The role of granulation in a changing pharmaceutical landscape

David O’Connell, Director of Scientific Affairs at PCI Pharma Services, discusses the advantages and general principles of dry granulation roller compaction as an alternative to traditional wet granulation manufacturing — particularly for the development and production of oral solid dosage forms, including tablets and capsules containing highly potent active pharmaceutical ingredients (APIs)

Granulation is a process in which primary powder particles adhere to each other, resulting in larger, homogenous multiparticle entities or granules.

When performed without adding a liquid binder, this process is called dry granulation — whereby the powder blend is compacted by applying a force to the powder, which then causes adhesion and considerable size enlargement. The subsequent uniform granules can be further processed into tablets, capsules and powders for bottles or sachets.

Dry granulation can be achieved in two ways: slugging, in which a large compact is formed and then broken down into granules using a mill; or roller compaction, when material is compressed into a ribbon prior to the production of granules.

Dry granulation is required when wet granulation may be unsuitable as a manufacturing method. For example, if you have a moisture-sensitive compound, wet granulation would be challenging because of the need to add a liquid. In addition, any granulation technique that includes a drying stage would be unsuitable for a compound that either has a low melting point or is sensitive to heat.

What is roller compaction?

Roller compaction is a method of dry granulation that’s based on the aggregation and densification of dry powders into a solid mass known as a ribbon. This densification process is achieved by feeding a powder by gravity or auger screws through a set of directly opposed, counter-rotating rollers whereby the gap diameter between the rollers is decreasing.

The gap diameter is a key processing parameter; the powder is subjected to high pressure, resulting in an increased powder density and particle size within the milled granule.

The powder blend is actually compacted by the application of force, turning the dry powder into a solid mass. The purpose of dry granulation is to increase the bulk density of powders and increase the particle size to ensure a better flow of distributed material — an important factor in the production of tablets and capsules using high speed manufacturing equipment.

The process avoids the use of liquids and the high temperatures associated with wet granulation and subsequent drying methods, turning powder blends into densified sheets using the two compacting rollers. The ribbon is broken down into a specific granule size via a milling system, such as an oscillating mill.

The most important parameters in the dry granulation process are powder feeding, the applied compaction pressure and the gap diameters. The powder is fed into the rollers and — depending on the feed rate of powder, the gap diameter and force — the powder will be compacted into a predefined ribbon thickness. To ensure an end result of suitably uniform granule properties, precise process control is critical, and this is determined by the pressure at which the powder is forced through the rollers.

Benefits of roller compaction

The benefits of roller compaction compared with a wet granulation method really depend on the compound itself. If you have, for example, a moisture-sensitive compound, wet granulation could prove very difficult in terms of inducing potential impurities.

By contrast, the roller compaction process does not require a liquid binder and therefore, in principle, would be a more suitable option. In addition, should a compound have either a low melting point or be heat-sensitive, wet granulation with a drying stage would not be appropriate and roller compaction would be a more suitable process.

It is also safe to assume that roller compaction is both more energy and time-efficient: the absence of a drying stage delivers lower energy costs and a more efficient means of processing as it requires less time to produce the granules.

Other forms of dry granulation exist, such as slugging. Slugging involves producing a large compact on a tablet press prior to milling and further processing.

This method may cause some inherent challenges, however, as material with a low bulk density and small particle size will generally not flow (efficiently) into the die of a tablet press, which may lead to inconsistent and fluctuating compaction results after the milling stage.

This is one explanation regarding why this method of dry granulation is being used less and less in practice, particularly given that roller compaction is able to offer an effective alternative.

Another advantage of roller compaction is that the continuous processing design means development and pilot batches can take place on the same machine as commercial batches. This mitigates the scale-up issues that can occur during process development or GMP bulk production.

Different types of roller compaction and advantages

The two main categories of roller compaction are essentially based on the gap between the rollers. The first being fixed gap rollers and the second being when the gap is described as “floating,” meaning that it’s possible to change the distance between the rollers depending on the powder properties.

A generally accepted opinion is that the floating option is more advantageous. A fixed gap can lead to inconsistent powder flow and, consequently, the production of a non-homogenous ribbon. With technology that offers a floating gap option, the distance between the rollers will alter depending on the amount of powder provided; the force applied then remains constant.

This ensures that fluctuations in the granules are minimised, resulting in a more uniform or homogenous granulate.

Following compaction, the ribbons are milled using a screen with a sizing mesh that limits the upper particle size. Oscillating milling provides a gentle process that avoids creating fines within the resulting granules. The granulate can then be further processed into either a tablet or capsule dosage form with increased confidence of dose uniformity.

Increasingly specialised and potent medicines

The pharmaceutical landscape continues to evolve, with more products being deemed to be potent. The reason for this is that as the biological activity and specificity of the API increases, the dosage strength decreases. Any compound classified as potent requires specialist handling to protect the scientists/operators from a predetermined exposure limit.

Traditional techniques that rely on personal protective equipment (PPE) are being replaced with the use of contained engineering solutions to ensure operator protection. With this in mind, fully contained roller compaction should form part of any decision process when a company is looking to outsource development or manufacturing operations … or the company should consider building its own such internal capabilities using existing technologies.

At PCI, a decision was made to invest in technology to safely process potent, multi-API compounds in a purpose-built facility. The dedicated unit was built according to the philosophy of utilising fully contained engineering solutions, eliminating PPE and processing molecules with an occupational exposure limit (OEL) down to 0.01 µg/m3.

As a service provider, PCI had seen and responded to the increase in the potent development landscape by offering best-in-class solutions. Within the first 12 months of opening the facility, however, a number of customers specifically requested potent dry granulation — owing to their compounds being sensitive to either heat and/or moisture. PCI took the decision to install a fully contained roller compactor to meet this growing need.

The roller compactor (Figure 1) was designed with a stainless-steel plate positioned against the rollers and, contained within a negative-pressure isolator, an oscillating mill. Integrated spilt butterfly containment valves handle material transfer from intermediate bulk containers.

Figure 1: PCI roller compaction technology

In terms of post-process cleaning, the PCI roller compactor contains numerous spray nozzles that are used to wet down the gross contamination prior to a machine strip down and placement into a parts washer.

In summary, there are many different types of granulation techniques available. The decision regarding which method is selected will depend on multiple factors, including the physiochemical characteristics and potency of the compound. In each instance, it is important to use all known information and available experience to make the most informed choice … and ensure the greatest chance of success for any development project.

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