Simulation of Roll CompactionSimulation of Roll Compaction

Bruno C. Hancock, PhD

Acknowledgements• Glenn Carlson• Mike Cavanaugh

g

• Beth Langdon• Jeff Moriarty• Matthew Mullarneyy• Cindy Oksanen• Chris Sinko• Barbara Spong• Barbara Spong• Andre Zinchuk

Outline

• Motivation• Scale-up parameters• Approach taken• Verification• Limitations• Custom instrument design

Motivation

• Roll compaction process development consumes a i ifi t t f d f i t tsignificant amount of powder for equipment set-up

and to achieve steady-state operation

• Can the process by simulated to save material early in development?in development?

C t i t• Constraints– Quick and simple

Achieve proof of concept using existing equipment– Achieve proof-of-concept using existing equipment– Fit-for-purpose

Roll compactionp

Powder

PowderRibbons Granules

Ribbon

(Images courtesy of PharmTech magazine)

History• Fuel “briquette” production

took off in 1870s Europe & USUS

• Initially horizontal fixed rollers used ; gravity-fed

• Used today for variety of y ymetal ores & chemicals

• Frank Chilson developed a pgranulator in mid-1950s

• Fitzpatrick started to make pharmaceutical mills in p1940s

• First “Chilsonator” Model SN in late 1950s

(Slide courtesy of Ian Smales)

ine)

ech

mag

azi

of P

harm

Tees

cou

rtesy

(Im

age

(Images courtesy of PharmTech magazine)

Feeder

Rolls

Mill

Lab scale Pilot scale

(Images courtesy of Vector Corp)

Important considerations for simulation

1. Continuous process2 N d t d t d

• Can we simulate using a batch process?2. Need to understand

critical product attributes3. Need to identify important

batch process?• How best to characterize

product (ribbons)?3. Need to identify important process parameters

4. Slow compaction & low ti f

p ( )• Process parameter

criticality?N d f lcompaction forces

5. Integral feeding & milling operations

• No need for complex hydraulics

• May need to simulateoperations May need to simulate feeding and milling

Solid Fraction Spectrum

TabletsTablets

Ribbons

P dPowders

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0Solid Fraction

Ribbon Solid Fraction SurveyyThickness and solid fraction of ribbons produced

during clinical manufacturing(n = 23, Vector type compactors)

Parameter Solid Fraction Thickness (mm)

Mean 0.71 1.91

Maximum 0.80 3.43

Minimum 0.57 1.33

Tools for scale-up of solid fractionTools for scale up of solid fraction

Calipers(Sample dimensions)(Sample dimensions)

Mi i j l ’ t bl Mini jeweler’s table saw(rectangular sample preparation)

Helium pycnometer(true density)

Ribbon Solid Fraction Determination

mm

Flat or serrated ribbons

t

)**(Fρρ

s

t

e VtlwVS +==

nwthVs **139.0*)( −=w1 w2

l2

t1h1w1 w2

l2

t1h1

Sample

l

2

Ribbon

SerrationSample

l

2

Ribbon

Serration

l1

t2h2

l1

t2h2

Ribbon Solid Fraction by Displacement

GeoPyc (Micromeritics Corp)

Comparison of methods

Ribbon Solid Fraction by Lasery• Includes automated weighing• Irregular shaped samples OK• Irregular shaped samples OK

Laserwww.customlabsoftware.com/

SF Testing Method Comparison 2:1 Avicel PH102:Lactose Fast Flo Placebo

3mm; 6 RPM; knurled rollers on Gerteis Mini-Pactor

0.85

0.9

3mm; 6 RPM; knurled rollers on Gerteis Mini Pactor Data points are average of n = 3

0.75

0.8

0 6

0.65

0.7

ract

ion

.

0.5

0.55

0.6

Sol

id F

Caliper Method

Laser SF Tester

0.4

0.45

0 2 4 6 8 10 12 140 2 4 6 8 10 12 14Gerteis Roll Force (kN/cm)

Tensile Strength DeterminationF

W t

RIBBON SAMPLE

1

2 3L

1.8

2T tWLF

23σ

××

=

1 01.21.41.61.8

(kg)

σT - Tensile Strength

0.40.60.81.0

Forc

e (

Ribbon fracture

0.00.2

500 700 900 1100Time (nominal)

Sample Dimensions:~ 10mm X 25mm

Precision of Ribbon Tests

• Solid fraction– Mean measurement RSD ~3 %

Ribbon SFs of 0.66 & 0.69 are equivalentS f & ffRibbon SFs of 0.66 & 0.70 are different

