Dr Robin Meier reveals why twin-screw granulation is an efficient starting point to enter the world of continuous manufacturing
Twin-screw granulation (TSG) is a well-established and extensively described method to perform wet granulation continuously.
In the beginning of the 2000s and the following years, the process was described and followed up by several research groups.[1, 2] TSG is a fully continuous process by design and can be a starting point for pharmaceutical companies to launch activities related to continuous manufacturing.
Compared to batch granulation, continuous granulation is characterised by a constant in- and output of material through the processing zone.
Powder is delivered to two screws, which are co-rotating in a barrel, and transport and shear the material along the process to the granulator outlet.
The major difference between TSG and extrusion is the missing die plate at the end of the machine. Consequently, the wet material does not experience a strong densification, but solely falls out of the granulator. The TSG-setup yields several advantages, such as:
* Short process residence times <1min-10s
* Fast and efficient reaction to process deviations
* Reduction of machine footprint and GMP area:
the amount of produced granules is determined by the production time
* Tthereby, elimination of scale- up issues
* Mixing and granulation in one step
* Possibility to implement 100% in-line product quality- control
* No disposal of failure batches – only non-conforming material is rejected
* Execution of experimental plans in shortest time
The definitive TSG does not exist. In fact, a TSG provides plenty of adjustable parameters and possibilities to vary the setup.
Furthermore, different machines, mainly feeders, can be employed alongside the process, which increase the degree of freedom of the system even further.
The BCG (Bohle Continuous Granulator) is divided into five zones of equal length, from which the last three can be tempered independently from each other.
The temperatures of the different zones are major parameters, which can manipulate the product characteristics, especially during the granulation of freely soluble compounds.. Within the recently developed versionof the BCG, a highly effective and flexible tempering of the barrel from above and below the screws is realised.
The barrel of the BCG is openable to allow a fast changeover of the screw configuration as well as a fast cleaning and inspection of the processing zone.
Furthermore, each of the five zone offers the possibility to insert different ports in it, to facilitate feeding and the application of process analytical techniques.
An important characteristic is the screw diameter and the length to diameter ratio of the screws. To cover a wide range of throughputs from a few kg/h up to more than 50kg/h, at L.B. Bohle by standard a screw diameter of 25mm and a length of 25 x D is applied, but this is flexible to the specific process demands.
Virtually an infinite number of different screw configurations is conceivable by combining different types of elements, which results in granules of different characteristics.
Porosity, compactibility, granule size, etc. are subject to this influence. Conveying elements are used to convey the material through the barrel with minimal input of shear energy.
The pitch of the elements can also be varied, to alter the conveyed mass per screw-revolution.
Kneading elements are thin discs or longer blocks. The imparted shear energy increases and the conveying capacity decreases with an increasing advanced angle of the kneading zone. An intermediate between these two extremes is represented by distributive flow elements, which feature conveying capacity as well as shear energy.
The ratio of inner and outer diameter of the screw elements influences the amount of material that can be transported and thus the maximum possible fill-level of the TSG. The fill-level depends on the feed-rates of the material, the screw geometry and the screw-speed, which is another important factor to be varied.
The introduction of liquid into the process is of major importance and the accuracy and precision of this sub-process has to be ensured.
The liquid can be pure water, a binder solution or an organic solvent, depending on the formulation and the desired granulation mechanism. Within the BCG, a pressurised pump is employed to deliver the liquid in a pulsation-free way, even at lowest feeding rates or viscosities >1 Pas.
The application of openings smaller than 0.5mm prevents a blockage of the nozzles through bypassing powder, guarantees process stability and prevents the creation of huge and lumpy granule- nuclei due to the generated small liquid droplets. Thereby, wetting uniformity of the whole mass and the granulation of even hydrophobic powders becomes easily feasible.
The flexibility of TSG and ease of adopting the process make it a perfect and versatile tool for the continuous production of granules during R&D and production phases, and thus can be a door opener into the world of continuous manufacturing.
Dr Robin Meier is manager Scientific Operations at L.B. Bohle.
References: I. Ghebre-Sellassie, M.J. Mollan, N. Pathak, M. Lodaya, M. Fessehaie, Continuous production of pharmaceutical granulation, US 6499984 B1, (2002). 2 E.I. Keleb, A. Vermeire, C. Vervaet, J.P. Remon, Twin screw granulationas a simple and efficient tool for continuous wet granulation, Int. J. Pharm., 273 (2004) 183-194. 3 J. Vercruysse, D. Córdoba Díaz, E. Peeters, M. Fonteyne, U. Delaet, I. Van Assche, T. De Beer, J.P. Remon, C. Vervaet, Continuous twin screw granulation: influence of process variables on granule and tablet quality, Eur. J. Pharm. Biopharm., 82 (2012) 205-211.