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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
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)
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 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 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
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
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