How to Scale-Up Scientifically

Michael Levin, Ph. D.

Process Analytical Instrumentation - Monitoring and Control East Hanover, New Jersey, USA www.mcc-online.com
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Metropolitan Computing Corporation

Dimensional Analysis
Dimensional analysis is a method for producing dimensionless numbers that completely describe the process. The analysis should be carried out before the measurements have been made, because dimensionless numbers essentially condense the frame in which the measurements are performed and evaluated. It can be applied even when the equations governing the process are not known.

Dimensional Analysis Dimensional Analysis

Similarity: geometrical kinematic dynamic

For any two dynamically similar systems, all the dimensionless numbers necessary to describe the process have the same numerical value.
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Dimensional Analysis Dimensional Analysis

Np = P / ( n3 d5) Newton (power) Froude Fr = n2 d / g 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]
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Dimensional Analysis Dimensional Analysis

Scientific scale-up procedure: 1. Describe the process using a complete set of dimensionless numbers, and 2. Match these numbers at different scales. This dimensionless space in which the measurements are presented or measured will make the process scale invariant.
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Dimensional Analysis Dimensional Analysis -theorem (Buckingham)

Every physical relationship between n dimensional variables and constants (x0, x1, x2, , xn) =0 can be reduced to a relationship

(0 ,1, , m) = 0
between m = n - r mutually independent dimensionless groups, where r = number of dimensional units, i.e. fundamental units (rank of the dimensional matrix).

Dimensional Analysis Dimensional Analysis

Relevance List
list of all variables thought to be crucial for the process being analyzed
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Dimensional Analysis Dimensional Analysis

Dimensional Matrix
Rows: basic dimensions Columns: quantities from the Relevance List
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Application to mixing-granulation process

Typical Instrumentation Signals

s4 s3

s5

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Endpoint Determination

Target particle size mean Target particle size distribution Target granule viscosity Target granule density

Principle of equifinality
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Granulation End Point and Product Properties

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Case Study I: Leuenberger (1979,1983)

Bier HP, Leuenberger H, Sucker H. Determination of the uncritical quantity of granulating liquid by power measurements on planetary mixers. Pharm Ind 4:375-380, 1979 Leuenberger H. Scale-up of granulation processes with reference to process monitoring. Acta Pharm Technol 29(4), 274-280, 1983

Quantity 1 2 3 4 5 6 7 8 Power consumption Specific density Blade diameter Blade angular velocity Binder amount Bowl volume Gravitational constant Bowl height

Symbol P d n m Vb g h

Units Watt kg / m3 m rev / s kg m3 m / s2 m

Dimensions ML2 T-3 M L-3 L T-1 M L3 LT-2 L

The Relevance List

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Case Study I: Leuenberger (1979,1983)

The Dimensional Matrix Mass M Length L Time T Core matrix 1 3 0 d 0 1 0 n 0 0 1 P 1 2 3 Residual Matrix m 1 0 0 Vb 0 3 0 g 0 1 -2 h 0 1 0

The transformed Dimensional Matrix M 3M + L -T

Unity matrix 1 0 0 d 0 1 0 n 0 0 1 P 1 5 3

Residual Matrix m 1 3 0 Vb 0 3 0 g 0 1 2 h 0 1 0
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Case Study I: Leuenberger (1979,1983)

group Expression = Np = q t / (Vp ) Definition Newton (Power) number Specific Amount of Liquid Vp Volume of particles q = binder addition rate t = binder addition time Fractional Particle Volume Froude Number Ratio of Lengths 0 = P / (1 * d5 * n3) 1 = q / (1 * d3 * n0)

2 = t / (0 * d3 * n0) 3 = g / (0 * d1 * n2) 4 = h / (0 * d1 * n0) 0 = (1, 2, 3, 4)

= (Vp / Vb)-1 = Fr-1 =h/d

Assumption: groups 2, 3, 4 are essentially constant Conclusion: 0 = (1)

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Case Study I: Leuenberger (1979,1983)

5 different planetary mixers (Dominici, Glen, Molteni); batch sizes from 3.75 kg up to 60 kg.
Power number vs. Granulating Liquid
25 20 Np 15 10 5 0 7 12 17 22 27 Specific Amount of Granulating Liquid

S4 S5

Binder amount

S3

S5 S4 S3

Constant rate of binder addition proportional to the batch size

Batch Size

Adapted from Bier, Leuenberger and Sucker (1979)

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Case Study II: Landin et al. (1996)

Landin M, York P, Cliff MJ, Rowe RC, Wigmore AJ. Scale-up of a pharmaceutical granulation in fixed bowl mixer-granulators. Int J Pharm 133:127-131, 1996

Quantity 1 2 3 4 5 6 7 Power consumption Specific density Blade diameter Blade speed Dynamic viscosity Gravitational constant Bowl height

Symbol P d n g h

Units Watt kg / m3 m rev / s Pa * s m / s2 m

Dimensions ML2T-3 M L-3 L T-1 M L-1 T-1 LT-2 L

The Relevance List

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Case Study II: Landin et al. (1996)

The Dimensional Matrix Mass M Length L Time T 1 3 0 Core matrix d 0 1 0 Unity matrix M 3M + L -T 1 0 0 d 0 1 0 n 0 0 1 P 1 5 3 n 0 0 1 P 1 2 3 Residual Matrix 1 -1 -1 g 0 1 -2 h 0 1 0

The transformed Dimensional Matrix

Residual Matrix 1 2 1 g 0 1 2 h 0 1 0
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Case Study II: Landin et al. (1996)

group 0 1 2 3 Expression P / (1 * d5 * n3) / (1 * d2 * n1) g / (0 * d1 * n2) h / (0 * d1 * n0) = Np = Re-1 = Fr-1 =h/d Definition Newton (Power) number Reynolds number Froude Number Ratio of Lengths

= = =

0 = (1, 2, 3,) or Ne = (Re, Fr, h/d).

