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Pharmaceutical Manufacturing and Packing Sourcer

Comparing Granulation Methods

Harald Stahl at GEA Pharma Systems offers a specialist insight into different granulation technologies and how their application can optimise plant performance

There are a number of granulation technologies available to pharmaceutical manufacturers. Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. However, while there are many different technologies, each with their own strengths and weaknesses, most companies make a choice simply based on their own experience. This article introduces the different processes and provides guidance on their respective benefits.


Single Pot
A mixer or granulator that dries granules in the same equipment without discharging is commonly called a single pot (see Figure 1). The granulation is done in a normal high shear processor; however, care must be taken to avoid the formation of lumps as they cannot be broken down before drying. There are various options for drying in single pots. The basic drying principle relies on the application of a vacuum in the bowl, thus drastically lowering the evaporation temperature of the used granulation liquid. The traditional heat source comes from the heated dryer walls. The heat transfer is related to the surface area of the dryer walls and the volume of product treated. Therefore, this direct heating method is most effective for small scale, organic solvents or low quantities of binder fluids. The introduction of stripping gas into the pot allows lower final moisture content to be achieved, which is only required in some particular applications. A small quantity of gas is introduced in the bottom of the equipment, which passes through the product bed, improving the efficiency of vapour removal. However, as the heated wall is the only source of drying energy, linear scale-up is not possible. This problem is exacerbated if:

  • The material to be processed is heat sensitive (as this limits the wall temperature)
  • Water is used as a granulation liquid (it has a relatively high boiling temperature under vacuum and a high heat of evaporation compared to organic solvents)
  • It is used for larger-scale production (the surface/volume ratio deteriorates as the volume increases)

Microwave energy can be used to overcome these limitations. This provides a further source of energy and has the additional advantage, with organic solvents, that only pure organic vapours must be treated on the exhaust side, and not a mixture of solvent and large volumes of process gas, as would be required in most other wet granulation technologies.

Fluid Bed Spray Granulation
Granulation can be performed using fluid beds fitted with spray nozzles. While for many years the top spray position was preferred, now the advantages of tangential spray systems have become obvious. The main advantage is the location of the spray nozzle, in an area with significantly higher shear forces, so allowing the processing of formulations that previously could only be granulated in high shear processors. Additionally, the introduction of a new range of fluid beds also eliminates the difficulty of scale-up.

Over recent years fluid beds have improved dramatically in response to competition from single pot technology. As can be seen in Figure 2, it is possible to have completely closed material handling by a closed link with up- and downstream equipment. Also, fully automatic cleaning (clean-in-place) in fluid beds using stainless steel filters has now reached a level that compares favourably with what is possible in a single pot.

Integrated High Shear Granulation and Fluid Bed Drying
This is the most common configuration used on an industrial scale for the production of pharmaceutical granules (see Figure 3, page 59). Again, this system allows full integration with upstream and downstream equipment, and even includes a wet mill between the granulator and dryer. With modern control systems it is easy to load, mix and granulate a second batch in the high shear granulator while drying the previous batch in the fluid bed prior to discharge. All equipment can be cleaned-in-place using a single automatic process.

Continuous Granulation
As a result of various FDA initiatives brought in to improve product quality and to reduce the risk of product failure, there is a huge interest in continuous processing. A typical installation is shown in Figure 4. The system has three modules: a wet high shear granulation module; a segmented dryer module; and a granule conditioning module.

In the granulation module, dry ingredients are dosed individually or premixed into the continuous high shear granulator. After a small dry mix section, the granulation liquid is added, so each particle receives the same amount of liquid. The particles follow a granulation track, which mimics the granulation in a batch process. Narrow tolerances between granulation screws and the barrel minimise back-mixing. The whole wet granulation process takes place in a few seconds, with only a few grammes of product in process at a given time, resulting in faster start-up and no losses. The particle size can be adjusted by changing the working level in the granulator; this results in a continuous flow of wet granules with a constant quality and density that is transferred to the dryer. There are no oversized agglomerates and thus no wet milling.

The dryer module, based on the fluid bed drying principle, splits the continuous flow of granules in packages of 1.5kg, with each placed in a separate segment of the dryer. When the content of a segment has reached the desired moisture level, it is emptied and transferred to the granule conditioning module and refilled with a new package of wet granules. The drying curve of each package is monitored. In the granule conditioning module, the dried granules can be measured for critical quality attributes such as particle size distribution, humidity and content uniformity. At any time, there are only six to nine kilograms in process, which minimises the amount at risk in case of an incident (for example a power failure). The system can handle capacities from 500g to several tonnes, so there is no need for scale-up. The unit’s small size and modular construction allows for a fast deployment and makes it easy to install with existing equipment.

