powder flow issues in addopt - formulation · 2018-04-23 · advanced digital design of...
TRANSCRIPT
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ADVANCED DIGITAL DESIGN OF PHARMACEUTICAL THERAPEUTICS
A l e jandro Ló pez 1, V i n cenz ino V i vacqua 1, Mo jtab a G h ad ir i 1, Ch u nle i Pe i 2, J am e s E l l i ott 2, Ro b e rt H am m o nd 1 an d Kev i n J Ro b e rts 1
1U n i v e rs i t y o f L e e d s a n d 2U n i v e rs i t y o f C a m b r i d g e
Powder Flow Issues in ADDoPT
POWDER FLOW 2018: COHESIVE POWDER FLOW, 12 APRIL 2018, ROYAL SOCIETY OF CHEMISTRY, LONDON, UK
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ADDoPT: A UK Government-Industry-Academia collaboration
2
Part-funded under the Advanced
Manufacturing Supply Chain Initiative (AMSCI*)
*A BIS initiative delivered by Finance Birmingham and Birmingham City Council
Instigated by the Medicines Manufacturing Industry Partnership (MMIP)
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Digital Design – An Integrated Pathway from Molecules to Crystals to Medicines
3
Quality systems
Release profiles Materials properties
Particle attributes
Surface chemistry
Formulation Processing rules
Manufacturing classification Downstream Upstream
Product and Process Design
Product Performance
Crystallisation Filtration Washing Drying
Active Ingredient
(API)
Milling Blending
Compaction Coating
Primary Manufacturing - Secondary Manufacturing
15/04/2018
Define a system for top-down, knowledge-driven Digital Design and Control for drug products and their manufacturing processes
Bring together the range of predictive models
Design and control of optimised development & manufacturing processes through data analysis and first principle models
Processes Products Performance
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Two-Pronged Approach in Cohesive Powder Flow Analysis
4
q Cambridge: Quasi-static characterisation and role of material properties by DEM Modelling of Ring Shear Test for powder flowability (Chunlei Pei and James Elliott)
q Leeds: Powder characterisation under dynamic conditions
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Schulze Ring Shear Test RST-XS (standard)
Volume: ~ 30 ml
Cross-sectional (annular) area: 24.23 cm2
Outer radius: 32 mm; inner radius: 16 mm
16 bars (3 mm in height) at top and bottom*
Rotational speed • 7.5 mm/min; 0.05 rpm ( half of the max.) • 0.5 rpm (modelling)
8
DEM model for ring shear test ß Linear cohesion vs JKR ß Flow function (ffc) ß Particle shape ß Rescaling
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Cohesion Model in DEM 6
ÿ Linear cohesion (LC) model ÿ Cohesive energy density (J/m3) ÿ Proportional to the contact area ÿ Without the work of adhesion
ÿ JKR model ÿ Surface energy (J/m2) ÿ Work of adhesion
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Flow Function from DEM 7
Normal stress at pre-shear: 2081 Pa
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Particle Shape 8
ω
Fconst ÿ Spherical vs Elongated ß Equivalent volume diameter ß JKR cohesion ongoing
Aspect ratio = 2
Aspect ratio = 4
Sphere N
omin
al sh
ear s
tress
(Pa)
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Breakage Models The Influence of Particle Shape and Adhesion 9
The particle shape plays a role in the angle of friction of failure which also varies the intercept on the axis of shear stress.
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Mod
ellin
g
Expe
rimen
tal
Work Outline: Dynamic Regime
15/04/2018
Account for environmental effects (Manipulation of surface energy) -Silanisation of glass beads and/or paracetamol
CFD-DEM Rocky DEM + Ansys Fluent
EDEM + Ansys Fluent
Effect of cohesion
Effect of shape
Effect of strain rate
Effect of air drag
DEM Rocky DEM
EDEM (Clumped spheres)
Calibration ÿ Coefficient of Restitution ÿ Friction (static, dynamic) ÿ Surface Energy – Drop test
Rheological Model
10
Validation FT4
FT4 Screw Feeder
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Rocky DEM (ESSS) 11
ÿDeltahedron (faces=16, corners=10): ÿFaceted cylinder (faces=12, corners=20): ÿActual paracetamol shape (faces=25, corners=44):
ÿDodecahedron (faces=12, corners=20):
ÿTruncated polyhedron (faces=14, corners=16):
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Rocky DEM (ESSS) Contact model 12
ÿContact deformation: Linear spring hysteresis model ÿ 𝑘𝑘𝑛𝑛𝑛𝑛 ÿ 𝑘𝑘𝑛𝑛𝑛𝑛 ÿ µ
ÿ Adhesion model ÿ Luding’s model1 ÿ 𝑘𝑘𝑎𝑎𝑎𝑎𝑎
1Luding, S. (2008), Granular matter, 10, 235-246.
