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Information about Tableting & Scale up

Changing tableting machines and scale up

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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

Formulation

Instrumentation

Page 25

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

Formulation

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

Page 28

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

Page 29

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

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

Page 37

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

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