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Case Study II: Landin et al. (1996)

Fielder PMA 25, 100 and 600 Liter
Power Number Relationships
100 PMA 25 PMA 100 10
Np

PMA 600

0.1 100 1000 10000

Re * Fr * h / D

100000

Np = 7.96 x 102 (Re * Fr * h / d)-0.732

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Case Study II: Landin et al. (1996) Concerns: Geometric Similarity Interpretation of data from Mixer Torque Rheometer
Kinematic viscosity vs. dynamic viscosity Re = pseudo Reynolds number = wet mass consistency number

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Case Study III: Faure et al. (1998)

Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. A methodology for the optimization of wet granulation in a model planetary mixer. Pharm Dev Tech 3(3):413-422, 1998

Planetary Mixers Hobart AE240, dual bowl 5L and 8.5L Np = k (Re * Fr * h/d)-s r2 > 0.92
Assumptions:
Drive speed ~ blade speed h/d ~ Vm / Vb (fill ratio) ~ m / ( R3) fill ratio for Hobart bowl Re = pseudo Reynolds number = wet mass consistency number
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Case Study IV: Landin et al. (1999)

Landin M, York P, Cliff MJ, Rowe RC. Scaleup of a pharmaceutical granulation in planetary mixers. Pharm Dev Tech 4(2):145-150, 1999

Planetary Mixers Collette MP20, MP90, and MPH 200 Bowl sizes (L): 5, 20, 45, 90, 200 Np = k (Re * Fr * h/d)-s r2 > 0.95
Assumptions:
Drive speed ~ blade speed h/D ~ Vm / Vb (fill ratio) ~ m / ( R3) Re = pseudo Reynolds number = wet mass consistency number
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Case Study V: Faure et al. (1999)

Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators, Eur J Pharm Sci, 8(2):85-93, 1999

Collette Gral Mixers (8, 25, 75 and 600 Liter)

no geometric similitude: significant distortion factor no dynamic similitude due to different wall adhesion, lid interference -> PTFE lining

Np = k (Re * Fr * m / ( R3))-s

r2 > 0.93
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Case Study VI: Hutin et al. (2004)

Hutin S, Chamayou A, Avan JL, Paillard B, Baron M, Couarraze G, Bougaret J. Analysis of a Kneading Process to Evaluate Drug SubstanceCyclodextrin Complexation. Pharm Tech, October 112-123, 2004

Quantity 1 2 3 4 5 6 7 8 Power consumption Specific density Blade radius Blade speed Dynamic viscosity Gravitational constant Powder bed height Blade length

Symbol P r n g h l

Units Watt kg / m3 m rev / s Pa * s m / s2 m m

Dimensions ML2T-3 M L-3 L T-1 M L-1 T-1 LT-2 L L

The Relevance List

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Case Study VI: Hutin et al. (2004)

Aoustin kneader (2.5 and 5 Liter) Np = k (Re * Fr * h/r * r/l))-s

r2 > 0.99

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Finale Dimensional Analysis provides a powerful scientific technique for scaleup This technique is proven by a century of engineering applications Rational scale-up should replace empirical approach in pharmaceutical applications
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References
Bier HP, Leuenberger H, Sucker H. Determination of the uncritical quantity of granulating liquid by power measurements on planetary mixers. Pharm Ind 4:375-380, 1979 Buckingham E. On physically similar systems; Illustrations of the use of dimensional equations. Phys Rev NY 4:345-376, 1914 Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. A methodology for the optimization of wet granulation in a model planetary mixer. Pharm Dev Tech 3(3):413-422, 1998 Faure A, Grimsey IM, Rowe RC, York P, Cliff MJ. Applicability of a scale-up methodology for wet granulation processes in Collette Gral high shear mixer-granulators, Eur J Pharm Sci, 8(2):85-93, 1999 Horsthuis GJB, van Laarhoven JAH, van Rooij RCBM, Vromans H. Studies on upscaling parameters of the Gral high shear granulation process. Int J Pharm 92:143, 1993 Hutin S, Chamayou A, Avan JL, Paillard B, Baron M, Couarraze G, Bougaret J. Analysis of a Kneading Process to Evaluate Drug SubstanceCyclodextrin Complexation. Pharm Tech, October 112-123, 2004 Landin M, York P, Cliff MJ, Rowe RC, Wigmore AJ. Scale-up of a pharmaceutical granulation in fixed bowl mixer-granulators. Int J Pharm 133:127-131, 1996 Landin M, York P, Cliff MJ, Rowe RC. Scaleup of a pharmaceutical granulation in planetary mixers. Pharm Dev Tech 4(2):145-150, 1999 Leuenberger H. Scale-up of granulation processes with reference to process monitoring. Acta Pharm Technol 29(4), 274-280, 1983 Levin M. (ed.). Pharmaceutical Process Scale-Up. Marcel Dekker, New York, 2002. Merrifield CW. The experiments recently proposed on the resistance of ships. Trans Inst Naval Arch (London) 11:80-93, 1870 Rayleigh, Lord. The principle of similitude. Nature 95 (2368, March 18):66-68, 1915 Reynolds O. An experimental investigation of the circumstances which determine whether the motion of water shall be direct or sinusous, and of the law of resistance in parallel channels. Philos Trans R Soc London 174:935-982, 1883 Zlokarnik M. Dimensional Analysis and Scale-Up in Chemical Engineering. Springer-Verlag, 1991 Zlokarnik M. Problems in the application of dimensional analysis and scale-up of mixing operations. Chem Eng Sci 53(17):3023-3030, 1998

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