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

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

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

Granule Growth Granule formation and growth can be described by two mechanisms Nucleation of particles 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.

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

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 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.

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 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.

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 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

Granulation End Point and 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 Benefits of Mixer Instrumentation Machine troubleshooting Formulation fingerprints Batch reproducibility Process optimization Process scale-up

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

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.

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.

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”.

Use of Froude Numbers for mixer comparisons

Use of Froude Numbers for mixer comparisons

Use of Froude Numbers for mixer comparisons

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

PMA mixers characteristics

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

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.

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

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

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

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.

Topiramate Tablets Comments & Questions? 07/24/2000