Scale-Up Approaches

In practice, since most blends are not particularly sensitive to blend speed, and available blenders are often at a fixed speed, the speed closest to 

5 rpm would be selected. If the initial blend times were 15 minutes at 15 rpm, the total revolutions of 225 must be maintained with the 25 ft scale. Assuming 11.5 rpm were selected, this would amormt to a 19.5-minute blend time. Although this approach is convenient and used often, it remains empirical. 

Common violations of this approach that can immediately cause problems include the attempt to scale from one geometry to another (e.g., V-blender to in-bin blender), changing fill level without concern to its effect, and keeping blending time constant while changing blender speed. 

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Yang et al. (1995) described the application of this scale-up approach. Comprehensive testing programs were performed on two relatively large-scale simulation units for a period of several years a 30-cm diameter (semicircular) Plexiglas cold model and a 3-m diameter (semicircular) Plexiglas cold model, both operated at atmospheric pressure. 

Precautions should be taken, especially in a scale-up approach, when dealing with exothermic reactions in the microwave field. Due to the rapid energy transfer of microwaves, any uncontrolled exothermic reaction is potentially hazardous (thermal runaway). Temperature increase and pressure rise may occur too rapidly for the instrument s safety measures and cause vessel rupture. 

It is important to add heat transfer scale-up considerations to the scale-up approach for liquid parenteral solutions as heat transfer applications may play a considerable role in preparation of these products. For heat transfer applications, constant horsepower per unit volume is used to achieve approximately similar heat transfer coefficients for the same type of impeller. This approach is a close approximation since the effect of horsepower on the heat transfer coefficient (ho) is relatively small ... 

In situations where a complete description of the physical behavior of a system is unknown, scale-up approaches often involve the use of dimensionless groups, as described in Chapter 1. Unlike flow behavior in a blender, the flow behavior of powder through bins and hoppers can be predicted by a complete mathematical relationship. In light of this, analysis of powder flow in a bin or... 

Stress-strain type equations have been developed for the compaction process, which help provide an understanding of the mechanisms involved in forming a tablet, as well as allowing for the prediction of compaction results. This predictive power of the compaction process is the basis for many scale-up approaches. However, there are compression and consolidation process aspects which are dependent on manufacturing scale, e.g., speed-sensitive materials, and this results in many problems encountered in transferring a technology to production scale. Unfortunately, these scale-sensitive processes have not been as extensively studied, and are less understood. 

There are many scale-up approaches that vary from simple to complex. Each approach s success rate varies based on the specific formulation, the process... 

Another scale-up approach, which is simple to understand, is to scale-up the compaction force based on the roller width. In this approach, once the desired tablet characteristics (i.e., tablet dissolution, granule flow, minimal tablet weigh variation, tablet hardness, and minimal tablet friability) are obtained, the ribbon compaction force is noted during processing from the known roll width. As the product is scaled up, the applied force is scaled up based on the roller width. Table 5 provides several examples of scale-up factors that can be used as a guide. This technique has been found to be successful, but may have some limitations as the entire scale-up relationship may not be linear. 

Izumi, T., Enomoto, S., Hosiyama, K., Sasahara, K., Shibukawa, A., Nakagawa, T., and Suguyama, Y. (1996). Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J. Pharmacol. Exp. Ther. 277 1630-1641. 

Use the scale-up approach and the kinetic approach to design fixed-bed adsorption columns based on laboratory or pilot column data. 

Two macroscopic methods to design adsorption columns are the scale-up and kinetic approaches. Both methods rely on breakthrough data obtained from pilot columns. The scale-up method is very simple, but the kinetic method takes into account the rate of adsorption (determined by the kinetics of surface diffusion to the inside of the adsorbent pore). The scale-up approach is useful for determining the breakthrough time and volume (time elapsed and volume treated before the maximum allowable effluent concentration is achieved) of an existing column, while the kinetic approach will determine the size requirements of a column based on a known breakthrough volume. 

Example 7.1 Fixed-bed column design by the scale-up approach... 

A wastewater flowrate of 180 m /day has a TOC (total organic carbon level) of 200 mg/L. A flxed-bed GAC adsorption column wiU be used to reduce the maximum effluent concentration to 8 mg/L. A breakthrough curve. Figure 7.12, has been obtained from an experimental pilot column operated at 2(BV)/hr. Other data concerning the pilot column are mass of carbon = 4.13 kg, water flowrate = 15 L/hr, and packed carbon density = 400 kg/m. Using the scale-up approach, determine the values of the following parameters for the design column ... 

Taking into account the fact that the description of the pore structure of the catalyst particle is very much simplified, we can conclude that the predictions are good and that they provide an example of a satisfactory scale-up approach based on the physico-chemical properties and kinetic behaviour of the system. 

Some common terms used in preparative-scale liquid chromatography are summarized in Table 11.4, The production rate, specific production, or the recovery yield provide suitable objective functions to judge the relative success of individual methods. For efficient use of the separation system, the production rate and the recovery yield should be maximized. Invariably, this results in operating the column in an overloaded condition. Unfortunately, column operation under nonlinear conditions is complex, and optimum conditions are not as easy to predict as the less demanding, although less powerful, scale-up approach. To scale up an analytical separation, the same column packing, column length, and mobile phase velocity are used, and the column diameter increased... 

Figure 11.7. Application of the scale-up approach for the isolation of bilirubin isomers by high-pressure column liquid chromatography.

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