Manufacturing Pharmaceutical Granules : Is the Granulation Endpoint a Myth?

The moist agglomeration process by high-shear mixing/granulation, i.e. the wet massing, screening and subsequent drying is a wide spread but critical unit operation. Since for decades formulators are looking for the correct “end-point” of this important process, i.e. when do you need to stop massing or stop with the addition of granulating liquid? What is the correct amount of granulating liquid? A similar situation exists in case of the moist agglomeration in fluidized bed equipment. In the latter case the simultaneous drying of the still moist granules have to be taken into account. Recently a science-based virtual equipment simulator could be developed mimicking the granule size evolution in a fluidized bed granulator during the addition of granulating liquid. For the simultaneous drying the Mollier chart is used. With this virtual equipment simulator it is possible to simulate “crash situations”, i.e. by overwetting or by an incorrect use of the parameter setting. However the determination of the “end-point” depends only on the operator, who desires a certain granule size distribution and a well-defined final moisture content of the batch. Thus the existence of a process intrinsic “end-point” has to be questioned. The same situation can be reported in case of high-shear mixing/granulation based on many years of research. In fact nobody could clearly show the existence of an intrinsic “end-point”. However during the continuous addition of a granulating low viscous liquid a sudden increase in power consumption can be measured, which levels off. Such a measurement depends on the formulation and leads to an “early signal” not to the “end-point”. This signal can be used for a tight control of the granulation process and leads to a low batch to batch variability in the final granule size distribution. The latter is the goal of the PAT (Process Analytical Technology) Initiative emphasizing "Quality by Design".