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Wet Granulation Scale-up Experiments Scale-up Approach with Dimensional Numbers • The effect of process parameter (i.e., impeller speed, liquid addition rate) on the process and thus on granule characteristics are evaluated based on mechanistic understanding. • Use dimensional numbers as variables rather than individual process parameters. This will decrease the number of variables need to be varied, thus the number of experiments ( includes explicitly includes liquid addition rate, implicitly includes impeller speed and liquid addition mode). • Determine the design space at the smallest scale for the given formulation based on dimensional numbers and validate the design space for larger scales with less experiments compared to DOE approach. 10 0 Mechanical Dispersion Crumb 10 -1 1 St p def Intermediate 10 -2 Nucleation Steady Growth Rapid Growth 0.1 10 -3 Drop Controlled Caking 10 0.01 0.1 1 a Induction -4 0 0.2 0.4 0.6 Smax 0.8 1 1.2 1.4 2 Design of Scale-up Experiments Optimum conditions from Duquesne University Wet Granulation experiments: Liquid content :5 % Liquid addition rate :15 ml/min Impeller Speed :500 rpm Wet massing time :30 sec The liquid percentage is kept same as the smallest scale experiments. The sensitivity to liquid amount is tested around the optimum liquid level that was obtained at small scale. 3 Design of Scale-up Experiments • Ratio of fill height to granulator diameter at all scales should be kept constant. Granulator size Granulation Batch Size (kg) Diameter of the granulator bowl (cm) Fill height / Diameter 4l 0.6 17 10 l 1 24.6 75 l 9.72 52.5 0.27 0.15 0.15 4 Design of Scale-up Experiments • The spraying time and the dimensionless spray flux need to be kept constant. 4l = 0.11 For constant spraying time, the values for larger scales with single nozzle are calculated assuming 100 m drop size: 10 l = 0.15 and 0.18 (Close to small scale) 75 l = 0.34 and 0.50 (Too high compare to small scale, therefore higher amounts of lumps should be expected. Can be 5 lowered by using two nozzles) Design of Scale-up Experiments • Impeller speed was scaled according to constant tip speed and constant Froude number (Fr) rules (provided that the impeller speed is above the critical Froude number for constant tip speed rule. Constant Fr: N 2 D1 N 1 D2 4l Constant tip speed: N: Impeller speed D: Impeller diameter 10 l N 2 D1 N 1 D2 75 l 340 rpm 500 rpm 195 rpm 420 rpm 290 rpm 6 Intermediate Scale (10 l) Batch 96251-1 96251-2 96251-3 96251-4 96251-5 96251-6 96251-7 96251-8 96251-9 96251-10 96251-11 96251-12 96251-13 96251-14 96251-15 Impeller Liquid Content (% Liquid Liquid Wet Speed of liquid amount Addition Rate addition Massing (rpm) to solid amount) (g/min) time (sec) Time (sec) 420 420 420 420 340 340 420 420 420 420 420 420 420 420 420 6 5 3 4 4 4 4 5 5 5 5 5 5 5 5 28.5 28.5 28.5 28.5 28.5 249.6 249.6 28.5 28.5 28.5 28.5 28.5 28.5 28.5 28.5 126 105 63 84 84 10 10 105 105 105 105 105 105 105 105 30 30 30 30 30 30 30 60 0 30 30 30 30 30 30 a Median Particle Size (µm) % of lumps (> 1 mm) 0.15 0.15 0.15 0.15 0.18 0.18 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 0.15 280 175 220 201 207 212 286 275 277 283 297 302 289 293 1.58 0.20 0.69 0.20 1.08 0.90 2.02 3.91 4.04 2.00 2.94 2.32 3.02 2.11 7 Effect of Liquid Content 80 3% 4% 5% 70 60 f(lnx) 50 40 30 20 10 0 2 10 3 Size ( m) 10 8 Summary • Lump formation is low due to the low drop penetration time and low dimensional spray flux. • The granulation material is easy to process at low liquid contents ( < 6%), not large clumps are formed, but the whole mixture become very sticky if the critical moisture content is exceeded. • The formulation seem to be insensitive to most of the operating conditions with the given fill ratio, granulator geometry, and drying conditions and analysis methods. 9 Large Scale (75 l) Batch Impeller Liquid Content Speed (% of liquid (rpm) amount to solid amount) 96251-21 290 5 Liquid Addition Rate (g/min) 277 96251-22 290 5 277 96251-23 195 5 277 96251-24 290 5 277 96251-25 290 4 277 96251-27 195 5 277 Liquid addition time (sec) Wet Massing Time (sec) 105 30 105 30 105 30 105 30 84 30 105 30 a Median Particle Size (µm) % of lumps (>1 mm) 0.34 272 284 10.80 13.52 0.50 280 10.28 0.34 422 33.51 0.34 250 9.56 0.50 301 17.8 0.34 10 Comparison of PSDs- 10 l and 75 l 80 10 L 75 L- const. Fr 75 L- const. tip speed 70 60 f(lnx) 50 40 30 20 10 0 2 10 3 Size ( m) 10 11 Summary • Although the median particle sizes matches with the 10 l scale, the amount of lumps are much higher at 75 l due to the doubled dimensional spray flux. • Further analysis of Stdef and Smax is needed to evaluate the effects of liquid amount and impeller speed on the PSD. 12