This document discusses tableting processes and scale-up considerations. It summarizes differences between tablet presses, including mode of die fill, compression mechanism, speed, and dwell time. Dimensional analysis techniques are presented for characterizing wet granulation and tableting using dimensionless groups. The current SUPAC guidelines for manufacturing changes are outlined, with a call to re-evaluate based on mechanistic understanding using dimensional analysis.
Tableting Process Factors and Scale-Up Using Dimensional Analysis
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
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
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
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)
30. Page 26
•Pre-Recorded Data
•Artificial Profiles
•Theoretical Profiles
(Punch Displacement vs. Time)
Position Control Profile
Hydraulic Compaction Simulator
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
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)
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]
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)
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