To investigate the influence of four selected process variables, atomizing air pressure, column velocity, insert diameter and air cap area/opening, in Precision Granulation™
Methodology
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Process variables investigated in the experimental design
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|
Factor
|
Low level (-)
|
Middle level (0)
|
High level (+)
|
|
Atomizing air pressure (bar)
|
0.3
|
1.2
|
2.0
|
|
Column velocity (m/s)
|
5
|
7
|
9
|
|
Insert diameter (mm)
|
24
|
30
|
40
|
Response variables for evaluating the granulations:
- LOD after liquid addition, fraction of discharged yield > 2 mm, granule size distribution and friability (on unmilled granulations)
- Poured bulk and tapped densities, Hausner ratio, Carr index (on milled granulations)
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Figure 6: Flow chart of granulation and granule characterization for the PG experimental design
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PG
MP-1 (Aeromatic-Fielder); batch size=1kg
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Liquid Addition
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Inlet temperature
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60°C
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Drying
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Inlet temperature
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80°C
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Atomizing air pressure
|
0.3 bar
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Air flow volume rate
|
80m3/h
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Dried to LOD <2% and/or bed temperature >50°C
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LOD after liquid addition
(IR 100, Denver Instruments)
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Granules
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Fraction of discharged yield > 2mm
Size analysis by sieving
(Sonic sifter, ATM)
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Milling
(197S, Quadro Comil) through 94R screen at 1500 rpm
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Milled granules
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Granule friability
Granules in 0.18-0.85 mm size fraction
tumbled with rubber ball
(29.3 mm diameter; 15 g) in friabilator (EF-2, Electrolab) for 150
rounds at 25 rpm. Granule friability=% weight loss of fines through
0.18 mm aperture size sieve after friability testing.
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Poured bulk and tapped densities (JEL)
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Table 6 Experimental design*** for investigating the influence of 4 selected PG process variables
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Run
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Atomizing air pressure (bar)
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Column velocity (m/s)**
|
Insert diameter (mm)
|
Air cap area / opening
|
|
1
|
-
|
+
|
0
|
+
|
|
2
|
+
|
+
|
-
|
0
|
|
3
|
-
|
+
|
+
|
-
|
|
4
|
-
|
-
|
+
|
-
|
|
5
|
0
|
0
|
-
|
+
|
|
6
|
-
|
-
|
-
|
+
|
|
7
|
-
|
+
|
+
|
0
|
|
8
|
+
|
-
|
+
|
-
|
|
9
|
+
|
-
|
0
|
+
|
|
10
|
-
|
-
|
-
|
0
|
|
11
|
+
|
+
|
-
|
-
|
|
12
|
+
|
+
|
0
|
+
|
|
13
|
+
|
-
|
0
|
0
|
|
2a*
|
+
|
+
|
-
|
0
|
|
6a*
|
-
|
-
|
-
|
+
|
|
4a*
|
-
|
-
|
+
|
-
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2b*
|
+
|
+
|
-
|
0
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|
1a*
|
-
|
+
|
0
|
+
|
* |
Indicates repeat runs. Data collected included in statistical analysis. |
** |
Corresponding to column velocities at high, middle and low levels, binder spray rates set at 36, 28 and 20 g/min and air flow volume rates at 143, 111 and 80 m3/h, respectively. Spray rates and air flow volume rates chosen for maintaining the same change in humidity between inlet and outlet conditions during binder liquid addition stage. |
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Table 7 Physical properties of lactose 200M powder mix for the experimental design study
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Property
|
Value
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Mass median diameter, D50%*
|
0.032 mm
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Span *
|
1.48
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Poured bulk density
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0.547 (± 0.008) g/mL
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Tapped density
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0.808 (± 0.004) g/mL
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Hausner ratio
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1.48 (± 0.03)
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Carr index
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32.33 (± 1.33) %
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LOD
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1.91 (± 0.46) %
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* Particle size analysis by laser scattering (LA-910, Horiba)
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Results
Experimental design study - Granule characteristics
- Low LODs (about 2%) for runs 4 and 4a - due to non-homogeneous distribution of binder solution to powder mass. Overwetting in column resulted in formation of caked material around the spray nozzle. While the caked material was overwetted, material fluidizing outside the column (where sampling for LOD was performed) was underwetted.
