Scale-Up Considerations in Granulation

Particle and Systems Design Centre, Division of Chemical Engineering, School of Engineering, The University of Queensland, 

Scale-up of any engineering process is a great technical and economic challenge. Scale-up of granulation processes, in particular, is difficult and often problematic due to the inherently heterogenous nature of the materials used. However, recent improved understanding of the rate processes that control granulation improves our ability to do rational scale-up. 

There are two situations where process scale-up is needed (1) commercialization of newly developed processes and products and (2) expansion of production capacities in response to increased market demand. 

For pharmaceutical applications, the challenge is almost always associated with new product development. Scale-up in the pharmaceutical industry is unique in that experiments at laboratory and pilot scale are also required to produce product of the desired specification for different stages of clinical trials. This gives additional constraints and challenges to engineers and technologists during scale-up. 

A change in scale invariably impacts on process conditions and, consequently, on the product quality. For pharmaceutical industries, the Food and Drug Administration (FDA) ranks the impacts on the drug product arising from changes of process conditions including production scales into three levels as shown in Table 1 (1). Level 1 is reserved for changes that are unlikely to have any detectable impact on the formulation quality and performance (2). For all practical purposes, scale-up should aim to achieve an impact equivalent to or less than Level 1. 

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He Y, Liu X. Litster JD. Scale up considerations in granulation. In Parikh DM, ed. Handbook of Pharmaceutical Granulation Technology. Boca Raton, Florida Taylor and Francis Group, 2005 459 90. 

Campy, D. Eaves, T. Grudzinski, E. Worthington, H. Scale up considerations in fluidized bed granulation air flow rates and air pressure distribution. British Pharmace. Conference 1974, 76p. 

High-shear granulation has been one of the most commonly used methods to produce granules since the early 1980s (4). Hence, this chapter discusses in detail, the equipment, process variables, formulation requirements, granulation end-point determination, and scale-up considerations of the high-shear granulation process. 

Insightful understanding of the granulation processes is essential for the identification of key variables and parameters for the dimensional analysis and scale-up considerations. While development of definitive mathematical models for the granulation processes is incomplete, the scaling approaches recommended in this chapter help reduce uncertainty during new product development and transfer to industrial sites. 

The most important characteristics of the final formulation to be compacted are particle size and particle size distribution, density and/or porosity, powder flow, cohesiveness, and lubrication. Particle size, particle size distribution, and density and porosity of the formula will not be addressed here because they are the result of other operations in the scale-up sequence, such as granulation and milling. They should be evaluated as part of those specific operations. It should be noted, however, that the influence of particle size on powder flow and, therefore, on uniform die fill is very important to the compaction operation, but is not a result of it. The one consideration to keep in mind during scale-up is the speed of the press, which will directly affect the time available for the die filling to occur. This is an important parameter to observe carefully. 

Scaling up the process in a low-shear granulator is a daunting task. Scale-up equations are usually proprietary to the mixer manufacturers and little is written about them in the literature. The equations have a sound basis in science but are ameliorated by constants and factors that take into consideration empirical feedback and intuition concerning the machine function. 

A section is dedicated to the interpretation of granulation experiments performed at different scales and how these can be used in scale-up of the process from laboratory and pilot size to full-scale industrial equipment. It is only very recently that criteria for such scale-up have become available mainly from theoretical considerations of granule growth and breakup at the micro-scale, and this new knowledge is briefly presented. Finally, some recent computations are presented in which the process of both agglomeration and... 

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