Part 3: To prepare Acetaminophen granules by Precision-Granulation™ and Top Spray Fluid Bed Granulation

Methodology

Preparation of Acetaminophen PG and TS-FBG granules

Table 13 - Physical properties of the Acetaminophen powder mix 

Property	Value
Mass median diameter, D50% *	0.047 mm
Span *	1.55
Poured bulk density	0.335 (± 0.011) g/mL
Tapped density	0.589 (± 0.004) g/mL
Hausner ratio	1.76 (± 0.07)
Carr index	43.12 (± 2.08) %
LOD	1.08 (± 0.41) %

• *Particle size analysis by laser scattering (LA-910, Horiba)

Model drug : Acetaminophen
Acetaminophen has been described as a cohesive powder that tends to agglomerate quickly during granulation to give large aggregates (3). Difficulties in granulating acetaminophen for producing tablets with good quality have also been reported.

Results

Table 14 - LOD, discharged yield and size distribution of Acetaminophen granules prepared by PG and TS-FBG

Granulation batch	Granulation method	Column velocity (m/s)	Spray rate /g/min)	Binder solution (kg)	Concentration of Povidone binder solution (% w/w)	LOD after liquid addition (%)	Discharged yield (%)	Fraction of discharged yield >2 mm (%)	Mass median dia. D50% (mm)	Span
TSAce 01	TS-FBG	N/A	27 then reduced to 23	0.5	10	7.08	91	7.46	0.405	1.23
PGAce13	PG	7	28	0.5	10	9.47	86	0.96	0.291	1.29
PGAce09	PG	9	36	0.5	10	7.99	90	0.12	0.262	1.16
PGAce07	PG	7	30	0.333	15	7.39	91	0.07	0.244	1.30
PGAce10	PG	9	38	0.333	15	5.12	86	0.17	0.259	1.21

For PG : With same amount of povidone, concentration of binder solution varied by changing proportion of water (e.g. 0.95 kg, 0.45 kg and 0.283 kg for 5%, 10% and 15% binder solutions, respectively) in binder solution. Spray rates adjusted to give the same rate of water addition to the powder mix.

Effect of concentration of binder solution on PG

• 10% and 15% binder solutions gave acetaminophen PG granules with similar mean sizes (0.24-0.29 mm).
• Batches prepared with 15% binder solution had lower LODs after liquid addition.
• In preliminary trials, 5% binder solution was also employed for PG. The greater net gain of solvent during liquid addition increased the weight of the powder mass and the tendency for the down flow bed to stop fluidizing. With column velocity fixed at a constant value (7 or 9 m/s), the set air flow volumes were insufficient for supporting the increasing weight of the powder mass towards the end of the liquid addition phase.

Influence of column velocity on PG

• For the same concentration of binder solution, higher column velocity (higher drying capacity associated with greater air flow volume rate) gave lower LODs after liquid addition.
• Material movement during liquid addition improved with higher column velocity. The resultant granulations had tighter size distributions (smaller span values).

Comparison of Acetaminophen PG and TS-FBG

• Higher spray rates can be used for PG compared to TS-FBG.
• TS-FBG granules had larger mean size, greater amount of discharged yield > 2 mm and were more friable than PG granules.
• Milling resulted in a greater change in size distribution for TS-FBG granules - due to presence of a greater proportion of larger size granules in the original unmilled granulation.
• Poured bulk and tapped densities of both unmilled and milled TS-FBG granules were lower than those of the PG batches. Hausner ratios and Carr indices of PG and TS-FBG granules were between 1.17-1.2 and 14.4-16.7%, respectively, indicating that the granulation processes improved the flow properties of the Acetaminophen powder mix.

Conclusion

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

• PG produced good quality granules with adequate flow and strength for tabletting. The quality of these tablets was comparable to those of tablets prepared from TS-FBG and HSG.
• Porosity, strength, bulk density and tapped density of PG granules were intermediate to those of HSG and TS-FBG granules. PG granules had the lowest Carr index and Hausner ratio values. For equivalent tablet weight and hardness, PG tablet batches showed faster disintegration times.
• Preliminary studies with the two grades of lactose and powdered sugar suggested that PG can offer an alternative to existing methods for investigating granulation of  "difficult-to-granulate" materials.

Part 2: To investigate the influence of 4 selected process variables, atomizing air pressure, column velocity, insert diameter and air cap area/opening, in Precision-Granulation™

• The statistical analysis indicated that PG size distribution responses and density responses of the milled granulations were dependent on atomizing air pressure, column velocity, insert diameter and air cap area/opening within the low and high levels investigated.
• For size distribution responses, atomizing air pressure appeared to be the most important factor while air cap area/opening was the least important. For poured bulk and tapped densities of milled granulations, column velocity was predicted to be the most critical factor while air cap area/opening was the least critical.
• Within the study range, mean granule size was predicted to increase with increase in insert diameter and decrease in atomizing air pressure, column velocity and air cap area/opening. Poured bulk and tapped densities of the milled granulations were predicted to increase with an increase in column velocity and a decrease in atomizing air pressure, insert diameter and air cap area/opening.

Part 3 : To prepare Acetaminophen granules by Precision Granulation and Top Spray Fluid Bed Granulation

• Acetaminophen PG granules were less friable and had smaller mean size and relatively low proportion of over size particles than the TS-FBG granules. These findings suggested that there may be a better distribution of the binder solution in PG. PG granules also had higher poured bulk and tapped densities. The PG and TS-FBG granules had comparable Hausner ratio and Carr index values.
• Higher spray rates (higher water/solvent addition rate) may be used in PG where binder solution is delivered in an upward direction co-current to the flow of material through the spray zone and column. In TS-FBG, binder solution addition and air flow are in a counter-current direction. Compared to TS-FBG, wetted particles in PG experience greater drying.
• Lower concentration of binder solution had the effect of increasing the solvent load delivered. Addition of a substantially greater amount of water to the powder mass increased the tendency for the down flow bed to stop fluidizing if spray rate and/or air flow were not re-adjusted accordingly during the liquid addition phase to compensate for the heavier solvent load.
• Material movement during PG improved with the use of a higher column velocity (associated with higher air flow volumerate). The greater drying capacity also supported higher spray rates for granulation.