- Most PG runs had discharged yields of 70-90% and gave granulations with < 3% w/w oversize particles (> 2 mm). Low discharged yields for runs 4 and 4a (42-48%) and relatively high proportions of oversize particles for runs 4, 4a, 6 and 6a (12-17%) - attributed to higher tendency for overwetting in column with combination of low column velocity (associated with low air flow volume) and low atomizing air pressure.
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Table 8 LOD after liquid addition, discharged yield and fraction of yield > 2 mm
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|
Run
|
LOD after liquid addition (%)
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Discharged yield (%)
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Fraction of discharged yield > 2 mm (%)
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|
1
|
9.34
|
89.43
|
0.23
|
|
2
|
5.42
|
89.01
|
0.34
|
|
3
|
10.47
|
93.93
|
2.73
|
|
4
|
2.18
|
48.25
|
13.77
|
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5
|
8.39
|
93.32
|
0.23
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|
6
|
5.80
|
80.52
|
17.01
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|
7
|
9.33
|
93.00
|
0.11
|
|
8
|
9.05
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88.70
|
2.04
|
|
9
|
8.97
|
90.27
|
0.02
|
|
10
|
10.16
|
87.85
|
0.15
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|
11
|
10.25
|
85.62
|
2.61
|
|
12
|
4.81
|
91.48
|
0.15
|
|
13
|
9.07
|
90.06
|
0.06
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|
2a*
|
8.74
|
81.21
|
1.55
|
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6a*
|
6.06
|
70.50
|
14.72
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|
4a*
|
2.61
|
41.74
|
12.88
|
|
2b*
|
4.06
|
84.45
|
1.85
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1a*
|
11.37
|
88.28
|
0.39
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* Indicates repeat runs.
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Table 9 Granule size distribution and friability
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Run
|
D50% (mm)
|
D25% (mm)
|
D75% (mm)
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Span
|
Friability (%)
|
|
1
|
0.390
|
0.563
|
0.252
|
0.80
|
2.08
|
|
2
|
0.189
|
0.269
|
0.128
|
0.75
|
3.87
|
|
3
|
0.600
|
0.935
|
0.373
|
0.94
|
1.26
|
|
4
|
0.732
|
1.329
|
0.353
|
1.33
|
7.75
|
|
5
|
0.232
|
0.388
|
0.156
|
1.00
|
3.65
|
|
6
|
0.382
|
0.706
|
0.230
|
1.25
|
3.75
|
|
7
|
0.335
|
0.487
|
0.222
|
0.79
|
2.77
|
|
8
|
0.468
|
0.831
|
0.292
|
1.15
|
4.20
|
|
9
|
0.263
|
0.390
|
0.201
|
0.72
|
5.72
|
|
10
|
0.286
|
0.445
|
0.210
|
0.82
|
4.24
|
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11
|
0.239
|
0.454
|
0.153
|
1.26
|
3.41
|
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12
|
0.196
|
0.269
|
0.134
|
0.69
|
5.90
|
|
13
|
0.254
|
0.386
|
0.195
|
0.75
|
5.93
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2a*
|
0.210
|
0.331
|
0.141
|
0.90
|
9.34
|
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6a*
|
0.384
|
0.631
|
0.240
|
1.02
|
5.31
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4a*
|
0.805
|
1.412
|
0.447
|
1.20
|
8.35
|
|
2b*
|
0.227
|
0.367
|
0.146
|
0.97
|
5.89
|
|
1a*
|
0.368
|
0.559
|
0.233
|
0.91
|
1.80
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* Indicates repeat runs.
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Table 10 Poured bulk and tapped densities, Hausner ratio and Carr index values of milled PG granules
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Run
|
Poured bulk density (g/mL)
|
Tapped density (g/mL)
|
Hausner ratio
|
Carr Index (%)
|
|
1
|
0.524
|
0.616
|
1.18
|
14.98
|
|
2
|
0.515
|
0.612
|
1.19
|
15.86
|
|
3
|
0.527
|
0.614
|
1.17
|
14.27
|
|
4
|
0.505
|
0.597
|
1.18
|
15.34
|
|
5
|
0.491
|
0.589
|
1.20
|
16.65
|
|
6
|
0.478
|
0.572
|
1.20
|
16.49
|
|
7
|
0.479
|
0.571
|
1.19
|
16.11
|
|
8
|
0.456
|
0.532
|
1.17
|
14.29
|
|
9
|
0.435
|
0.525
|
1.21
|
17.20
|
|
10
|
0.462
|
0.554
|
1.20
|
16.60
|
|
11
|
0.546
|
0.649
|
1.19
|
15.97
|
|
12
|
0.491
|
0.590
|
1.20
|
16.73
|
|
13
|
0.437
|
0.528
|
1.21
|
17.18
|
|
2a*
|
0.529
|
0.629
|
1.19
|
16.00
|
|
6a*
|
0.476
|
0.566
|
1.19
|
15.85
|
|
4b*
|
0.498
|
0.582
|
1.17
|
14.47
|
|
2b*
|
0.520
|
0.626
|
1.20
|
16.98
|
|
1a*
|
0.531
|
0.620
|
1.17
|
14.41
|
|
* Indicates repeat runs.
