tableting & scale up

Changing Tableting Machines in Scale-Up and Production:

Ramifications for SUPACFDA 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

MAKING A TABLET

UPPERPUNCH

LOWERPUNCH

UPPERPUNCH

LOWERPUNCH

LOWERPUNCH

UPPERPUNCH

LOWERPUNCH

UPPERPUNCH

LOWERPUNCH

Apparent density Tapped density Deformation

Fracture, Plastic Flow Fusion

TABLETING PROCESS

HARDNESS(bonding)

DISSOLUTION(porosity)

Adapted from K. Marshall (1999a)

COMPACTIONincrease in mechanical strength

(consolidation of particles)

COMPRESSIONreduction in bulk volume

(displacement of gaseous phase)

COMPRESSION MECHANISMS

YESPARTLYVISCO-ELASTIC(starch)

NONOBRITTLE(emcompress)

YESPARTLYBRITTLE-PLASTIC(lactose)

YESNOPLASTIC(avicel)

NOYESELASTIC(rubber)

TIME DEPENDENTREVERSIBLE


COMPACTIBILITY PROFILE

0

2

4

6

8

0 5 10 15 20Compaction Force (kN)

Har

dnes

s (k

P)

starch

avicellactose

emcompress


0

20

40

60

80

100

0 5 10 15 20

Compaction Force (kN)

Poro

sity

(%)

COMPRESSIBILITY PROFILE

starch

avicel

lactose

emcompress

COMPACTIBILITY PROFILE

0

2

4

6

8

0 1 2 3 4Compaction Force (kN)

Har

dnes

s (k

P) AvicelHigh speed

AvicelLow speed

0

20

40

60

80

100

0 1 2 3

Compaction Force (kN)

Poro

sity

(%)

AvicelHigh speed

AvicelLow speed

COMPRESSIBILITY PROFILE

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 (%)


SpeedForce

FACTORS IN TABLETING

Press Force Press Speed

Hardness Porosity

Surface Area

Dissolution

Disintegration

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

�Compressibilityarea under porosity – log applied pressure plot

�Compaction Rate Sensitivityarea between two compactibility curves plots for two speeds that differ by a factor of 10

Tableting Equipment

Tableting Cycle

DIFFERENCES IN TABLET PRESSES

� Mode of die fill (SUPAC IR/MR)� gravity� force feed� centrifugal� compression coating

� Mode of Compression� To constant thickness

› Variations in porosity� To constant force

› Variations in thickness� Effect of Precompression


� Effect of Speed� Hardness � Porosity � Temperature � Power of compaction � Lamination and capping � Disintegration time � Dissolution time

Contact Time and Dwell Time

Forc

e

Dwell Time

Contact Time

Compression Event

Contact Time: when punch head is in contact with the wheelDwell Time: when flat portion of punch head is in contact with the wheel

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 PH106Riva Piccola

Manesty BetapressMCC Prester

PRODUCTION PRESSES

RESEARCH PRESSES

Korsch PH336Kilian TX40AKikusui Libra2

Hata HT-AP38-SU

MCC Presster


�Compression Roll Diameter

� Press Deformation Factor

� Tooling Geometry� porosity with tip curvature

� Instrumentation

What can be measured on a tablet press?

� Compression

� Precompression

� Ejection

� Speed and turret position

Compression Measurement

FORCE SENSOR

die

COMPRESSION ROLL

SERVOMOTOR

WEIGHTADJUSTMENTCAM

TABLETTHICKNESS

ADJUSTMENT

STRAIN GAUGES

Compression Transducer

FORCE SENSOR

die

TABLET PRESS SIMULATION

Functions:Functions:•• Load Control Load Control •• Position ControlPosition Control

Hydraulic Compaction Simulator

CROSSHEADS

HYDRAULICACTUATOR

COMPRESSIONLOAD CELL

PUNCHES AND DIE

• Impossible to calculate• Pre-recorded data depends on

(Force vs. Time)

