Fluid Bed Granulating (Granulation)

There are a number of granulation technologies available to pharmaceutical manufacturers. Given the importance of granulation in the production of oral dosage forms, this paper offers advice on various process and looks at the implications of two different applications.
Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. However, there are many different technologies each having different strengths and weaknesses. Most companies choose which one to use simply based on their own experience.This article introduces different processes, compares them objectively and offers unbiased advice on the merits of each system. It then looks at the implications of selection on two different applications.

Comparison of granulation processes

Tables I – III provide a brief overview of the implications of particular granulation methods. All information shown assumes ‘normal’ products. Some special products may behave differently.

Table I Comparison of processes — general aspects
	Option 1 Single pot	Option 2 High shear force mixer and FBD	Option 3 Top spray granulation	Option 4 Continuous top spray process	Option 5 Spray drying	Option 6 Pelletizing
Scales available LS LS LS (TS) TS (TS) Laboratory scale (LS) TS TS TS PS PS PS Technical scale (TS) PS PS PS       Production scale (PS)
Definition of batch	++	++	++	Material container	Material container	Material container
Scalability	+	+	+	++ (down?)	++(down?)	++(down?)
Need for special building	Weight	Height	Height	Integration into building	Height	Integration into building
Energy/kg (5)	>0.25 kW/kg	>0.25 kW/kg	>0.37 kW/kg	>0.37 kW/kg	>7.5 kW/kg	>0.5 kW/kg
Yield	>99.5%	>99%	>99%	>99%	>99%	>98%
(1) Granulation with 10% granulation liquid (TS15%) (2) Granulation with 15% granulation liquid (TS15%) (3) Mix all components of formulation in liquid form (TS20%); drying step at the end of primary production can be saved (4) Granulation with 20% granulation liquid (TS15%) (5) Only drying energy   Key: ++ very good; + good; +- fair; - poor; -- very poor

Table II Comparison of processes — formulation aspects.
	Option 1 Single pot	Option 2 High shear force mixer and FBD	Option 3 Top spray granulation	Option 4 Continuous top spray process	Option 5 Spray drying	Option 6 Pelletizing
Containment	++	+	++	+	+	-
Handle organic solvents	++	+	+	+	+	+
Heat sensitive materials	++	+	+	(+)	(+)+(-)	(+)
Limitations by different formulations	None (behaviour of material if exposed to microwaves)	None	PSD of raw materials	PSD and flow properties of raw materials	Fine grades of raw materials required if worked from suspensions	Limited
Amount of granulation liquid required	8–15%	8–15%	15–30%	15–30%	>100%	15–50%

Table III Comparison of granule characteristics.
	Option 1 Single pot	Option 2 High shear force mixer and FBD	Option 3 Top spray granulation	Option 4 Continuous top spray process	Option 5 Spray drying	Option 6 Pelletizing
Dust/fine particles	<12%	<8%	<5%	<3%	<1%	None
D50: PSD	100-800 μm	120-800 μm	150-600 μm	120-400 μm	150-300 μm	800-2000 μm
Span (6):	2.5-3	2.5	2	2.5	1.5	<1
Homogeneity	+	+	+	(+)	++	+
Flow properties	+	+(+)	+	+	+	++
Bulk density	0.7 g/cm3	0.8 g/cm3	0.7 g/cm3	0.7 g/cm3	0.6 g/cm3	Near physical density
Dissolution	+	+	++	++	++	-
(6) Span=(D90D10)/D50

Production scenario 1

A dedicated plant for the production of 1000 tonnes of granules of a water-based formulation.
The amounts of granulation liquid are estimated as shown in Table I. Further, it is assumed that cleaning is required once a week for only a few hours because it is a dedicated installation; the plant is operated in three shifts for 5 days each week; and the plant achieves 20 productive hours per day and 200 productive days per year.
Working on these assumptions, 5 tonnes of granules must be produced per day.Table IV shows the results for the different production scenarios.To complete this table (for the batch machines), the batch times were evaluated.These are based on customers' experiences and calculations regarding the drying capacity of the different equipment. Some materials with special granulation/drying properties may achieve entirely different batch times. By calculating the number of batches per day, the required batch size of 5 tonnes of granules per day was determined. For the single pot option it was not possible to achieve the requested throughput using only one machine. For all continuous processes, equipment with the requested throughput is available.To include the necessary investment costs in the table is extremely complicated as this depends on many other factors in addition to the granulation equipment and needs, and must, therefore, be evaluated carefully, case by case.

Table IV Key figures of production scenario 1.
	Option 1 Single pot	Option 2 High shear force mixer and FBD	Option 3 Top spray granulation	Option 4 Continuous top spray process	Option 5 Spray drying	Option 6 Pelletizing
Equipment scale	1200 L (3 plants)	High shear 2000 L; fluid bed of adequate scale	Product container size: 3200 L	250 kg/h	250 kg/h	250 kg/h
Batch size	417 kg	715 kg	1000 kg	-	-	-
Batch time	5 h	2 h 50 min	4 h	–	–	–
Throughput				250 kg/h	250 kg/h	250 kg/h

Production scenario 2

Installation for the production of four different water-based granulated products, each with a capacity of 32 tonnes per year.
The amounts of granulation liquid are estimated as shown in Table I.The process length for each product should be 1 week. It is also assumed that cleaning must be done only at the end of each process, which means that Friday is not a productive day. Further assumptions are that the plant is operated in two shifts for 5 days each week and that the plant achieves 16 productive hours per day and 200 productive days per year.

Table V Key figures of production scenario 2.
	Option 1 Single pot	Option 2 High shear force mixer and FBD	Option 3 Top spray granulation	Option 4 Continuous top spray process	Option 5 Spray drying	Option 6 Pelletizing
Equipment scale	400	High shear 600 L; fluid bed of adequate scale	Product container size:600 L	50 kg/h	50 kg/h	50 kg/h
Batch size	160 kg	240 kg	200 kg	-	-	-
Batch time	5 h	3 h	4 h	–	–	–
Throughput				50 kg/h	50 kg/h	50 kg/h