Hartmut vom Bey & Barbara Fretter provide a comparison between a small-scale mill and roller compaction production unit
When developing a dry granulate with Gerteis roller compactors, the first trials are performed with very small amounts of material. Sometimes the densification step for the small amount of material can be simulated by a compaction simulator as well. Using conventional small lab scale mills for milling the compacts results in different particle size distributions as the functional principle is not comparable to later production scale roller compactor.[1]
To allow more reliable predictions during early development, the company has developed a small-scale mill (manual mill) that eliminates the described difficulties. The Small Scale Mill inherits the same milling principle as the company’s Pactor production machines. The particle size distribution (PSD) from the Small Scale Mill provides reliable indications about the granule characteristics of the future production. Therefore, the mill is an excellent scale-up tool.
Influencing Factors of the Milling Step on Particle Size Distribution
One important influencing factor on the PSD of granulates is, of course, the material itself. API and mixtures have a huge impact on the PSD.
Beside the material/formulation, roller compaction process parameters have also affected the PSD of the granulate. A ranking of the influencing process parameter for roller compaction is given in Fig. 1.[1] The most important parameter is the ribbon density, which is a result of the specific roll force and gap used in the roller compactor. This applies for production roller compactors from Gerteis in the same way as for lab roller compactors. A higher ribbon density, which is achieved by increasing the specific roll force, results in stronger ribbons and therefore larger particles. Of course, the mesh size used has also an important influence on the final particle size distribution, because it limits the upper particle size. During development the influence of the mesh size is often examined.
Influence of Specific Roll Force on Particle Size Distribution
Coming back to the influence of the specific roll force on the PSD, which has the major impact on the roller compaction granulate qualities and should therefore be the focus of the development work for the dry granulation process. In Fig. 2 Avicel 101 is taken as an example for this effect. Increasing the densification by using higher specific roll forces results in coarser particles, although the width of their distribution remains constant. The number of fines is usually reduced at higher roll forces during roller compaction.[2] However, the extent of the influence of the roll force depends on the used pharmaceutical formulation and cannot be generalised.
Features of the Mill
In some situations, e.g. during development, when the API (active pharmaceutical ingredient) is rare or very expensive, it is desirable to be able to mill small amounts. Prior studies showed that small lab or household mills are not suitable for achieving the same PSD as roller compactors for production.[1] Therefore, a Small Scale Mill (manually operated) was developed by Gerteis that reproduces the grinding principles of the Pactor line. The various wire mesh screens and rasping screen are changeable, which allows the user to mount different mesh sizes, depending on the requirements. The material – tablets or roller compactor ribbon pieces – is forced through the screen by milling bars, which are manually operated. The material is processed into the milling chamber and final granules are collected in a drawer. A few grams of material up to 50g can be milled in one pass, which is often enough for first tableting experiments. The overall design of the manual mill is constructed for an easy use: mounting and cleaning of all parts is simple and fast. The material used in construction complies with all pharmaceutical requirements.
Comparison of the Two Solutions
For comparing the performance of the Small Scale Mill, four different excipients were tested.[1] The same material concerning densification and strength was milled with the manual mill and the Macro-Pactor (production scale roller compactor).
The results in Fig. 3 show good correlations between the granulates obtained by the Small Scale Mill and Macro-Pactor for all four substances. All granulates follow the typical PSD of dry granulates, which is rather broad. A certain amount of fines (particles below 100 µm) is present, but below 10 -20%. Small differences between both units can be observed in the extent of the strongest particle fraction between 1000 µm and 1400 µm, which lead to a slight shift of the particle size distribution towards coarser particles for the Small Scale Mill. The extent of this small deviation seems to be material specific. They are caused by the other process parameters of the Macro-Pactor, which cannot be transferred to the manually operated Small Scale Mill. During scale-up these process parameters will be optimised, hence the small differences in particle size distribution can be neglected during development.
From the results it can be concluded that both solutions show almost identical particle size distribution and that therefore, the Small-Scale Mill is an ideal tool for milling small amounts of material to representative granulates.
REFERENCES:
1. Potschadl, J., PhD Theses, Scale-down des Walzenkompaktierprozesses Entwicklung eines Trockengranulats im Kleinstmaßstab University of Bonn (2013)
2. Wiesweg, S., PhD Theses, Einflussfaktoren des Walzenkompaktierprozesses auf die Partikelgrößenverteilung von Granulaten, University of Bonn (2009)
Hartmut vom Bey is with Gerteis & Barbara Fretter is with Solids Development Consult
