Closing the gap in series scale up of high shear wet granulation process using impeller power and blade design

This paper investigates the use of impeller work combined with an understanding of the significance of the impeller power inflection point during granulation to monitor, control, and scale up high shear wet granulation processes in the pharmaceutical industry. High shear wet granulations were carried out in a series of PMA Fielder granulators (25, 65, 150, and 300-L) with a geometric similar bowl at conditions of constant water addition time and constant tip speed. The results suggested that the granulation process can be effectively scaled up using a linear relationship between the impeller power inflection point (percent of water added at the point where the impeller load starts rising) and the Froude number in PMA Fielder granulator. To close the gap in the series scale up of wet granulation processes, it is desirable to design a granulator at small scale that performs similarly to a full scale commercial granulator such that no variables have to be significantly changed during scale up. A customized 6-L granulator (Fluid Air, Inc.) was designed with a similar bowl geometry as the 300-L Fielder granulator with a specialized blade of lower angle. It is illustrated in this paper that a 6-L granulator can be directly scaled up to a 300-L granulator using constant tip speed and percentage water addition, with the same impeller work and drug product performance. Granulation scale up using the impeller power as the endpoint measurement, combined with a proper impeller blade design can significantly reduce expenditure and time and accelerate the progression of drug product to market, by eliminating stepwise series scale up, and minimizing drug substance requirements.

Graphical AbstractThe figure above demonstrated that the gap in the series scale up of a high shear wet granulation process can be closed by designing the impeller blade of the right contact angle for a pilot scale granulator (6 L granulator with a 20° blade angle) such that the impeller power/water addition profiles match that of a commercial scale granulator (300 L granulator with a 41° blade angle) operated at a constant tip speed, 5.5 m/s. The inflection points are identical, 22% w/w water added. This suggests that if the impeller blade is designed base on impeller blade power consumption between scales direct granulation scale up can be effectively achieved using the same processing parameters of tip speed, and percent water addition.Figure optionsDownload full-size imageDownload as PowerPoint slide