High Shear Granulation Scale-Up

Mohsen Sadatrezaei Pharm.D.

Geneva Pharmaceutical
Dayton, NJ
ntroduction
et granulation is used to improve . . .
FIow
CompressibiIity
Bio-avaiIabiIity
Homogeneity
EIectrostatic properties
StabiIity
Densification
AggIomeration
Shearing and compressing action of the impeIIer
Mixing, granuIation and wet massing
PossibiIity of overgranuIation due to excessive wetting
PossibiIity of producing Iow porosity granuIes
Liquid bridges
CoaIescence
Breakage of the bonds
Specific surface area
Moisture content
IntragranuIar porosity
Heating
Evaporation
Mean granuIe size
actors in High shear wet granulation
ranule rowth
ranule formation and growth can be described by two
mechanisms
(a) Nucleation of particles
(b) Coalescence between agglomerates
Coalescence
PIastic deformation upon coIIision
Surface water
AbsoIute moisture content vs. Liquid
saturation
H (1 - r) p
S =
r
Moisture content on dry basis
s ranular porosity
p Particle density of the feed material
ranule growth in high shear mixer
ffect of feed material on ranule growth
in high shear mixer
rom: Hand book of Pharmaceutical granulation Page 162
ranule growth in high shear mixer
This demonstrates the characteristic features of the aggIomeration of
insoIubIe, cohesive powders in high shear mixers. The growth rate is very
sensitive to the amount of Iiquid phase and to processing conditions, in
particuIar the impeIIer rotation speed and processing time.
iquid addition phase
(3 minutes)
Kneading phase
(7 minutes)
Decreasing IntragranuIar porosity
ranule growth by nucleation Coalescence/Densification
CriticaI moisture content
ranulation process development of a cohesive, fine,
water insoluble material
igh shear ranulation
ranulation properties are influenced by
Apparatus variabIes
Process variabIes
Product variabIes
pparatus variables
Shear forces in a high shear mixer are very dependent on the mixer
construction
BowI design
ImpeIIer design
Chopper design
A smaII change in shape, size or incIination
of the bIade tips have a significant effect on
the impact of the mass.
hiIe the fIuidized state in a fIuidized bed granuIator is nearIy
independent of the construction of the apparatus, shear forces
in a high shear mixer are very dependent on the mixer
construction. ConsequentIy, apparatus variabIes are more
essentiaI when using high shear mixers. Size and shape of the
mixing chamber, impeIIer and chopper differ in different high
shear mixers.
pparatus variables
ReIative Swept voIume: The voIume
swept out per second by the impeIIor
divided by the voIume of the mixer.
The reIative swept voIume has
considered to reIate to the work input on
the materiaI which is assumed to provide
densification of the wet mass.
#elative swept volume
The reIative swept voIume seems to be an appropriate
parameter when comparing the effect of size and construction
of the mixing tooIs.
Equipment Inclination angle of Impeller
Relative Swept
volume/s impeller
speed
Diosna P 25 36H 1.37
PMA 25 29H 0.75
PMA 65 30H 0.71
Diosna P 50 39H 1.08
PMA 150
30H
0.61
Diosna P 250 54H 0.52

rom: Pharm. Ind. 48, 1083 (1986)

