Pär Almhem President Modwave
Dominik Sander Gebrueder Loedige Machinenbau GmbH
Drug makers have traditionally employed continuous manufacturing for large volumes of a limited number of products. They also prefer direct compression when manufacturing solid dose products continuously. Because of these tendencies, continuous manufacturing systems have been primarily designed for high throughput direct compression. However, some molecules resist manufacture through this method—leading to an interest in continuous systems for wet granulation of solid dose products. Manufacturers can take multiple approaches to applying wet granulation to solid dose products.
One technology—wet granulation in a continuous ring layer mixer, combined with a continuous fluid bed dryer—produces highly uniform granules. These granules closely resemble ones produced in traditional batch high shear granulators. By combining the continuous wet granulator with a continuous fluid bed system with controlled retention time and temperature control, the system can produce highly uniform granules over short or long operation periods for a range of applications— from process development to higher volume productions.
One challenge? Most systems are designed for a throughput that is higher than ideal for development purposes. A system sized to support R&D, process development, and small scale manufacturing now exists—the CM1 system for small scale continuous granulation in a ring layer mixer combined with a continuous fluid bed dryer.
Continuous Granulation Using a Ring Layer Mixer
For running a continuous wet granulation with downstream drying process, a pre-mixed product (from a continuous mixer or a feeding hopper) is gravimetrically filled into the feeding port of the continuous granulator CM. In case mixing requirements are not very high, the granulator can also be utilized for a combined mixing and granulation process. The system is based on the high peripheral speed of the mixing shaft tools, up to 40 m/s, resulting in a centrifugal force forming a concentric annular layer—or ring layer—of product. At the same time, the product is moved from the inlet through the machine towards the outlet. Depending on the progress and product characteristics, the mixing tool configuration on the mixing shaft allows for division of the mixing chamber into zones of different shear intensity using transporting, dispersing, and mixing elements.
To ensure that liquid components are absorbed by the powder particles, and not cover the mixer walls or shaft, the liquids are introduced directly into the product ring layer through tangentially installed liquid feed pipes through the mixer drum wall. With the addition of the liquid binder, a true high shear granulation takes place in the ring layer. This granulation is characterized by a very uniform particle size distribution. The resulting granule structure is comparable with that of conventional batch high shear granulation processes. Granules exit the machine through a discharge opening straight into a continuous fluid bed system.
Continuous Drying in a Modified Fluid Bed System
The continuous dryer is operating based on the fluid bed process. In order to avoid wide retention time variations in the machine, the dryer is equipped with an integrated conveying screw that allows for a forced, controlled conveying of the granules through the machine. Drying is carried out by fluidizing the product with conditioned warm air while the product is conveyed through the dryer using the screw. The screw rotates close to the bottom of the half cylindrical sieve. By adjusting the rotation speed of the screw, the retention time of product in the dryer—and thus the drying time—can be controlled with a high degree of accuracy. Depending on the dryer size, it can be designed with several inlet air chambers. For each chamber, air flow and temperature can be adjusted in order to carry out the drying process accurately. The dry granules are discharged from the dryer by gravity into a discharge funnel and can be further processed (e.g. by a sieve mill) before they leave the system for a container or e.g. a tablet press.
Granucon 1 - Continuous Mixing, Granulation and Drying in Small Scale
The Granucon 1 is a unit performing continuous mixing, granulation & drying in an integrated system. It is designed primarily for product development and small-scale production. It was designed with special focus on small throughputs considering the limited availability and/or high cost of APIs in development stages. The core of the system is a continuous ring layer granulator with 1l volume and a down-stream continuous fluid bed dryer. With modified mixing elements, the granulator can also be used as a continuous mixer for dry blending.
For mixing and granulation processes, the raw materials are dosed by gravimetric feeding systems into the mixer/granulator. Liquid addition and dosing can take place e.g. via a geared pump. The system is designed for throughputs of 2-5 kg/h for granulation applications.
The standard Granucon 1 system configuration includes:
• Ring layer mixer CM 1
• Fluidized bed dryer LCF 1
• Two gravimetric feeders
• Pump for the granulation liquid
The system is implemented as a modular design combining the process units with central controls, which enables flexible, integrated system control as well as simple acquisition and visualization of process data. An OPC-UA interface is available for data recording and meets the challenges in implementation of Industry 4.0.
The first complete Granucon 1 system was recently installed at a university in Germany, where it is used for research and development.
Currently, the Granucon system is available in the following standard sizes and throughputs:
Machine type (Granulation) Throughput*
Granucon 1 2 – 5 kg/h
Granucon 5 5 – 25 kg/h
Granucon 10 10 – 65 kg/h
Other sizes can be offered per end user’s requests.