|
- Poured bulk and tapped densities of milled granulations were lower than those of the original lactose 200M powder mix.
- Hausner ratio and Carr index values were also lower, indicating that the milled PG granules had better flow properties than the powder mix.
|
Statistical Analysis
|
Table 11 P values from ANOVA and R2 values from summary of Fit data
|
|
Responses for granule characterization
|
Significance of process variables in ranges under investigation at 95% confidence interval
|
R2
|
|
LOD after binder liquid addition (%)
|
Not significant (P=0.1774)
|
0.5029
|
|
Fraction of discharged yield > 2 mm (%)
|
Not significant (P=0.1226)
|
0.5448
|
|
Granule friability (%)
|
Not significant (P=0.0467, i.e. 0.05)
|
0.6335
|
|
D50%
|
Significant (P < 0.0001)
|
0.9272
|
- LOD after liquid addition, fraction of discharged yield > 2 mm and granule friability responses were independent of the process variables.
- Granule size distribution and density responses were dependent on the process variables.
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Table 12 Effects and interactions of the process variables on granule responses
|
|
Response
|
Process variables
|
P value
|
Effect / Interaction
|
|
D50%
|
|
|
Atomizing air pressure
|
<0.0001*
|
-0.235
|
|
Insert diameter X Column velocity
|
0.0058*
|
-0.160
|
|
Insert diameter
|
0.0151*
|
0.143
|
|
Column velocity
|
0.0637**
|
-0.063
|
|
Air cap area/opening
|
0.0986**
|
-0.087
|
|
Air cap area/opening X Atomizing air pressure
|
0.2251
|
0.054
|
|
Poured bulk density
|
|
|
Column velocity
|
<0.0001*
|
0.057
|
|
Atomizing air pressure
|
0.0001*
|
-0.041
|
|
Insert diameter X Column velocity
|
0.0011*
|
-0.038
|
|
Insert diameter
|
0.0048*
|
-0.032
|
|
Air cap area/opening
|
0.0154*
|
-0.026
|
|
Air cap area/opening X Atomizing air pressure
|
0.7933
|
0.002
|
|
Tapped density
|
|
|
Column velocity
|
<0.0001*
|
0.063
|
|
Atomizing air pressure
|
0.0002*
|
-0.042
|
|
Insert diameter
|
0.0005*
|
-0.047
|
|
Insert diameter X Column velocity
|
0.0013*
|
-0.039
|
|
Air cap area/opening
|
0.013*
|
-0.028
|
|
Air cap area/opening X Atomizing air pressure
|
0.3246
|
0.008
|
|
* Statistically significant (P< 0.05)
** 0.05 <P< 0.1
|
- For mean granule size, atomizing air pressure was the most important process variable while air cap area/opening was the least important.
- Column velocity had the most important effect on density responses of milled granulations while air cap area/opening was the least critical process variable.
- An interaction between column velocity and insert diameter was significant at P <0.05.
- Granule size increased with increase in insert diameter and decrease in atomizing air pressure, column velocity and air cap area/opening (Figure 7).
- Poured bulk and tapped densities of the milled granulations generally increased following an increase in column velocity and a decrease in atomizing air pressure, insert diameter and air cap area/opening (Figure 7).
|
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Figure 7: Cube plots of predicted mean size and density responses at high (+) and low (-) levels of atomizing air pressure, column velocity, insert diameter and air cap area/opening
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(a) D50% (mm)
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|
|
(b) Poured bulk density (g/mL)
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|
|
(c) Tapped density (g/mL)
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