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Surface Energy vs Adhesive Stiffness 13
Comparison in terms of work of adhesion based on parameters by Thornton & Ning2
2Ning, Z. (1995). Elasto-Plastic Impact of Fine Particles and Fragmentation of Small Agglomerates. PhD Thesis. Aston University
3Pasha, M. et al. (2014), Granular matter, 16, 151-162
Luding1 Pasha et al.3
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Faceted vs Rounded Particles 14
Material Property Particles Geometry
Density (kg/m3) 2450 7800
Young’s Modulus (GPa) 0.1 100
Interaction Property Particles-particles Particle-geometry
Restitution coefficient (no cohesion) 0.8 0.8
Restitution coefficient (with cohesion) 0.4 0.4
Sliding friction coefficient 0.3 0.1
Rolling friction coefficient 0.01 0.01
Parameters used in the simulations
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Faceted vs Rounded Particles 14
2 mm mean volume diameter
Faceted
0
1000
2000
3000
4000
5000
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheres
rounded cylindersL/D=3
faceted
Aspect Ratio L/D:3 # of faces:16 # of corners:10
L/D=3
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Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
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0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
-
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
-
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
-
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
-
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
-
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
spheresdeltahedron L/D=1faceted cylinder L/D=1Actual shapeDodecahedronTruncated Polyhedron
No Cohesion
Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle
15
2 mm mean volume diameter
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16
Energy Comparison at 100 mm s-1 and 5° Helix Angle
0
1000
2000
3000
4000
0 5 10 15 20 25 30 35 40
Cum
ulat
ive
Ener
gy m
J
Penetration Depth mm
Paracetamol Kadh=0
Truncated Poly Kadh=0
Paracetamol Kadh=0.1
Truncated Poly Kadh=0.1
Paracetamol Kadh=0.15
Truncated Poly Kadh=0.15
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100
1000
10000
100000
0.01 0.1 1 10
Aver
age
Dev
iato
ric S
tres
s Pa
Tip Speed m/s
Spheres
Faceted
Regime Transition: Effect of Shape 17
2 mm mean volume diameter, no cohesion
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Regime Transition: Effect of Cohesion 18
Spheres, 2 mm diameter
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100
1000
10000
0.01 0.1 1 10
Aver
age
Devi
ator
ic S
tres
s Pa
Tip Speed m/s
No cohesion Kadh=0.1 Kadh=0.2
Regime Transition: Effect of Cohesion 18
Spheres, 2 mm diameter
-
100
1000
10000
0.01 0.1 1 10
Aver
age
Devi
ator
ic S
tres
s Pa
Tip Speed m/s
No cohesion Kadh=0.1 Kadh=0.2
Regime Transition: Effect of Cohesion 18
Spheres, 2 mm diameter
-
100
1000
10000
0.01 0.1 1 10
Aver
age
Devi
ator
ic S
tres
s Pa
Tip Speed m/s
No cohesion Kadh=0.1 Kadh=0.2
Regime Transition: Effect of Cohesion 18
Spheres, 2 mm diameter
-
100
1000
10000
0.01 0.1 1 10
Aver
age
Devi
ator
ic S
tres
s Pa
Tip Speed m/s
No cohesion Kadh=0.1 Kadh=0.2
Regime Transition: Effect of Cohesion 18
Spheres, 2 mm diameter
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Inertial Number 19
