This article was published in Pharmaceutical Technology Europe in November 2004. The article is written by Harald Stahl, who is the senior Pharmaceutical Technologist at GEA Pharma Systems, Mauchener Strasse 14, D-79379 Müllheim, Germany.

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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.

Granulation methods:

General aspects of granulation

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

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