� Press brand, model, tooling� Press force and speed� Formulation� Instrumentation

Load Control ProfileHydraulic Compaction Simulator

•Pre-Recorded Data

•Artificial Profiles

•Theoretical Profiles

(Punch Displacement vs. Time)

Position Control ProfileHydraulic Compaction Simulator

depends on� Press brand, model, tooling� Press force and speed� Formulation� Instrumentation

Pre-Recorded Position Control Profile


� Sinusoid, saw-tooth, single-ended, etc.� Useful for basic compaction research� Useful for test standardization� Do not simulate tablet presses

Artificial 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

Theoretical Position Control Profile


™

PRESS 1 PRESS 2

PRESS 3

Mechanical Compaction SimulatorThe New Generation

Tablet Press Replicator

�mimic press geometry�match press speed�match tablet weight�match tablet thickness�match tooling� control speed� control force

The Presster™

CASE STUDY

Correlations Between a Hydraulic Compaction Simulator, Instrumented Manesty Betapress and the PressterTM

G. Venkatesh et al., AAPS Meeting, 1999

PRODUCT QUALITY RESEARCH

� Data from� Instrumented Press� Compaction Simulator� The Presster

� Physical Tests for Submissions� SUPAC Guidance� Expert Systems� Artificial Neural Networks� Dimensional Analysis

DIMENSIONAL ANALYSIS

DIMENSIONAL ANALYSISΠ-theoremEvery 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)


Case Study:

WET GRANULATION

Granulation End Pointand Product Properties

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 NumberRe = . d2 . n / Reynolds NumberFr = d2 . n / g Froude Numberh/d ratio of characteristic lengths


d - impeller diameter [L]h - height of granulation bed in the bowlg - 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]

Gral 300

Gral 150

Gral 75

Gral 25Gral 10

0.00 0.50 1.00 1.50 2.00 2.50 3.00

Froude Numbers for Collete-Gral High-Shear Mixers

Wet Granulation

PMA 1800

PMA 800

PMA 600PMA 300

PMA 150

PMA 65

PMA 25

PMA 10

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

P1250P1000

P800

P600P400

P250

P100P50

P25

P10

0 0.5 1 1.5 2

Froude Numbers for Diosna High-Shear Mixers

Wet Granulation

VG-3000VG-2000VG-1000VG-800VG-600

VG-400VG-200

VG-100VG-50

VG-25VG-10

VG-5VG-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

VG-600P600

PMA 600VG-200

P250PMA 300

Gral 300VG-50

P50PMA 65

Gral 75VG-10

P10PMA 10

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

DIMENSIONAL ANALYSISTableting

1. Geometric factors

d - die diameter [L]

h - tablet thickness [L]

2. Physical propertiesc = ΔV / (Δp V) - compressibility factor [M-1LT2]

where V - volume of the tablet; p - applied pressure

3. Process parametersp - Compression pressure [ML-1T-2]

s - Compression speed [LT-1]

t - Contact time [T]


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.

CURRENT SUPAC IR/MR� Changes in batch size

� Level 1 (equipment of same design and operating principles, vary in capacity up to a factor of 10 the size of the pilot batch)

� 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� Level 1 (equipment of same design and operating principles, may vary

in capacity)� Level 2 (equipment of different design and operating principles)

� Manufacturing Process Changes� Level 1 (different operating conditions, such as operating speeds

within original approved application ranges)� Level 2 (different operating conditions, such as operating speeds

outside of original approved application ranges)

� Keith Marshall (Keith Marshall Associates)� Gopi Venkatesh (SmithKline Beecham)� Colleen Ruegger (Novartis)� Marko Zlokarnik (Bayer Austria)

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

Acknowledgements

tableting & scale up

Technology

compaction force kn

mode of compression

punch deformation

lower compression roll

upper compression roll

tablet press simulation

compaction increase

tablet presses