Part I - Methodology & Results

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Precision Granulation™ - Part I - Methodology

Part 1 - To compare Precision Granulation™ (PG) with Top Spray Fluid Bed Granulation (TS-FBG) and High Shear Granulation (HSG) for tabletting

Figure 1 : Preparation and characterization of PG, TS-FBG and HSG granules
PG, TS-FBG, HSG

Fractionated using a riffler (Retsch). Granules >10 mm separated out.
Granules
Size analysis by sieving (VS 1000, Retsch)
. Mass median diameter, D50%
. Span [ (D25% -D75%) / D50% ]

Milling

through 1.25 mm aperture size sieve using sieve granulator (FGS, Erweka)
Granules in
0.71-1.0 mm size fraction
Milled granules
Granule strength
(EZ Test -100N, Shimadzu)
Poured bulk and tapped densities (STAV 2003, JEL)
Granule porosity
(PoreSizer 9320, Micromeritics)
Angle of repose
(Powder tester, Hosokawa Micron)

. Settings chosen for TS-FBG and HSG were fairly typical settings for obtaining good TS-FBG and HSG/drying processes

 

Figure 2 : Tabletting and tablet characterization of PG, TS-FBG and HSG batches
Milled granules + 1% Magnesium Stearate

Tabletting
Single station tablet machine (E2, Manesty) with 9.5 mm flat-faced punch and die set.

Tablets
Tablet hardness (6D, Schleuniger)
Weight variation
Disintegration time (PTZ1, Pharmatest)
Friability (TA3, Erweka)

 

Table 2: Process conditions for Precision Granulation , top spray fluid bed granulation and high shear granulation trials
a) Precision Granulation™ (PG)
Equipment

MP 2/3, Aeromatic-Fielder
Batch size

5 kg
Amount of granulating liquid

1.7 kg (15% povidone solution) unless otherwise stated
Inlet air flow volume rate

250 m3/h unless otherwise stated
Inlet air temperature

80°C unless otherwise stated
Column diameter

150 mm unless otherwise stated
Insert diameter

60 mm
Air cap area/opening

Full/standard unless otherwise
b) Top Spray Fluid Bed Granulation (TS-FBG)
Equipment

MP 2/3, Aeromatic-Fielder
Batch size

12 kg
Amount of granulating liquid

4 kg (15% povidone solution)
Inlet air flow volume rate

300 m3/h
Inlet air temperature

70°C
Atomizing air pressure

1 bar
Spray rate

125 g/min; 162 g/min -> 120 g/min (start with fast spray rate and then reduce spray rate)
Drying time

8 min; 10.3 min
c) High Shear Granulation (HSG)
Granulation
Equipment

PMA 65, Aeromatic-Fielder
Batch size

18 kg
Amount of granulating liquid

2.7 kg (water)
Phase during granulation
Impeller speed
Chopper speed
Premix
300 rpm
1500 rpm
Liquid addition
350 rpm
1500 rpm
Wet massing
400 rpm
1500 rpm
Drying
Equipment

MP 2/3, Aeromatic Fielder
Inlet air flow volume rate

500 m3/h
Inlet air temperature

70°C
Drying time

18 min
Final loss on drying (LOD)

2.8%

 

Table 3 Settings for the PG trial batches
a) Lactose 200M PG trials with povidone as a wet binder
PG batches
Atomizing air pressure (bar)
Column diameter (mm)
Inlet air temp. (°C)
Air flow volume rate (m3/h)
Column velocity (m/s)
Spray rate (g/min)
Drying time (min)
Final LOD (%)
PG 19
0.5
150
80
250
3.9
130
no drying
4.9
PG 23
0.25
150
80
250
3.9
140
3.3
2.5
PG 24
0.25
150
80
250
3.9
140
3.4
2.1
PG 26
0.5
150
80
250
3.9
139
4
1.9
PG 30
0.25
150
50
300
10.6
79
4
2.0
b) PG trials with 2 grades of lactose and powdered sugar
PG batches
Material
Atomizing air pressure (bar)
Air cap area / opening
Granulating liquid - water (kg)
Spray rate (g/min)
Drying time (min)
Final LOD (%)
PG 17
Lactose 200M
0.25
full / standard
2.53
109
3
2.8
PG 41
Lactose 450M
0.25
full / standard
3
118
2.7
2.6
PG 39
Lactose 450M
0.25
1/4
3
119
5.3
3.0
PG 44
Powdered sugar
0.25
1/4
1.5
81
2.4
2.2

 

