When developing a tablet or capsule, three widely used technologies are often considered to produce solid dosage forms: direct compression, wet granulation and dry granulation, explains Todd Stutzman, Director of Pharmaceutics at Catalent
In direct compression, the active pharmaceutical ingredient (API) is blended with excipients and the blend is subsequently compressed into a tablet or used to fill a capsule. This is an economical way of producing a solid dosage form, but it requires the API to have good flow properties and minimal lot-to-lot variation in the physical properties of both the API and the excipients.
This technology is often used for formulations with lower drug loads when the blend properties are largely influenced and controlled by the excipient properties.
In a wet granulation process, the API and excipients are combined in a high energy mixer into which a solution is added during the mixing process. The blend is then dried and milled to form granules. This method requires more equipment than direct compression and is not suitable for heat- or moisture-sensitive APIs.
There may also be challenges during scale-up when larger granulation equipment is required.
In a dry granulation process, the blend is first compacted by being passed between two rollers and then milled to form granules. This is not a suitable option if high pressure results in physical or chemical changes to the API; but, unlike wet granulation, this process is appropriate for APIs that are sensitive to heat and/or moisture.
Dry granulation is also preferred compared with wet granulation when considering the overall cost-of-goods, energy consumption and/or environmental impact, as well as the potential to scale-up from development to full-scale cGMP commercial production using the same equipment.
A significant advantage of dry granulation compared with direct compression is its applicability to formulations containing an amorphous solid dispersion. These are prepared by spray drying, can have poor flow and low bulk densities, and require densification to improve processability. Therefore, dry granulation — and roller compaction in particular — may be the best option for these formulations.
During roller compaction, a blend of the API and intragranular excipients is passed between two counter-rotating rollers to generate ribbons. In the roller compactor, the blend experiences increasing pressure, reaching a peak before ribbon release.
The ribbon is then milled into granules, blended with extragranular excipients and compressed into tablets or filled into capsules. The flow, density and uniformity of the precompaction blend all impact the target properties of the final dosage form and should be closely monitored during development.
A filler/diluent and binder are typically included in the preroller compaction blend because, if included at the extragranulation phase, segregation could occur. However, it is important to include disintegrants and glidants as both intragranular and extragranular components to ensure acceptable disintegration times and optimal flow of both the pre- and final blend.
Similarly, it is important to add lubricants intragranularly for the rollers or other surfaces in the roller compactor, as well as extragranularly for the compression and encapsulation processes.
When a high drug load is required, the blend is largely influenced by the API, making formulation more challenging because it is limited by the API’s physical properties. With a lower drug load, it is possible to adjust the blend properties and improve processability by selecting appropriate excipients.
In other cases, even at lower drug loads, API properties may still not be amenable to developing a formulation and process for roller compaction.
In general, a blend is formulated using the mass of the individual components; however, the bulk density of each component is also important when producing a precompaction blend. The volume contribution has a greater impact on the overall performance of the blend; for example, a spray dried dispersion with a mass contribution of 25% w/w may have a volume contribution of 50% v/v owing to the low bulk density.
It is recommended to evaluate the flow properties under various configurations to anticipate any challenges that may be encountered during scale-up. Parameters such as roll pressure, roll gap, roll speed, roller surface and screw speed, as well as blend time and lubrication time, should be studied during the development of the roller compaction process.
Additional processing features to consider include removing trapped air from the powder using vacuum, along with choosing the size of the ribbon sieving screen. For example, as the material is compacted, air escapes from the powder; applying a vacuum can result in stronger and more uniform ribbons by reducing the disruption caused by air.
Finally, the size of the screen used during the milling process is one of the most important processing parameters because it ultimately determines the size of the granules.
Establishing milled granule particle size distribution is important as it not only affects the flow of the material in downstream processing, such as in encapsulation or compression, but also impacts the resultant surface area and its relationship with the dissolution profile.
Design of Experiment (DoE) studies can help to identify the influence of the process parameters and can be used to optimise the formulation. A formulation DoE might investigate the levels of API and excipients, as well as their impact when included intragranularly or extragranularly, and establish critical formulation variables (CFVs).
Following the development of a small-scale process, the next steps are to scale-up the procedure and ultimately implement commercial-scale production of the solid dosage form.
In some cases, the roller compaction equipment may not change as the batch size increases; in others, the process may be redesigned because of a change in the roller compaction technology (such as the direction of the feed or the type of milling).
As the drug product manufacturing process is scaled-up and demand for the active increases, the API manufacturing process is also likely to be modified. This could result in changes to the physical characteristics of the API, so a thorough characterisation of these properties is required.
The particle size distribution and morphology of each API lot should be assessed using multiple techniques, such as sieve analysis, laser diffraction and image analysis techniques. If differences in API properties are discovered at this stage, it could be necessary to modify various process parameters, the roller compaction technology or even the formulation.
Both the particle size and the bulk density of the API and excipients will impact the uniformity of the precompaction blend, and the uniformity of the precompaction blend directly impacts the uniformity of the granules, the final blend and, ultimately, the final dosage form.
Once the granules have been manufactured and the API has been trapped within the granules, it may not be possible to improve the uniformity. Therefore, physical characterisation of the precompaction blend must be done to optimise the feed of the blend into the roll gap.
If the same roller compaction equipment is being used during scale-up, many of the process parameters may be retained.
However, as the size of the precompaction blend is increased and the hopper/bin geometry potentially changes, it is important to study the flow properties of the larger precompaction blend.
Two types of bulk material flow must be considered: mass flow and funnel flow. In mass flow, the material moves uniformly through the hopper or bin. In funnel flow, material first flows out of the centre, leaving material near the walls to eventually collapse and flow out of the hopper/bin.
Funnel flow subjects the blend to variation, which may adversely impact the uniformity of the ribbons. The hopper configuration should prevent or alleviate these flow issues; but, additional forces, such as vibration, may be required to make the material flow. And, while aiding the process, these forces could also lead to segregation.
The flow properties should also be considered when implementing closed-system transfers. These can reduce the variation caused by manually scooping the precompaction blend into the hopper, but they may also present additional challenges if the flow properties are not amenable to this type of transfer.
Physical characterisation of the ribbons and milled granules is critical, especially when the commercial-scale roller compaction equipment differs significantly from the small-scale version.
In this situation, the process parameters will be optimised to ensure the scaled-up process produces ribbons and granules with similar characteristics to those produced during development. The ribbon consistency should be maintained from the small- to the larger-scale process so that when the ribbons are milled, they have the same porosity and particle size distribution.
During the development of the scaled-up process, it may also be necessary to re-evaluate the lubrication efficiency. Intragranular lubricant prevents the material from sticking to the rollers and ensures the consistent production of ribbons.
As the batch size increases, the processing time for roller compaction will also increase and the lubrication that was acceptable for a shorter run may no longer be effective. Additional lubricant is often incorporated into the final blend as an extragranular component; like the intragranular lubricant, its level may need to be optimised for longer compression and encapsulation runs.
Roller compaction is an excellent solution for many APIs, including those prepared as amorphous solid dispersions.
Following small-scale proof-of-concept studies, further characterisation of the API, excipients, preroller compaction blends, ribbons, granules and, finally, the roller compaction equipment is critical to the successful operation of a scaled-up, integrated tablet or capsule development solution.