Process VariabIes
mpeller rotation speed
Chopper rotation speed
oad of the mixer
iquid addition method
iquid flow rate
Wet massing time
Product variables
Characteristics of the feed materials
ParticIe size and size distribution
SoIubiIity in the Iiquid binder
WettabiIity
Packing properties
Amount of Iiquid binder
Characteristics of Iiquid binder
Surface tension
Viscosity
ranulation end point
etermining the end point, and then reproducibiIity
arriving at that same end point as equipment size and
modeI changes are encountered, has been a continuaI
chaIIenge for the formuIation scientist
hat is the end point? hen you stop your mixer!
%arget particle size mean
%arget particle size distribution
%arget granule viscosity
%arget granule density
Principle of equifinality
ranulation nd Point
and Product Properties
ranulation end point determination
Hand test
QuaIitative
Subjective
Inconsistent
Emerging methods
Acoustic Emission (Int. J. Pharm 205, 2000 79 - 71)
Image processing (Powder Tech. 115, 2001 124 - 130)
Off Iine methods
Torque RheoIogy (Mass consistency)
GranuIation particIe size
In Iine instrumentation
Main impeIIer motor amperage
Main impeIIer motor power
Main impeIIer shaft torque
TypicaI Power and Torque Curves
Machine troubIeshooting
FormuIation fingerprints
Batch reproducibiIity
Process optimization
Process scaIe-up
Machine troubIeshooting
FormuIation fingerprints
Batch reproducibiIity
Process optimization
Process scaIe-up
enefits of Mixer nstrumentation
Forces in high shear GranuIation
cceleration F1
Frictional F2
Centripetal F3
Centrifugal F4
%he data on centrifugaI acceIeration reveaI that one might
expect higher compaction forces in smaIIer machines at the
same IeveI of tip speed.
rom: Hand book of granulation technology
page191
Forces in high shear GranuIation
scaIe-up approach 1 from Horsthius et aI.(1993)
reIative swept voIume
bIade tip speed
Froude number r = n
2
d / g
n - impeIIer speed [T
-1
]
d - impeIIer diameter [L]
g - gravitationaI constant [LT
-2
]
%hey concIuded that maintaining an equaI Froudes number at
different scaIes resuIted in comparabIe particIe size distribution.
Use of Froude Numbers for mixers comparison
Froude number
Being dimensionIess it is independent of machine size
Ratio of centrifugaI force to gravitationaI force
Can be a criterion of dynamic simiIarity of mixers
In a recent pubIication by MichaeI Levin
different mixers have been compared by the
range of Froude number they can produce. A
matching range of Froude numbers wouId
indicate the possibiIity of scaIe-up even for the
mixers that are not geometricaIIy simiIar.
ral 300
ral 150
ral 75
ral 25
ral 10
0.00 0.50 1.00 1.50 2.00 2.50 3.00
Froude Numbers for Collete-ral igh-Shear Mixers
Use of Froude Numbers for mixer comparisons
PM 1800
PM 800
PM 600
PM 300
PM 150
PM 65
PM 25
PM 10
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50
Froude Numbers for FieIder High-Shear Mixers
Use of Froude Numbers for mixer comparisons
'-600
P600
PM 600
'-200
P250
PM 300
ral 300
'-50
P50
PM 65
ral 75
'-10
P10
PM 10
ral 10
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00
Comparative Froude Numbers for High-Shear Mixers
Use of Froude Numbers for mixer comparisons
scaIe-up approach 2 from Rekhi et aI. (1996)
Constant impeIIer tip speed
GranuIating Iiquid voIume proportionaI to batch size
et massing time inverseIy proportionaI to RPM
PMA mixers characteristics
scaIe-up approach 3, Using power number
correIations andin, M., P. York, M.J. Cliff(1996)
ependent of the concept of simiIarity
Geometric simiIarity
AII corresponding dimensions have same ratio
Kinematic simiIarity
AII veIocities at corresponding points have same ratio
Dynamic simiIarity
AII forces at corresponding points have same ratio
Ne = P / (8 n
3
d
5
) Newton (power)
r = n
2
d / g Froude
#e = d
2
n 8 / #eynolds
P - power consumption [ML
2
T
-5
]
8 - specific density of particIes [M L
-5
]
n - impeIIer speed [T
-1
]
d - impeIIer diameter [L]
g - gravitationaI constant [LT
-2
]
- dynamic viscosity [M L
-1
T
-1
]
Dimensionless numbers
scaIe-up approach 3, Using power number correIations
eing dimensionless, the relationship becomes general for a series of
geometrically similar high shear mixers regardless of their scale.
Ne = K(#e.Fr. h/D)
n
h = height of powder bed
D = Diameter
Power number relationship
Power Number ReIationships
0.1
1
10
100
100 1000 10000 100000
Iog (NRe * NFr * h / D)
I
o
g

(
N
P
)
PM 25
PM 100
PM 600
scaIe-up approach 3, Using power number correIations
Charge powders and switch on mixer
Note power reading
Add water at constant rate
At specific water contents note power reading and take sample
Measure density of sample
Measure viscosity of sample
Calculate Power, Reynolds and Froude numbers
Plot Power number relationship
ExperimentaI procedure
scaIe-up approach 3, Using power number correIations
scaIe-up approach 3, Using power number correIations
Perform experiments on smaII scaIe to define master curve for the
formuIation
Identify viscosity and density of wet mass that produces optimum
granuIes
Use these vaIues pIus machine variabIes to caIcuIate power needed on
desired Iarge scaIe mixer
Run Iarge scaIe mixer at the defined setting
Check mass using the mixer torque rheometer
scale-up strategy
Conclusion/#ecommendations
Design a process friendly formulation.
Make sure the process on the small scale is understood controlled.
ttempt to develop formulation/process in the same mixer model as the
production scale (eometric similarity)
Use the Froude number as an indication of the possibility of scale-up
between two different mixer.
%ry to work with slow impeller speed during development work in the lab
scale mixers to simulate production scale mixers.
Use relative swept volume as a good indication of how much work will be
done on the granulate.
stablish an ND PON% based on a reliable response factor and
characterize the granulation and tablet properties at the same end point.
Do an intentional overgranulation and undergrnulation and characterize
granulation/tabletting properties.
n most cases ranulation liquid can be scaled up linearly.
%ry to keep the mixer load ratio consistent in the small and large scale
mixers.
Comments & Questions?