Inertial number, I= 𝑑𝑑𝑝𝑝𝛾𝛾𝜌𝜌𝑝𝑝𝑃𝑃
Local Rheology The process is described by a single dimensionless number
q special case: γ(dp/g)0.5, assuming that P equals to ρpdpg
q ratio between the inertial timescale dp/(P/ρp)0.5
and macroscopic deformation timescale (1/γ). 𝛾𝛾 = 𝑉𝑉𝑤𝑤 𝐿𝐿⁄
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Inertial Number 19
Inertial number, I= 𝑑𝑑𝑝𝑝𝛾𝛾𝜌𝜌𝑝𝑝𝑃𝑃
Local Rheology The process is described by a single dimensionless number
𝜏𝜏 = 𝜇𝜇 𝐼𝐼 𝑃𝑃 𝜇𝜇 𝐼𝐼 is the bulk friction coefficient
q special case: γ(dp/g)0.5, assuming that P equals to ρpdpg
q ratio between the inertial timescale dp/(P/ρp)0.5
and macroscopic deformation timescale (1/γ). 𝛾𝛾 = 𝑉𝑉𝑤𝑤 𝐿𝐿⁄
Constitutive law:
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Inertial Number 19
Inertial number, I= 𝑑𝑑𝑝𝑝𝛾𝛾𝜌𝜌𝑝𝑝𝑃𝑃
Local Rheology The process is described by a single dimensionless number
𝜏𝜏 = 𝜇𝜇 𝐼𝐼 𝑃𝑃 𝜇𝜇 𝐼𝐼 is the bulk friction coefficient
q special case: γ(dp/g)0.5, assuming that P equals to ρpdpg
q ratio between the inertial timescale dp/(P/ρp)0.5
and macroscopic deformation timescale (1/γ). 𝛾𝛾 = 𝑉𝑉𝑤𝑤 𝐿𝐿⁄
Constitutive law:
𝜎𝜎𝑖𝑖𝑖𝑖 = −𝑃𝑃𝛿𝛿𝑖𝑖𝑖𝑖 + 𝜏𝜏𝑖𝑖𝑖𝑖 𝜏𝜏𝑖𝑖𝑖𝑖 = 𝜂𝜂𝑒𝑒𝑒𝑒𝑒𝑒 𝐼𝐼𝜕𝜕𝑢𝑢𝑖𝑖𝜕𝜕𝑥𝑥𝑖𝑖
𝜂𝜂𝑒𝑒𝑒𝑒𝑒𝑒 =𝜇𝜇 𝐼𝐼 𝑃𝑃
𝛾𝛾
3D Generalisation1
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑇𝑇𝑆𝑆𝑇𝑇𝑆𝑆𝑇𝑇𝑆𝑆 𝐸𝐸𝐸𝐸𝐸𝐸𝑆𝑆𝐸𝐸𝑆𝑆𝐸𝐸𝐸𝐸𝑆𝑆 𝐸𝐸𝐸𝐸𝑆𝑆𝐸𝐸𝑇𝑇𝑆𝑆𝐸𝐸𝑆𝑆𝑣𝑣
1P. Jop, Y. Forterre, O. Pouliquen, A constitutive law for dense granular flows, Nature 441 (2006), 727-30.
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Bulk Friction Coefficient 20
non-cohesive deltahedra
non-cohesive spheres
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.005 0.05 0.5
Bul
k fr
ictio
n co
effic
ient
m
Inertial number I
0.01 m/s
0.025 m/s
0.05 m/s
0.1 m/s
0.25 m/s
0.5 m/s
1 m/s
1.5 m/s
0
0.1
0.2
0.3
0.4
0.5
0.6
0.005 0.05 0.5
Bul
k fr
ictio
n co
effiv
ient
m
Inertial number I
0.01 m/s
0.05 m/s
0.1 m/s
0.25 m/s
0.5 m/s
1 m/s
1.5 m/s
Eq 𝜇𝜇 =𝜏𝜏𝑝𝑝
= 𝜇𝜇1 +𝜇𝜇2 − 𝜇𝜇1𝐼𝐼0 𝐼𝐼 + 1⁄
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Apparent Viscosity for Non-Cohesive Deltahedra 21
0
1
2
3
4
5
6
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5
ln (t
/g) P
a¥s
ln(I)
1 m/s 0.5 m/s 0.2 m/s 0.1 m/s 0.05 m/s 0.01 m/s
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Faceted Particles 22
0
1
2
3
4
5
6
7
8
9
10
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5
ln (t
/rpd
p2g2
)
ln(I)
spheres 2 mm
Deltahedra 2 mm
Dodecahedra 2 mm
Faceted cylinder 2 mm
Paracetamol 2 mm
Truncated Polyhedra 2 mm
Truncated cube 2 mm
no cohesion
𝜏𝜏𝜌𝜌𝑝𝑝𝑑𝑑𝑝𝑝2𝛾𝛾2
= 𝐸𝐸 𝐼𝐼
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Different Cohesion Levels 23
0
2
4
6
8
10
12
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5
ln (t
/rpd
p2g2
)
ln(I)
Spheres
Kadh=0 Kadh=0.1
Kadh=0.2
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Screw Feeder vs FT4 24
Regions where properties are evaluated
Rotational velocity: 2, 5, 10 and 20 rad/s
0
5
10
15
20
25
-12 -10 -8 -6 -4 -2 0
ln (t
/rpd
p2g2
)
ln (I)
Truncated cubes -> 20 rad/s
Kadh 0.1 -> 10 rad/s
Kadh=0.2 -> 10 rad/s
Kadh=0.2 -> 10 rad/s Spheres
Kadh=0.2 -> 30 rad/s
Kadh=0.2 -> 50 rad/s
Kadh=0.5 -> 10 rad/s
Kadh 0.15 -> 10 rad/s
Kadh=0.3 -> 10 rad/s
-
Screw Feeder vs FT4 25
The powder rheology in screw
feeders and FT4 are similar
Both systems – dimensionless
