Hartmut vom Bey & Barbara Fretter discuss the infinite PSD spiral driven by the amount of fines
During the development stage of dry granulation products, several considerations and optimisations must be made. In this context, an unfavourable progression can be observed that, in principle, is a self-perpetuating downward spiral from focusing on the amount of fines (Fig. 1). It’s an infinite particle size distribution (PSD) spiral: at best, it can result in numerous unnecessary trials; at worst, it could be concluded that roller compaction is not possible for a specific product.
A shift to much more complex and costly granulation methods is the consequence, along with further delaying time-to-market. Interestingly, some decisions that lead to this spiral are based on correct assumptions, but an important effect is often ignored.
The Start Of The Spiral
The entrance point into the spiral is often the choice of the granulator screen size. Based on wet granulation experience, too small screens (e.g., 0.8 mm or 1.0 mm) are chosen for normal sized tablets of 8 mm and larger. Due to a lack of other acceptance criteria, the particle size distribution and particularly the amount of fines is often used to evaluate the granules. Here, two problems arise. Firstly, there is no unique definition of fines. Some companies define everything below 355 µm as fines. In other regions, you can find definitions such as anything below 500 µm. Occasionally, 90 µm, 100 µm, or even the d10 can be used to categorise fines. Secondly, the amount of fines is not always an accurate parameter for predicting granule quality and flowability. According to the above definitions, Avicel pH 102 would have a huge amount of fines (Table 1). Its average particle size is 100 µm. Nevertheless, it has an excellent flowability and is used for direct compression. Even Avicel pH 101, with an average particle size of 50 µm is sufficiently flowable to be processed on rotary tablet presses. Both examples show that the amount of particles below 100 µm, 355 µm, or 500 µm is no suitable evaluation.
Nevertheless, based on this vague number, the conclusion is made that the amount of fines is too large. This assumption is the beginning of the downwards spiral. To counteract the increase in fines, the specific roll force is increased. In principle, this is a correct consideration. As shown in Fig. 2, a larger roll force results in coarser granules. But the side effect – which is actually the main effect – is that the granules become harder, and their re-compressibility decreases. The larger granules will become too coarse. Therefore, an even smaller screen will be used (hoping that the higher roll force and the smaller screen balances both effects out). Often this is not the case, and the amount of fines (however defined) has decreased considerably. Again, the specific roll force is increased, with the known consequences. In the end, if no satisfying granule is achieved, the worst-case conclusion is: roller compaction is not possible, or an additional re-circulation step is required. Even if such a product finally comes to production, it rarely has optimal properties.
What’s The Answer?
The solution for escaping the spiral of “small screen – more force – smaller screen – even more force…” is to take the opposite direction. In roller compaction, screens larger than 1mm are standard. Less roll force is needed, and the granules get softer. This is especially important when evaluating coarser particles. The re-compressibility becomes better, and the following tableting process becomes less problematic. Additionally, the amount of fines should not be taken as a decisive parameter. It gives no evidence about the resulting flowability of the granulate. This must be tested on a rotary press or filling system.
It is worth pointing out that low roll forces and large screens are no panacea. The optimal settings are product-dependent and must be established during development.
Hartmut vom Bey is with Gerteis Maschinen + Processengineering & Barbara Fretter is with Solids Development Consult