Scale-up of mixer granulators for effective liquid distribution

There is considerable anecdotal evidence from industry that poor wetting and liquid distribution can lead to broad granule size distributions in mixer granulators. Current scale-up scenarios lead to poor liquid distribution and a wider product size distribution. There are two issues to consider when scaling up: the size and nature of the spray zone and the powder flow patterns as a function of granulator scale. Short, nucleation-only experiments in a 25L PMA Fielder mixer using lactose powder with water and HPC solutions demonstrated the existence of different nucleation regimes depending on the spray flux Ψa—from drop-controlled nucleation to caking. In the drop-controlled regime at low Ψa values, each drop forms a single nucleus and the nuclei distribution is controlled by the spray droplet size distribution. As Ψa increases, the distribution broadens rapidly as the droplets overlap and coalesce in the spray zone. The results are in excellent agreement with previous experiments and confirm that for drop-controlled nucleation, Ψa should be less than 0.1. Granulator flow studies showed that there are two powder flow regimes—bumping and roping. The powder flow goes through a transition from bumping to roping as impeller speed is increased. The roping regime gives good bed turn over and stable flow patterns. This regime is recommended for good liquid distribution and nucleation. Powder surface velocities as a function of impeller speed were measured using high-speed video equipment and MetaMorph image analysis software. Powder surface velocities were 0.2 to 1 ms−1—an order of magnitude lower than the impeller tip speed. Assuming geometrically similar granulators, impeller speed should be set to maintain constant Froude number during scale-up rather than constant tip speed to ensure operation in the roping regime.

[1]  Torben Schæfer,et al.  Granulation: A Review on Pharmaceutical Wet-Granulation , 1987 .

[2]  J. Litster,et al.  Liquid distribution in wet granulation: dimensionless spray flux , 2001 .

[3]  Derek Wilkinson,et al.  Kinetics and mechanisms of growth in batch and continuous fluidized bed granulation , 1987 .

[4]  P. Mort,et al.  Critical parameters and limiting conditions in binder granulation of fine powders , 1997 .

[5]  P. Vonk,et al.  Scale-down of a high-shear pelletisation process: flow profile and growth kinetics , 1998 .

[6]  K. Miyanami,et al.  Scale-Up of Agitation Fluidized Bed Granulation. V. Effect of Moisture Content on Scale-Up Characteristics , 1997 .

[7]  Yoshitsugu Muguruma,et al.  Numerical simulation of particulate flow with liquid bridge between / particles simulation of centrifugal tumbling granulator , 2000 .

[8]  P. Vonk,et al.  Fluid bed agglomeration with a narrow droplet size distribution. , 2000, International journal of pharmaceutics.

[9]  Peter York,et al.  Scale-up of a pharmaceutical granulation in fixed bowl mixer-granulators , 1996 .

[10]  W L Davies,et al.  Batch production of pharmaceutical granulations in a fluidized bed. I. Effects of process variables on physical properties of final granulation. , 1971, Journal of pharmaceutical sciences.

[11]  B. Waldie,et al.  Growth mechanism and the dependence of granule size on drop size in fluidized-bed granulation , 1991 .

[12]  Torben Schæfer,et al.  Granulation in high speed mixers. I: Effects of process variables during kneading , 1983 .

[13]  H. Lieberman,et al.  CONTINUOUS PRODUCTION OF TABLET GRANULATIONS IN A FLUIDIZED BED. II. OPERATION AND PERFORMANCE OF EQUIPMENT. , 1964, Journal of pharmaceutical sciences.