Table 4 System for ranking the quality of the lactose 200M PG, TS-FBG and HSG tablet batches
Tablet characteristics
Ranking system
Weight variation

With "1" for batch with the smallest weight variation and "8" for batch with the largest weight variation.
Inlet air temperature

70°C
Friability

With "1" for the least friable batch (i.e. with least % weight loss) and "8" for the most friable tablet batch.
Disintegration time

With "1" for batch with the shortest disintegration time and "8" for batch with the longest disintegration time.
Coefficient of variation for disintegration time

With "1" for batch with the smallest coefficient of variation and "8" for batch with the largest coefficient of variation.
Coefficient of variation for hardness

With "1" for batch with the smallest coefficient of variation and "8" for batch with the largest coefficient of variation.

  • The 5 tablet characteristics were assigned equal weightage.
  • For each tablet batch, ranks of the 5 tablet characteristics were summed to determine its composite rank.
  • Tablet batches with the smallest and largest sum were assigned ratings of "1" and "8", respectively.
  • The batch with the smallest composite rank was considered to be the most ideal batch, i.e. with the best overall tablet quality, within the group of 8 tablet batches.

Precision Granulation™ - Part I - Results

Granule characteristics

Size distribution, porosity and granule strength of the lactose 200M PG, TS-FBG and HSG batches

Figure 3: Size distribution, porosity and granule strength of the lactose 200M PG, TS-FBG and HSG batches

  • HSG granules had the widest size distribution.
  • Granule porosity increased and granule strength decreased for HSG, PG and TS-FBG.

 

Poured bulk and tapped density, Hausner ratio and Carr index values of the lactose 200M milled PG, TS-FBG and HSG batches

Figure 4: Poured bulk and tapped density, Hausner ratio and Carr index values of the lactose 200M milled PG, TS-FBG and HSG batches

  • Poured bulk and tapped densities decreased for milled HSG, PG and TS-FBG.
  • Angle of repose values for the granulation batches ranged from 32.5 to 35.6°.

 

Tablet characteristics and composite ranking of the lactose 200M PG, TS-FBG and HSG batches
Figure 5: Tablet characteristics and composite ranking of the lactose 200M PG, TS-FBG and HSG batches
  • Group mean hardness and weight of the 8 tablet batches: 105.9 (±15.1) N and 282.6 (±15.3) mg.
  • PG 19 tablet batch ranked "1" in the composite ranking.
  • TS-FBG 33 batch ranked "2". TS-FBG 34, HSG 46 and PG 30 tablet batches shared the same ranking of "4".

PG feasibility trials on fine particles (lactose 450M) and powdered crystalline material (powdered sugar) with poor flow properties

Table 5 Granule and tablet characteristics of lactose and powdered sugar PG batches
a) Granule characteristics
Granulation batches
Material
Mass median diameter D50% (mm)
Span
Porosity (mL/g)
Granule strength (N)
Poured bulk density (g/mL)
Tapped density (g/mL)
Carr index (%)
Hausner ratio
Angle of repose (°)
PG 17
Lactose 200M
0.496
1.16
42.80
0.87
0.55
0.59
5.83
1.06
33.2
PG 41
Lactose 450M
0.326
1.49
43.02
0.92
0.57
0.66
13.25
1.15
34.5
PG 39
Lactose 450M
0.419
1.20
43.77
0.73
0.55
0.61
9.75
1.11
32.2
PG 44
Powdered sugar
0.336
0.76
44.11
1.08
0.47
0.52
8.67
1.10
37.4
b) Tablet characteristics
Tablet batches
Material
Tablet weight (mg)
Weight variation (%)
Friability (%)
Disintegration time (s)
Coefficient of variation for disintegration time
Tablet hardness (N)
Coefficient of variation for hardness
PG 17
Lactose 200M
282.1
3.1
0.23
158
20.4
113.1
5.4
PG 41
Lactose 450M
268.5
1.8
0.40
529
7.6
98.9
7.8
PG 39
Lactose 450M
302
1.5
0.38
640
12.1
116.0
6.0
PG 44
Powdered sugar
279.2
2.2
0.42
332
4.8
116.0
6.4
  • Both lactose 450M and powdered sugar could be granulated by PG.
  • A greater amount of granulating liquid (water) was used for preparing lactose 450M PG granules.
  • Tablets prepared from lactose 450M and powdered sugar PG granules with similar tablet weight and hardness had longer disintegration times than tablets made from the lactose 200M PG granules.

 

Precision Granulation™ - Materials

Part II

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