Scale-Up of the Compaction and Tableting Process

Alan Royce, Colleen Ruegger, Mark Mecadon, Anees Karnachi, and Stephen Valazza 

To address the issue of the scale-up of the tablet compaction process, this chapter will review the following (1) compaction, (2) predictive studies, (3) scale-up/validation process, (4) case studies, and (5) process analytical technologies. 

The compaction process has been studied extensively and macroscopically and it is well characterized. This is advantageous, since any understanding of the 

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. 

The compaction process can be described by a variety of force (or pressure)-displacement profiles, such as force versus time, force versus tablet porosity, and force versus tablet properties (hardness, friability, dissolution, etc.). The effect of compaction speed on a variety of tablet properties can also be studied. 

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To consider the subject of scale-up of the compaction and tableting process, one must consider the production of one tablet in 30 minutes, if one were a new graduate student using the Carver Hydraulic Laboratory Press for the first time, to a single-stroke Model E or Model F press at 60 tablets per minute, to a full-scale rotary tablet press at more than 2000 tablets per minute. 

Schwartz, J.B. Scale-up of the compaction and tableting process. In Pharmaceutical Process Scale-Up Levin, M., Ed. Marcel Dekker New York, 2002. 

Joseph B. Schwartz. 2002. Scale-up of the compaction and tablet protrassfrinHceutical Process Scale-Up, edited by Michael Levine, Marcel and Dekker Publishers, New York, NY, vol. 118, pp. 221-237. 

As already noted, the most important parameters or characteristics to observe during scale-up of the compaction process are tablet hardness (or tensile strength) and tablet dissolution. However, the following might also provide useful information. 

The first true compaction simulator capable of mimicking the compaction and ejection cycle of a rotary tablet press was reported by Hunter et al. in the 1970s (2), The evolution of such an instrument presented a novel tool for both powder compression research and scale-up of the tableting process. Celek and Marshall report that although compaction simulators are expensive to purchase, they present the following attributes ... 

Scale-up of the tableting process is a critical step in tablet manufacturing and often causes time consuming operations. Compaction simulators are de.signed to mimic high-speed rotary tablet presses with a minimum quantity of material in the early stage of... 

As shown in Figure 27, it is apparent that when the roller compaction force was scaled-up, the compactibility curve of the tablets shifted downward. Ideally, a formulator would prefer a 60 N hardness window of acceptable force. In this example, the flat part of the curve had no effect on friability and dissolution and thus could be processed. The example does show that for a roller compaction process, a scale-up factor must be considered for the roller compaction force early on in development. Factors that affect the tablet compactibility curve at scale-up include the roller compaction force and strain-rate sensitivity of the compact. 

The rate of tlie compaction process is another variable that should be considered throughout development, including scale-up. Typically, the development of a tablet formulation takes place on tablet presses that are relatively slow. The tableting rate is important to consider for several reasons. Blend flow is important to ensure bulk blend transfer into the tablet press (hopper) and consistent die fiU. Variation or difficulty in the bulk flow and die fill can contribute to tablet weight variation. As the compaction rate increases, the blended material must be able to... 

Through the use of DOE, a robust formulation and process were developed, resulting in tablets that could be produced at production scale. The compaction profile shifted slightly on scale-up to production, but tablet... 

There are several uses of tablet press instrumentation in the scale-up process itself. One of these involves obtaining a sample of the scale-up batch and compacting that sample on the pilot-plant or research instrumented tablet press on which the formulation has been previously evaluated. Similarity of the fingerprint or the various research plots (Heckel, force-displacement, radial vs. axial plots) is evidence that the scale-up batch is similar to the previously evaluated research batch [2]. 

It was demonstrated that dimensional analysis of the tableting process can produce a scientifically reliable way of predicting tablet properties across the range of materials and with diverse compaction mechanisms. A theoretically sound scale-up method is thus readily available for tableting equipment of different capacity. The method can be readily expanded to include other materials and tablet presses and other target quantities, such as tablet stability (disintegration) and bioavailability (dissolution). 

Compaction, also known as tableting, involves the compression of the blend into a unit dose. The mechanism for this type of processing has remained unchanged for quite some time. The main components of the compression cycle are pressure rolls, weight adjustment cam, ejection cam, and feed frame. The main considerations when scaling up is compression speed. Compression speed effects dwell time and feed rate. As you go from a small development compression machine to a high-speed production machine, the powder is processed much more rapidly. 

Using mechanical compaction simulators allows us to simulate the tableting process of rotary tableting machines to a greater extent than when using hydraulical compaction simulators. Thus they will be mainly used in formulation development and scale-up. 

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. 

Force measurements made without displacement values are still useful in identifying the dependency of tablet hardness (and other associated characteristics) on compaction force, and also the effect of the tablet press compaction speed on tablet strength (influence of dwell time/effective contact time). Dwell time dependency is an important scale-up factor for the tableting process, and evaluation of the sensitivity of a formulation to dwell time at small scale is useful, although the actual commercial dwell time is not always achievable on instrumented, small-scale tablet presses. 

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