shear stress = f(I)
Regions where properties are evaluated
Rotational velocity: 2, 5, 10 and 20 rad/s
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Screw Feeder vs FT4 25
0
2
4
6
8
10
12
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5ln
(t/r
pdp2
g2)
ln(I)
Screw Feeder
spheres Kadh=0
spheres Kadh=0.2
Truncated Cube Kadh=0.1, 20 rad/s
The powder rheology in screw
feeders and FT4 are similar
Both systems – dimensionless
shear stress = f(I)
Regions where properties are evaluated
Rotational velocity: 2, 5, 10 and 20 rad/s
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Screw Feeder vs FT4 25
0
2
4
6
8
10
12
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5
ln (t
/rpd
p2g2
)
ln(I)
FT4
Kadh=0 Kadh=0.1 Kadh=0.2
0
2
4
6
8
10
12
-5.5 -4.5 -3.5 -2.5 -1.5 -0.5ln
(t/r
pdp2
g2)
ln(I)
Screw Feeder
spheres Kadh=0
spheres Kadh=0.2
Truncated Cube Kadh=0.1, 20 rad/s
The powder rheology in screw
feeders and FT4 are similar
Both systems – dimensionless
shear stress = f(I)
Regions where properties are evaluated
Rotational velocity: 2, 5, 10 and 20 rad/s
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Rheological models 26
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Conclusions 27
ÿ Quasi-static and dynamic shear deformation of cohesive large particles have been simulated and the incipient yield and dynamic bulk friction and ‘effective’ shear viscosity are predicted.
ÿ Particle shape influences the angle of friction in bulk failure of particles
ÿ The presence of vertices in faceted shapes strongly influences the resistance to shear deformation
ÿ Approximating real crystal shapes by truncated polyhedron shapes provides a close match in flow energy and shear deformation behaviour between the two shapes
ÿ Shear stress normalised by the inertial stress is unified for faceted shapes with and without cohesion when expressed in terms of the inertial number
ÿ The same pattern of unification prevails for the conditions in screw feeders
ÿ Experimental validation is ongoing
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28
Thank you for your attention
Slide Number 1ADDoPT: A UK Government-Industry-Academia collaboration Digital Design – An Integrated Pathway from Molecules to Crystals to MedicinesTwo-Pronged Approach in Cohesive Powder Flow AnalysisSchulze Ring Shear TestCohesion Model in DEMFlow Function from DEMParticle ShapeSlide Number 9Work Outline: Dynamic RegimeRocky DEM (ESSS)Rocky DEM (ESSS) Contact modelSurface Energy vs Adhesive StiffnessFaceted vs Rounded ParticlesFaceted vs Rounded ParticlesShape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Shape Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Combined Shape and Cohesion Effect: Flow Energy Comparison at 100 mm s-1 and 5° Helix Angle Regime Transition: Effect of ShapeRegime Transition: Effect of CohesionRegime Transition: Effect of CohesionRegime Transition: Effect of CohesionRegime Transition: Effect of CohesionRegime Transition: Effect of CohesionInertial NumberInertial NumberInertial NumberBulk Friction Coefficient Apparent Viscosity for Non-Cohesive DeltahedraFaceted ParticlesDifferent Cohesion LevelsScrew Feeder vs FT4Screw Feeder vs FT4Screw Feeder vs FT4Screw Feeder vs FT4Rheological modelsConclusionsSlide Number 43