1. High Shear Granulation Scale-Up Mohsen Sadatrezaei Pharm.D.
Topiramate Tablets
High Shear Granulation Scale-Up
Mohsen Sadatrezaei Pharm.D.
Geneva Pharmaceutical
Dayton, NJ
07/24/2000

2. Introduction Wet granulation is used to improve . . . Flow
Topiramate Tablets
Introduction
Wet granulation is used to improve . . .
Flow
Compressibility
Bio-availability
Homogeneity
Electrostatic properties
Stability
07/24/2000

3. Factors in High shear wet granulation
Densification
Agglomeration
Shearing and compressing action of the impeller
Mixing, granulation and wet massing
Possibility of overgranulation due to excessive wetting
Possibility of producing low porosity granules
Liquid bridges
Coalescence
Breakage of the bonds
Specific surface area
Moisture content
Intragranular porosity
Heating
Evaporation
Mean granule size

4. Granule Growth
Granule formation and growth can be described by two mechanisms
Nucleation of particles
Coalescence between agglomerates

5. Coalescence Plastic deformation upon collision Surface water
Absolute moisture content vs. Liquid saturation
H (1 – ε) ρ
S = ε
H: Moisture content on dry basis
ε: Granular porosity
ρ : Particle density of the feed material

6. Granule growth in high shear mixer

7. Effect of feed material on Granule growth in high shear mixer
From: Hand book of Pharmaceutical granulation Page 162

8. Granule growth in high shear mixer
This demonstrates the characteristic features of the agglomeration of insoluble, cohesive powders in high shear mixers. The growth rate is very sensitive to the amount of liquid phase and to processing conditions, in particular the impeller rotation speed and processing time.

9. Critical moisture content
Granulation process development of a cohesive, fine, water insoluble material
Decreasing Intragranular porosity
Liquid addition phase
(3 minutes)
Kneading phase
(7 minutes)
Granule growth by nucleation
Coalescence/Densification
Critical moisture content

10. High shear Granulation
Granulation properties are influenced by:
Apparatus variables
Process variables
Product variables

11. Apparatus variables
Shear forces in a high shear mixer are very dependent on the mixer construction
Bowl design
Impeller design
Chopper design
While the fluidized state in a fluidized bed granulator is nearly independent of the construction of the apparatus, shear forces in a high shear mixer are very dependent on the mixer construction. Consequently, apparatus variables are more essential when using high shear mixers. Size and shape of the mixing chamber, impeller and chopper differ in different high shear mixers.
A small change in shape, size or inclination of the blade tips have a significant effect on the impact of the mass.

12. Apparatus variables
Relative Swept volume: The volume swept out per second by the impellor divided by the volume of the mixer.
The relative swept volume has considered to relate to the work input on the material which is assumed to provide densification of the wet mass.

13. Relative swept volume
From: Pharm. Ind. 48, 1083 (1986)
The relative swept volume seems to be an appropriate parameter when comparing the effect of size and construction of the mixing tools.

14. Process Variables Impeller rotation speed Chopper rotation speed
Load of the mixer
Liquid addition method
Liquid flow rate
Wet massing time

15. Product variables Characteristics of the feed materials
Particle size and size distribution
Solubility in the liquid binder
Wettability
Packing properties
Amount of liquid binder
Characteristics of liquid binder
Surface tension
Viscosity

16. Granulation end point Target particle size mean
What is the end point? When you stop your mixer!
Target particle size mean
Target particle size distribution
Target granule viscosity
Target granule density
Principle of equifinality
Determining the end point, and then reproducibility arriving at that same end point as equipment size and model changes are encountered, has been a continual challenge for the formulation scientist

17. Granulation End Point and Product Properties

18. Granulation end point determination
Hand test
Qualitative
Subjective
Inconsistent
Emerging methods
Acoustic Emission (Int. J. Pharm 205, – 71)
Image processing (Powder Tech. 115, – 130)
Off line methods
Torque Rheology (Mass consistency)
Granulation particle size
In line instrumentation
Main impeller motor amperage
Main impeller motor power
Main impeller shaft torque

