Scale-up issues

Scale-up is a challenging issue for fluidized-bed reactors, as illustrated by several spectacular feilures of commercial fluidized-bed processes vhich did not live up to the promise shown by laboratory- and pilot-scale reactors. With better understanding of the factors causing the worsening of performance, one can do a better job of avoiding the risks associated with scale-up. Useful tips were provided by Pell [5]. 

When catalytic fluidized-bed reactors are scaled up or scaled down, there is no universally accepted scaling procedure. One approach is to maintain the HID ratio constant another is to hold H constant and only vary the diameter or cross-sectional area. In addition, there is no consensus on whether the distributor of a small facility should be a fully scaled geometrically identical version of the distributor intended for the full-scale reactor, or a portion of the full-scale version. Often the latter is impractical. 

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Fig. 1. Design and scale-up issues for various mixing classes (see Table 1).

Two different microwave reactors for scale-up have been tested with special focus on handling, automation, workflow, and typical scale-up issues. The Synthos 3000 as a batch mode reactor provides a relatively large reaction volume (16 x 70 ml), allows high temperature and pressure (240°C/40 bar), and proved to be very robust. Handling of suspen-... 

This simplified description of molecular transfer of hydrogen from the gas phase into the bulk of the liquid phase will be used extensively to describe the coupling of mass transfer with the catalytic reaction. Beside the Henry coefficient (which will be described in Section 45.2.2.2 and is a thermodynamic constant independent of the reactor used), the key parameters governing the mass transfer process are the mass transfer coefficient kL and the specific contact area a. Correlations used for the estimation of these parameters or their product (i.e., the volumetric mass transfer coefficient kLo) will be presented in Section 45.3 on industrial reactors and scale-up issues. Note that the reciprocal of the latter coefficient has a dimension of time and is the characteristic time for the diffusion mass transfer process tdifl-GL=l/kLa (s). 

Stirred tank reactors are mostly used because they provide a rapid means of obtaining a uniform composition and temperature throughout the reaction mixture they also offer the flexibility required for the small-scale production of many different molecules. Companies such as Biazzi, Davy Process Technology (Buss loop technology), DeDietrich and others provide technology adapted to hydrogenations (i.e., pressures up to 100 bar and temperatures up to 200 °C) [45-47]. Here, some scale-up issues related to stirred tank reactors are described. 

Scale-up Issues for Densely Distributed Analytical Devices... 

The best data to use for determining whether an incompatibility exists will obviously be from testing the actual scenarios and conditions that are identified. However, this is often not practical or possible. Small-scale tests can be performed in a laboratory that can give an indication whether a reaction is expected. However, be wary of concluding that since no reaction is seen on a small scale, no effects will be realized in an industrial facility. Heat transfer effects and scale-up issues are especially important to be careful of when extrapolating small-scale results. Differences in heat transfer, mixing and other scale-up effects can cause a significant and potentially... 

Scale-up Issues—Equipment and Auxiliary System Sizing... 

If the desired yield target cannot be achieved then an antisolvent system can be selected using the same techniques. The antisolvent should be fully miscible with the primary solvent and have a low solubility for the solute. It should be noted that the addition of an antisolvent to reduce solubility and generate supersaturation may introduce scale up issues, caused by the differences in micro-mixing performance between the laboratory and manufacturing plant. 

Unfortunately, the publication by Williams and coworkers is one of the only reports of a scale-up problem involving liquids or semisolids in the pharmaceutical literature. A number of papers that purport to deal with scale-up issues and even go so far as to compare the properties of small versus large batches failed to apply techniques, such as dimensional analysis, that could have provided the basis for a far more substantial assessment or analysis of the scale-up problem for their system. Worse yet, there is no indication of how scale-up was achieved or what scale-up algorithm(s), if any, were used. Consequently, their usefulness, from a pedagogical point of view, is minimal. In the end, effective scale-up requires the complete characterization of the materials and processes involved and a critical evaluation of all laboratory and production data that may have some bearing on the scalability of the process. 

In addition to the scale-up issues mentioned in the previous case studies, there are scale-up issues specific to bilayered tablets. These specific issues include mixing of the granulation on the die table during compression,... 

Summary of scale-up issues Scaling-up the fluid-bed process clearly faces many hurdles that are both similar and, at the same time, different from those faced with pan-coating processes. Additional complexity stems from the nature of the substrate that is likely to be coated in the fluid-bed process, as well as the fact that, very often, the applied coating has a very important role to play in drug delivery. 

To summarize, the significant aspects of pharmaceutical scale-up are presented in this book in order to illustrate potential concerns, theoretical considerations, and practical solutions based on the experience of the contributing authors. In no way do we claim a comprehensive treatment of the subject. A prudent reader may use this handbook as a reference and an initial resource for further study of the scale-up issues. 

Some questions a formulator needs to address up front are What are the marketing plans What are the potential obstacles to uniformity Is the active raw material physically and chemically consistent What are the physical plant constraints Addressing these and other questions in the early stages of development could aid in avoiding many scale-up nightmares. Additionally, the identification of potential scale-up issues forces the formulator to consider commercialization of the drug delivery system. Too often, formulation scientists develop tablet formulations in a bubble, only to be later handed off to some poor process development person who has to make it work. 

In an effort to overcome the dwell time/scale-up issues. Metropolitan Computer Corporation (MCC) has developed a single-station development tablet press that reproduces the compaction event time of manufacturing-scale tablet presses. The Presster (see Fig. 6) can be set up to match the rate, roll wheel configuration, and tooling of any manufacturing-scale tablet press. This enables the formu-lator to eliminate compaction rate as a variable upon scale-up. It does require that early in development the formulation scientist identify the tablet press that the commercialized product will run on. This is in keeping with the theme of this chapter—begin a development project with the end in mind. 

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