High Shear Granulation Scale-UpMohsen Sadatrezaei Pharm.D.

Geneva PharmaceuticalDayton, NJ

Introduction

Wet granulation is used to improve . . .

Flow Compressibility Bio-availability Homogeneity Electrostatic properties Stability

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

Factors in High shear wet granulation

Granule Growth

Granule formation and growth can be described by two mechanisms

(a) Nucleation of particles

(b) Coalescence between agglomerates

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

Granule growth in high shear mixer

Effect of feed material on Granule growth in high shear mixer

From: Hand book of Pharmaceutical granulation Page 162

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.

Liquid addition phase

(3 minutes)

Kneading phase

(7 minutes)

Decreasing Intragranular porosity

Granule growth by nucleation Coalescence/Densification

Critical moisture content

Granulation process development of a cohesive, fine, water insoluble material

High shear Granulation

Granulation properties are influenced by:

Apparatus variables Process variables Product variables

Apparatus variables

Shear forces in a high shear mixer are very dependent on the mixer construction

Bowl design Impeller design Chopper design

A small change in shape, size or inclination of the blade tips have a significant effect on the impact of the mass.

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.

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.

Relative swept volume

The relative swept volume seems to be an appropriate parameter when comparing the effect of size and construction of the mixing tools.

Equipment Inclination angle of Impeller Relative Swept

volume/s impeller speed

Diosna P 25 36 1.37 PMA 25 29 0.75

PMA 65 30 0.71 Diosna P 50 39 1.08

PMA 150 30 0.61 Diosna P 250 54 0.52

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

Process Variables

Impeller rotation speed

Chopper rotation speed

Load of the mixer

Liquid addition method

Liquid flow rate

Wet massing time

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

Granulation end point

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

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

Granulation End Pointand Product Properties

Granulation end point determination

• Hand test

Qualitative

Subjective

Inconsistent

• Emerging methods

Acoustic Emission (Int. J. Pharm 205, 2000 79 – 71)

Image processing (Powder Tech. 115, 2001 124 – 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

Typical Power and Torque Curves

Machine troubleshooting Formulation fingerprints Batch reproducibility Process optimization Process scale-up

Machine troubleshooting Formulation fingerprints Batch reproducibility Process optimization Process scale-up

Benefits of Mixer Instrumentation

Forces in high shear Granulation

Acceleration F1

Frictional F2

Centripetal F3

Centrifugal F4

The data on centrifugal acceleration reveal that one might expect higher compaction forces in smaller machines at the same level of tip speed.

From: Hand book of granulation technology page191

Forces in high shear Granulation

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.

Use of Froude Numbers for mixers comparison

• Froude number

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”.

Gral 300

Gral 150

Gral 75

Gral 25Gral 10

0.00 0.50 1.00 1.50 2.00 2.50 3.00

Froude Numbers for Collete-Gral High-Shear Mixers

Use of Froude Numbers for mixer comparisons

PMA 1800

PMA 800

PMA 600

PMA 300

PMA 150

PMA 65

PMA 25

PMA 10

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50

Froude Numbers for Fielder High-Shear Mixers

Use of Froude Numbers for mixer comparisons

VG-600P600

PMA 600VG-200

P250PMA 300

Gral 300VG-50

P50

PMA 65Gral 75

VG-10

P10PMA 10

Gral 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

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

PMA mixers characteristics

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

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]

Dimensionless numbers

scale-up approach 3, Using power number correlations

Being dimensionless, the relationship becomes general for a series of geometrically similar high shear mixers regardless of their scale.

• Ne = K(Re.Fr. h/D)n h = height of powder bed

D = Diameter

Power number relationship

Power Number Relationships

0.1

1

10

100

100 1000 10000 100000log (NRe * NFr * h / D)

log

(N

P)

PMA 25

PMA 100

PMA 600

scale-up approach 3, Using power number correlations

• 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

Experimental procedure

scale-up approach 3, Using power number correlations

scale-up approach 3, Using power number correlations

• 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

scale-up strategy

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.

Comments & Questions?