COMPRESSION LOAD CELL Functions: • Load Control • Position Control Page 24
Hydraulic Compaction Simulator Load Control Profile (Force vs. Time) • Impossible to calculate • Pre-recorded data depends on Press brand, model, tooling
Press force and speed
Hydraulic Compaction Simulator Position Control Profile (Punch Displacement vs. Time) • Pre-Recorded Data • Artificial Profiles • Theoretical Profiles Page 26
Hydraulic Compaction Simulator Pre-Recorded Position Control Profile depends on
Press brand, model, tooling
Press force and speed
Instrumentation Page 27
Hydraulic Compaction Simulator Artificial Position Control Profile Sinusoid, saw-tooth, single-ended, etc.
Useful for basic compaction research
Useful for test standardization
Do not simulate tablet presses
Hydraulic Compaction Simulator Theoretical Position Control Profile Using Rippie & Danielson (1981) equation Does not account for flat head
Does not account for punch deformation
Does not account for press deformation
In and out of an empty die
Mechanical Compaction Simulator The New Generation Tablet Press Replicator PRESS 1 PRESS 2 PRESS 3 ™ Page 30
The Presster™ ! mimic press geometry ! match press speed ! match tablet weight ! match tablet thickness ! match tooling ! control speed ! control force Page 31
CASE STUDY Correlations Between a Hydraulic Compaction Simulator, Instrumented Manesty Betapress and the PressterTM G. Venkatesh et al., AAPS Meeting, 1999 Page 32
PRODUCT QUALITY RESEARCH ! Data from Instrumented Press G Compaction Simulator G The Presster G Physical Tests for Submissions ! SUPAC Guidance ! Expert Systems ! Artificial Neural Networks ! Dimensional Analysis ! Page 33
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) Page 35
DIMENSIONAL ANALYSIS Case Study: WET GRANULATION Page 36
Granulation End Point and Product Properties Page 38
DIMENSIONAL ANALYSIS Relevance List for wet granulation: 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] 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 Page 39
Wet Granulation Froude Numbers for Collete-Gral High-Shear Mixers Gral 10 Gral 25 Gral 75 Gral 150 Gral 300 0.00 0.50 1.00 1.50 2.00 2.50 3.00 Page 40
Wet Granulation Froude Numbers for Fielder High-Shear Mixers PMA 10 PMA 25 PMA 65 PMA 150 PMA 300 PMA 600 PMA 800 PMA 1800 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 Page 41
Wet Granulation Froude Numbers for Diosna High-Shear Mixers P10 P25 P50 P100 P250 P400 P600 P800 P1000 P1250 0 0.5 1 1.5 2 Page 42
Wet Granulation Froude Numbers for Powrex High-Shear Mixers VG-1 VG-5 VG-10 VG-25 VG-50 VG-100 VG-200 VG-400 VG-600 VG-800 VG-1000 VG-2000 VG-3000 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 Page 43
Wet Granulation Comparative Froude Numbers for High-Shear Mixers Gral 10 PMA 10 P10 VG-10 Gral 75 PMA 65 P50 VG-50 Gral 300 PMA 300 P250 VG-200 PMA 600 P600 VG-600 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 Page 44
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 - Compression pressure [ML-1T-2] p - Compression speed [LT-1] s t - Contact time [T] Page 45
DIMENSIONAL ANALYSIS By Buckingham’s Theorem, the Π set is Π1 = d / h Π2 = s • t / h Π3 = p • c Target quantity Predictor Equation h • c = f(Π1, Π2, Π3) h [ML-1T-2] hardness dissolution time θs [T] θs / t = f(Π1, Π2, Π3) 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. Page 46
CURRENT SUPAC IR/MR ! Changes in batch size Level 1 (equipment of same design and operating principles, vary in G capacity up to a factor of 10 the size of the pilot batch) Level 2 (equipment of same design and operating principles, vary in G capacity beyond a factor of 10 the size of the pilot batch) ! Manufacturing Equipment Changes Level 1 (equipment of same design and operating principles, may vary G in capacity) Level 2 (equipment of different design and operating principles) G ! Manufacturing Process Changes Level 1 (different operating conditions, such as operating speeds G within original approved application ranges) Level 2 (different operating conditions, such as operating speeds G outside of original approved application ranges) Page 47
Acknowledgements ! Keith Marshall (Keith Marshall Associates) ! Gopi Venkatesh (SmithKline Beecham) ! Colleen Ruegger (Novartis) ! Marko Zlokarnik (Bayer Austria) Page 48
Acknowledgements 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 Page 49
Presentación que realice en el Evento Nacional de Gobierno Abierto, realizado los ...
In this presentation we will describe our experience developing with a highly dyna...
Presentation to the LITA Forum 7th November 2014 Albuquerque, NM
Un recorrido por los cambios que nos generará el wearabletech en el futuro
Um paralelo entre as novidades & mercado em Wearable Computing e Tecnologias Assis...
Scale-up of Tablet Manufacturing Jari Pajander, PhD ... Tableting Small scale • Batch sizes from 15 to 300 tablets •Powder is weighed by hand
tablet scale-up process requires a solid understanding of compaction science. Typically, tableting involves two main processes: (1) compression and (2)
PROCESS SCALE UP OF IBRUFEN TABLET ... exist (e.g., tableting) where the term ‘‘scale-up’’ simply means enlarging the output by increasing the speed.
14.1 Scale-up of compaction and the tableting process ... example, it is very difficult to scale-up a tableting process for a blend with
Changing tableting machines and scale up. Changing tableting machines and scale up. Login JOIN. UPLOAD Menu. Categories. Art & Photos; Automotive; Business ...
Tutorial for Scale-Up Calculator, Version 2.0 Page 1 of 24 Scale-Up Calculator Tutorial The MCC Tableting Calculator
Chapter 32 – Development, Optimization, and Scale-up of Process Parameters: Tablet Compression. Dale Natoli, Michael Levin, ... Tableting Scale-up.
Pharmaceutical Process Scale-Up, Third Edition - CRC Press Book The third edition of ... New material on tableting scale-up and compaction.
EU Certifies Vetter’s Supply Chain is Better. Authorized Economic Operator FullRecognizes Company’s Operational Excellence Vetter, well-known CMO ...