• Tensile strength– Mean measurement RSD ~6 %

Ribbon TSs of 1.00 MPa & 1.06 MPa are equivalentRibbon TSs of 1.00 MPa & 1.10 MPa are different

Critical process parameters– roll dimensions

• diameter, width, type– material mass flow rate

• ribbon thickness & solid fraction (density)– compaction conditions

• force (pressure) & force application rate (roll speed & di t )diameter)

– feeding & milling conditionsfeeder design screen size etc• feeder design, screen size, etc

– environmental conditions• temperature and humidity• temperature and humidity

Simulation approach

<<Insert picture of tooling>>p g

Principal underlying simulationy g

Simulation Proof of Concept

5 0

6.0Real Ribbons

Si l t d Ribb

4.0

5.0

h (M

Pa)

Simulated Ribbons

3.0

e S

tren

gth

1 0

2.0

Ten

sile

0.0

1.0

0.45 0.50 0.55 0.60 0.65 0.70 0.75Solid Fraction

Scale-up30.0

58686-10-74 (Stability Lot)

53783-100-74 (Microformulation Lot)

20.0

25.0

d

( )

ED-G-111-402 (Clinical Lot)

15.0

% R

etai

ned

5 0

10.0

%

0.0

5.0

840 420 250 177 149 74 44 <44840 420 250 177 149 74 44 <44Particle Size Distribution (micrometers)

Limitations

• Shear forces are neglected– However, these are expected to be quite low in

pharmaceutical roll compactors• By pass is not simulated• By-pass is not simulated

– Easily accounted for by adding uncompacted powder to the ribbons

• Interaction with seals (at ribbon edge) not simulated– Solid fraction variability can be introduced by varying y y y g

compaction settings during the experiments• Feeding process is not simulated

– Same as for tablet compaction simulation

Unanswered questions

• Force/pressure measurements– See next slide

• Feeding simulation– Pulsing from screw feeders– Air entrapment

Optimal roll design• Optimal roll design– Smooth vs. knurled

• Lubrication• Lubrication– Friction with rolls?– Nip angle?– Nip angle?

• Milling simulation

Use in Formulation

50 70

One Example: Correlation between Roller Compactor Pressure and Simulator Compression Stress Can be Used for Process Scale-up

40

45

50

m2 )

60

70

MPa

)

Avicel PH 101Material AMaterial B

real ribbons

25

30

35

re (k

g f/c

m

40

50

Stre

ss (Msimulated ribbons

15

20

25

l Pre

ssur

20

30

pres

sion

5

10

15

Rol

10

20

Com

p

00.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80

Solid Fraction

0

Development of a custom instrument

• Motivation– Eliminate the need to use tablet compaction simulator– Portability

Increased level of powder containment– Increased level of powder containment– High volume/throughput operation– Custom software and analysis toolsCustom software and analysis tools

Touch Panel Control Screen & Electronics

Self Contained Compaction

A /A blArea/Assembly

Hydraulic DriveSystem

HEPA filtering unit

Linear Actuator/Position Sensor

Punch

HopperHopper

Sampling Assembly

Integrated Milling f Ribbof Ribbons

Custom milling simulatorg

• Diameter and width reduced

• Screens cut down to fit

Software Interface & Controls•User can select

degrees (o) or # of rotations for cw/ccw

movement

•Rotational speed•Rotational speed (0..180 RPM) is scaled

down to equivalent rotor tip speeds on

the Mini-pactorthe Mini pactor

•Counter counts number or rotationnumber or rotation

cycles•Run/Stop buttons allow the mill to be

38

run continuously until user hits stop

Experimental Verification• Ribbons from a single batch were milled using the Gerteis Mini-pactor and the milling simulator (under identical conditions)conditions)

• Granules were produced with an indiscernible difference in particle size distribution

Comparison of Granule PSD (Sympatec) from Gerties Mini-pactor and Mill Simulator [R6 lense; 0.2 bar pressure; 100% Vibri]

7

4

5

6

ncy

Granules from GerteisMini-pactorGranules from GSim Mill

2

3

4

% F

requ

e

39

0

1

1 10 100 1000 10000

Particle Size (μm)

Summaryy

• Simulation of roll compaction can be achieved by dif i th i fil t bl tmodifying the compression profile on a tablet

compaction simulatorTh i lifi ti / i ti i d• The simplifications/approximations required appear to be reasonable

• Material property tests for ribbons need to be• Material property tests for ribbons need to be developed and implemented

• The impact of processing changes can be studied in• The impact of processing changes can be studied in detail using less than 100g of powder blend

• If needed a custom simulator can be readily builtIf needed, a custom simulator can be readily built