New trends in the production of pharmaceutical granules: the classical batch concept and the problem of scale-up.

The moist agglomeration process, i.e. the wet massing, screening, and subsequent drying is often a critical unit operation. The correct amount of granulating liquid and the correct monitoring and detection of the granulation kinetics are important issues. The method to monitor the kinetics needs to be robust and should be applicable for any batch size. In this context, the theory of scale-up and the monitoring of the moist agglomeration process are reviewed. It has to be kept in mind that the production of granules in the pharmaceutical industry is still based on a batch concept. This concept offers many advantages with respect to quality assurance as a batch can be accepted or rejected. From experience, it is well known, however, that the scale-up of the batch size may lead to problems. This fact is due to the variety of the equipment involved and to the fact that there is a lack of well-known 'scale-up invariant' parameters. A survey of the granulation end-point detection procedure shows that the majority of the equipment manufacturers offer mixer/kneaders for the moist agglomeration process instrumented with a power consumption device. In this review, this and other approaches are discussed and emphasis is placed on how to best use the power consumption method. The question of robust formulations leads to the conclusion that, for a robust dosage form design, new concepts such as percolation theory have to be applied. A typical example is presented, which illustrates the effect of a percolation phenomenon.