There are a number of granulation technologies available to pharmaceutical manufacturers. Given the importance of granulation in the production of oral dosage forms, this article offers advice on various processes.

Granulation Technology

In the pharmaceutical industry, the three most common granulation processes for solid dosage form production are wet granulation, dry granulation (roll compaction) and direct blending. Given the importance of granulation in the production of oral dosage forms — most fine pharmaceutical compounds require granulation to improve their flowability and processing properties prior to tableting — and the technique’s extensive use in the industry, it’s essential to understand the principles and options, which are summarized below. An obvious advantage of roll compaction is that no moisture is involved in the process; it is therefore an ideal way to process compounds that are physically or chemically unstable when exposed to moisture. Furthermore, it’s not necessary to dry the granules produced and, hence, typically more energy efficient. 

Dry Granulation: This process is used to form granules without using a liquid solution, because the product to be granulated may be sensitive to moisture and heat or does not compress well. Forming granules without moisture involves compacting and size reduction of the mix to produce a granular, free flowing blend of uniform size. Thus, the primary powder particles are aggregated under high pressure using swaying or high shear mixer-granulators. Dry granulation can be done in two ways: either a large tablet (slug) is produced in a heavy duty tableting press or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor/chilsonator). When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying degrees of densification. The roller compactor (granulator-compactor) uses an auger-feed system that will consistently deliver powder uniformly between two pressure rollers. The powders are compacted into a ribbon or small pellets between these rollers and milled through a low-shear mill. When the product is compacted properly, it can then be passed through a mill and final blend before tablet compression.

Wet Granulation: The process of adding a liquid solution to powders involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent that must be volatile, so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The liquid solution can be either aqueous-based (safer) or solvent-based. Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder is required. Once the solvent/water has been dried and the powders have formed a more densely held mass, then the granulation is milled. 

The process can be very simple or very complex depending on the characteristics of the powders and the available equipment. In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules that are subsequently dried. A subsequent screening stage breaks agglomerates of granules. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. Because direct compressing is not the best technology for many active substances, wet granulation is still a preferred method. Even if the active substance is sensitive to hydrolysis, modern equipment (a fluidized bed, for example) eliminates all problems in wet granulation.

Finally, wet granulation involves the production of a granule by the addition of liquid binders to the powder mixture. Both continuous direct compression (CDC) and continuous mixing for the dry granulation processes involve the individual loading and accurate feeding of the active pharmaceutical ingredient (API) and a variety of excipients into a continuous blender.

Granulation Technologies

GEA supplies engineering services, complete production/process plants and standalone oral solid dosage machines to customers in the pharmaceutical industry. GEA provides proven solutions for the most challenging dosage forms such as oncology drugs, multiple unit pellet system (MUPS) tablets, effervescents and multilayer pellets. Also, as experts in containment, we offer the largest variety of solutions for contained processing, based on our unrivalled experience in containment risk analysis to identify the most appropriate solution. The following section introduces the different granulation processes, compares them objectively and presents unbiased advice on the merits of each system.

Single Pot

UltimaPro Single Pot Processors

A mixer/granulator that dries granules in the same equipment without discharging is commonly known as a single pot processor (or one-pot processor). 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 lowering the evaporation temperature of the 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. 

Introducing stripping gas into the pot allows a very low final moisture content to be achieved (only required in 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 vapor 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); if water is used as a granulation liquid (it has a relatively high boiling temperature under vacuum and a high heat of evaporation compared with organic solvents); and if 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 vapors 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

Pharma Product Fluid Bed R&D Contained

Granulation can be done using fluid beds fitted with spray nozzles. Although, 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, which is in an area with significantly higher shear forces that now allows the processing of formulations that could only previously be granulated in high shear processors. Additionally, the introduction of the new FlexStream™ range of fluid beds also eliminates the difficulty of scale-up. In recent years, fluid beds have improved dramatically in response to competition from single pot technology. It is now possible to contain material handling using a closed link with up- and downstream equipment. In addition, fully automatic cleaning (CIP) in fluid beds using stainless steel filters has now reached a level that compares favorably with what is possible in a single pot.

Fluidized Spray Drying (FSD)

Spray Dryer PharmaSD final

FSD produces granules from a liquid in a one-step process. 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 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 atomized at the top of the tower in a concurrent mode. After the liquid is evaporated, the subsequently formed particles 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. Systems have, therefore, been developed in which the external pipe work does not come into contact with the product.

Integrated High Shear Granulation and Fluid Bed Drying

Pharma Technology Granulation

This is the most common configuration used on an industrial scale for the production of pharmaceutical granules. 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 whilst drying the previous batch in the fluid bed prior to discharge. All equipment can be cleaned in place in a single automatic process.

Melt Granulation: In a melt granulation process, the binder solution of a standard wet granulation process is replaced with a meltable binder. This binder can be added in molten form, but the high shear process offers the benefit of allowing the binder to be added in its solid state. Melting is achieved by the energy added through the mixer friction and the heated jacket of the bowl.

Effervescent Products: A very small amount of water is added to start the pre-effervescent reaction: some of the carbon dioxide is released during granulation, but water is also produced as a reaction product; this then acts as a granulation fluid producing more carbon dioxide and also more water. This avalanche needs to be stopped at a certain point by starting the drying process and removing the water. This can be done using a high shear granulator with subsequent fluid drying by discharging the material at the end of the granulation process into a pre-heated fluid bed dryer.

Continuous Granulation

Consigma 25

As a result of various regulatory initiatives to improve product quality and to reduce the risk of product failure, there is a huge interest in continuous processing. A typical 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 whole wet granulation process takes place in a few seconds with only a few grams 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 1.5 kg, drying them each 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 is only 6–9 kg in process, which minimizes the amount at risk product loss. The unit’s small size and modular construction allows for a fast deployment, easy scale-up and makes it easy to install with existing equipment.

Beyond the Granulator

For full compliance with national, local and in-house regulations, GEA offers a range of emission control options, including solvent recovery systems, outlet filters and full containment plants. Equipment can be supplied to meet explosion-proof and pressure shock standards as required. Our high shear granulator plants and granulation and drying process expertise is based on a wealth of experience and a long history of research and development. With plants installed around the world and, quite literally, thousands of tests performed, we have established a solid base of expertise related to the needs of the pharmaceutical manufacturing industry. We have the right solution for your granulation application.