Fluidised Spray Drying
This process produces granules from liquid in a one-step process (see Figure 5). One option is to produce the active in the primary production as granules, so that it only requires blending with excipients suitable for direct compression for secondary processing. This can only be done with actives that are tacky (in a wet state) – otherwise the addition of a binder is necessary. Another possible use of fluidised spray drying (FSD) technology is to mix all the ingredients into a solution or suspension and to produce granules in a one-step operation. During the FSD process, the liquid feed is atomised at the top of the tower in a co-current mode. After the liquid is evaporated, the particles generated leave the drying chamber together with the exhaust air. These particles are then separated in a cyclone or filter and reintroduced into the drying chamber, where they come into contact with wet droplets and form agglomerates. After these agglomerates have reached a certain weight, they cannot leave via the top of the tower with the exhaust air, but fall down into the integrated fluid bed at the bottom of the drying chamber. Here they are dried and cooled before being discharged. However, this type of equipment is difficult to clean, particularly the external pipe work, when changing to another product. Therefore, systems have been developed where the external pipe work does not come into contact with the product.


The selection of a granulation process and equipment is based on the company’s experience and the type of equipment already present in the company, but there are good reasons to carry out this selection process in a more objective way. The following factors should be considered:

  • Volume of production
  • Multi-purpose or dedicated plant
  • Product mix or volumes and campaign lengths (resulting in the required number of changeovers)
  • Existing products and processes (the process already registered for a particular product)
  • The need to process organic solvents
  • Tradition (know-how/policies)
  • Other applications to be done with the same equipment (coating and so on)
  • Potency of API (environmental/personnel)
  • Space/height available
  • Capital/operating costs


As the total cost of a manufacturing operation is a key decision criterion, a total cost of ownership (TCO) calculation should be performed on a case-by-case basis. Required input parameters are shown in Table 1. With this information it’s possible to do TCO calculations to compare different production scenarios.

Table 1: Assessment criteria for TCO calculation

Characteristics of production pattern
Average batch size (kg)
Time per batch (hours)
Average number of tablets per batch
Average number of batches per
Available working hours per day
Available working days per year
Total available working hours
per year
Time for cleaning between
batches (hours)
Time for campaign change-over
Number of operators for production
Number of operators for cleaning
Cost per operator (€/hour)
Yield of process (per cent)
Price of material (€/kg)

Characteristics of investment
Price for granulation equipment (€)
Depreciation time for equipment
Space requirement
GMP floor (m2)
GMP room (m2)
Technical floor (m2)
Technical room (m2)
Cost for GMP space (€/m2)
Cost for technical space (€/m2)
Depreciation time for equipment

Breakdown of the advantages and disadvantages of granulation technologies

Single Pot
: high containment, one-pot operation and a small footprint. The single pot granulation process can compensate fluctuations in raw material specification. It also boasts a very fast changeover and easy and safe handling of organic solvents, as well as a high yield and a limited need of operators. Furthermore, it offers a unique solution for effervescent production.
Disadvantages: limited throughput, no possibility for additional unit operations, and difficult to scale up.

Fluid Bed Granulation
: one-pot operation, a limited number of operators and a small footprint. It offers the possibility of additional unit operations, and the granules produced show excellent compression behaviour. The process is easy to scale up.
Disadvantages: handling of organic solvents is considerably more complex with this system. The machinery involved also has a large height requirement.

Integrated High Shear Granulator and Fluid Bed Dryer
: the technology is well established, and has a very high throughput. The granulation process using this method can compensate fluctuations in raw material specification, and offers the possibility of additional unit operations.
Disadvantages: a limitation in yield, a large footprint and height, as well as a long time for changeover. A large number of operators is also required. The handling of organic solvents requires complex setup with this technology, and scale-up is difficult.

Continuous Granulation Process
: a small footprint and height requirement and a minimal need for operators (especially if directly integrated with tablet press). It can compensate fluctuations in raw material specification, and offers a fast changeover and high yield, along with an easy scale up. Importantly, this option is also in line with latest FDA requirements.
Disadvantages: no possibility for additional unit operations, no possibility to work in gram scale, and handling of organic solvents requires complex setup with this process. FSD Spray Drying This is a totally different concept that requires the combination of primary and secondary production. This can create materials with tailor-made characteristics (enhanced bioavailability, incorporated taste-masking, suitable for direct compression, and so on) in a one-step operation.


This article is intended as a guide to the different technologies in use and their relative benefits. Every installation is, however, different and the specialist knowledge and experience will identify the best equipment for each application. Users are advised to seek this technical help well in advance of making decisions to ensure the optimum performance of their plants.

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Harald Stahl has a diploma in Physics and a PhD in Chemical Engineering. He worked for several years in the Pharmaceutical Development department of Schering AG in Germany. Since 1995 he has served within GEA in various positions, currently holding the position of Senior Pharmaceutical Technologist. He has given more than 200 presentations for various non-profit organisations and also has a profound experience holding training sessions on various aspects of pharmaceutical technology. His main fields of interest within pharmaceutical technology include granulation, drying and coating, process scale up and containment. He has also published more than 40 papers on various aspects of solid dosage forms.
Harald Stahl
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