19. Typical Power and Torque Curves

20. Machine troubleshooting Formulation fingerprints Batch reproducibility
Benefits of Mixer Instrumentation
Machine troubleshooting
Formulation fingerprints
Batch reproducibility
Process optimization
Process scale-up

21. Forces in high shear Granulation
Acceleration F1
Frictional F2
Centripetal F3
Centrifugal F4

22. Forces in high shear Granulation
From: Hand book of granulation technology page191
The data on centrifugal acceleration reveal that one might expect higher compaction forces in smaller machines at the same level of tip speed.

23. relative swept volume blade tip speed Froude number Fr = n2 d / g
scale-up approach 1 from Horsthius et al.(1993)
relative swept volume
blade tip speed
Froude number
Fr = n2 d / g
n - impeller speed [T-1]
d - impeller diameter [L]
g - gravitational constant [LT-2]
They concluded that maintaining an equal Froude’s number at different scales resulted in comparable particle size distribution.

24. Use of Froude Numbers for mixers comparison
Being dimensionless it is independent of machine size
Ratio of centrifugal force to gravitational force
Can be a criterion of dynamic similarity of mixers
In a recent publication by Michael Levin different mixers have been compared by the range of Froude number they can produce. “ A matching range of Froude numbers would indicate the possibility of scale-up even for the mixers that are not geometrically similar”.

25. Use of Froude Numbers for mixer comparisons

26. Use of Froude Numbers for mixer comparisons

27. Use of Froude Numbers for mixer comparisons

28. Constant impeller tip speed
scale-up approach 2 from Rekhi et al. (1996)
Constant impeller tip speed
Granulating liquid volume proportional to batch size
Wet massing time inversely proportional to RPM

29. PMA mixers characteristics

30. All corresponding dimensions have same ratio Kinematic similarity
scale-up approach 3, Using power number correlations Landin, M., P. York, M.J. Cliff(1996)
Dependent of the concept of similarity
Geometric similarity
All corresponding dimensions have same ratio
Kinematic similarity
All velocities at corresponding points have same ratio
Dynamic similarity
All forces at corresponding points have same ratio

31. Ne = P / ( n3 d5) Newton (power) Fr = n2 d / g Froude
scale-up approach 3, Using power number correlations
Dimensionless numbers
Ne = P / ( n3 d5) Newton (power)
Fr = n2 d / g Froude
Re = d2 n  /  Reynolds
P - power consumption [ML2T-5]
 - specific density of particles [M L-5]
n - impeller speed [T-1]
d - impeller diameter [L]
g - gravitational constant [LT-2]
 - dynamic viscosity [M L-1 T-1]
Being dimensionless, the relationship becomes general for a series of geometrically similar high shear mixers regardless of their scale.

32. D = Diameter scale-up approach 3, Using power number correlations
Power number relationship
Ne = K(Re.Fr. h/D)n h = height of powder bed
D = Diameter

33. Experimental procedure
scale-up approach 3, Using power number correlations
Experimental procedure
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

34. scale-up approach 3, Using power number correlations
scale-up strategy
Perform experiments on small scale to define master curve for the formulation
Identify viscosity and density of wet mass that produces optimum granules
Use these values plus machine variables to calculate power needed on desired large scale mixer
Run large scale mixer at the defined setting
Check mass using the mixer torque rheometer

35. Conclusion/Recommendations
Design a process friendly formulation.
Make sure the process on the small scale is understood controlled.
Attempt to develop formulation/process in the same mixer model as the production scale (Geometric similarity)
Use the Froude number as an indication of the possibility of scale-up between two different mixer.
Try 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.
Establish an END POINT 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.
In most cases Granulation liquid can be scaled up linearly.
Try to keep the mixer load ratio consistent in the small and large scale mixers.

36. Topiramate Tablets
Comments & Questions?
07/24/2000