David O’Connell, director Pharmaceutical Development at PCI Pharma Services discusses the advantages of dry granulation as an alternative to traditional wet granulation for the development and manufacturing of solid oral dosage forms, including tablets and capsules.
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Q: What exactly is roller compaction?
A: Roller compaction is a form of dry granulation, through the aggregation and densification of dry powders into a uniform solid mass (ribbon). The ribbon is then broken down into specific granule size via a milling system, which means that the powder particles are made to adhere to each other to form the larger multi-particulate units — the granules. Granulation can be performed without the addition of a liquid, so called ‘dry granulation’, which differs from a ‘wet granulation’ method, such as high shear granulation or fluidised bed granulation. In summary, with a dry granulation method, the powder blend is compacted by applying a force onto the powder, generally increasing the size of the granule.
Q: So how does this form of dry granulation work?
A: Dry granulation works by feeding a powder blend via gravity or feeding system to a set of directly opposed, rotating rollers. The powder is fed into a decreasing gap diameter between the rollers. The gap between the rollers is controlled, and the powder is subjected to high pressure or force — so it is designed to increase the bulk density, as well as the uniformity of the granule itself. The pressure applied and the gap diameters are the most important parameters in this dry granulation process.
Q: Why is the pressure or force applied so important?
A: The powder is fed into the rollers via frictional forces — depending on the amount of powder, the gap diameter and the given force, the powder will be ‘compacted’ into a pre-defined ribbon thickness. To ensure the end result of equal granule properties, a precise process control is critical, and this is determined by the pressure at which the powder is forced through the rollers — hence its importance.
Q: Does roller compaction offer any benefits over wet granulation?
A: It does and this really depends on the compound itself. If you have, for example, a moisture-sensitive compound, wet granulation could prove either very difficult or impossible in terms of inducing potentially toxic impurities. In contrast, the roller compaction process does not need the addition of a liquid binder and therefore provides a more suitable granulation process.
In addition, there is no drying stage with roller compaction and so if you have a compound that either has a low melting point, or is sensitive to heat, again wet granulation with drying would not be appropriate — whereas roller compaction would offer a more suitable option. With the addition of no drying stage, it delivers a more efficient means of processing, with less time to produce granules, and in theory, it can be a continuous batch process with a suitable feeding system.
Q: Do other forms of dry granulation exist?
A: Yes, an alternative method of dry granulation would be slugging — when a tablet press is used for the compaction of a large compact, which is then subjected to milling, prior to further processing. However, this may cause some inherent challenges. For example, materials with low bulk density and small particle sizes generally do not flow well into the die of a tablet press, which potentially leads to differences from one tablet (or ‘slug’) to the next, causing fluctuations in the forces applied to the individual tablets or slugs. This would then lead to differences in the mechanical strength, causing issues with the milling of the slugs and the granulate properties.
Q: Do different types of roller compaction exist?
A: Yes, there are two main categories, the first being where the gap between the rollers is fixed, the second is where the gap can be changed depending on the amount of powder introduced, which is described as ‘floating’.
Q: Does one offer any advantage over the other?
A: Consensus opinion does seem to think there is an advantage to the ‘floating’ option. If a fixed gap option is used, it can mean inconsistency in terms of the amount of powder that is drawn into the compaction area, leading to differing forces being applied to the powder bed. As in the case of slugging, this in turn would lead to fluctuations in the ribbon and granulate. However, by using technology offering a floating gap option, such as GERTEIS, the distance between the rollers will change according to the amount of powder provided and the force applied. This then remains constant, ensuring that fluctuations in the granules are minimised — resulting in a more uniform or homogenous granulate.
Q: So, what happens following the granulation stage?
A: Firstly, dry granulation using roller compaction technology is a continuous process if using integrated technology — which differs to that for wet granulation. Following compaction, the resulting ribbons are then milled immediately, using a screen with a set mesh size to limit the upper particle size. It is also worth stating here that milling should be as gentle as possible to avoid creating fines within the resulting granulate, as the overall process minimises fluctuations in the granules. The resulting granulate can then be further processed into either a tablet or capsule dosage form with increased confidence of dose uniformity.
Q: How does dry granulation in the form of roller compaction offer advantages within the arena of personalised medicines, which are becoming more prevalent?
A: Any compound that has been classified as potent requires specialist handling. Traditional techniques relying on personal protective equipment (PPE) are being replaced, through best and advised practice, with the use of contained engineering solutions to ensure the highest standards of safety and operator protection. With this in mind, identification of a solution able to offer fully contained roller compaction should form part of any decision process — whether you are looking to outsource to a CDMO, or build internal capabilities. Such technologies do exist and are becoming more commonplace.
David O’Connell, director Pharmaceutical Development at PCI Pharma Services
David O'Connell
As an example, we at PCI made a decision to invest in a fully contained roller compaction solution in response to the increase in the highly potent development landscape. However, within the first 12 months of opening the facility, a number of customers approached us specifically requesting dry granulation for very potent molecules, due to the compounds being sensitive to either heat and/or moisture. We therefore decided to install a fully contained roller compactor to address this growing need, allowing us to process molecules with an occupational exposure limit (OEL) as low as 0.01 µg/m3 within contained technological solutions. As a result of the success of this contained facility, we continued with this strategy for any new technologies we were looking to introduce and built the area of the site to house the roller compaction suite to the same standards. This ensured that from a customer perspective, we were able to offer parity between both wet and dry granulation solutions.