(557f) Twin-Screw Continuous Granulations: Technological and PAT Developments | AIChE

(557f) Twin-Screw Continuous Granulations: Technological and PAT Developments


Démuth, B. - Presenter, Budapest University of Technology and Economics
Nagy, B., Budapest University of Technology and Economics
Madarász, L., Budapest University of Technology and Economics
Fazekas, R. Á., Budapest University of Technology and Economics
Marosi, G., Budapest University of Technology and Economics
Farkas, A., Budapest University of Technology and Economics
Nagy, Z. K., Budapest University of Technology and Economics
Kovács, M., Budapest University of Technology and Economics
Pataki, H., Budapest University of Technology and Economics
Domokos, A., Budapest University of Technology and Economics

Continuous pharmaceutical manufacturing, both at upstream (active pharmaceutical ingredient, API production) and downstream (formulation technology) processing, is rapidly gaining interest as a promising way to improve efficiency, reduce operating costs and ensure easier scale-up and shorter time-to-market. Twin-screw processes such as continuous granulations are especially in the focus given that the majority of the product manufacturing lines contains a granulation step. Nevertheless, conversion from batch to continuous manufacturing entails the necessity of continuous process monitoring and an integrated quality control strategy. Real-time quality assurance of continuously manufactured products must be developed in order to be able to implement continuous manufacturing processes, the future of pharmaceutical manufacturing.

In this work, continuous twin-screw wet and melt granulations are discussed. In case of wet granulation, the goal was to develop a proper granulation process during which a drug with low dose can be homogenized. Furthermore, different kinds of PAT tools have been created to support this process: NIR and Raman spectroscopies were applied to monitor the active ingredient content, while dynamic image analysis was employed to in-line monitor and control the particle size of the obtained granules. Continuous melt granulation is also a promising downstream process. In this case, our aim was two-fold: to apply twin-screw melt granulation to obtain a powder readily tabletable and for the flowability enhancement of amorphous solid dispersion containing powders. Dynamic image analysis could be used in this process as well for the in-line particle size determination.

Materials AND Methods

Carvedilol (CAR) was used as model API for the granulation experiments. As excipients, lactose (Granulac® 230, Meggle Pharma, Wasserburg, Germany) and potato starch (Roquette Pharma, Lestrem, France) was applied, while the granulating agent was polyvinylpyrrolidone K30 (Kollidon® 30, BASF, Ludwigshafen, Germany) in 96% ethanol (Merck Ltd., Budapest, Hungary). For melt granulation experiments, crospovidone (Kollidon® CL, BASF) and polyethylene glycol with different moleculare weights (2000, 6000, and 20000, Sigma Aldrich, Budapest, Hungary) were used.

For the discussed processes, a TS16 extruder equipped with a special granulation die was applied (ProCepT, Zelzate, Belgium). Conveying and kneading zones are varied in this machine. The length-to-diameter ratio is 25.

A Kaiser RamanRxn2® Hybrid in situ analyzer (Kaiser Optical Systems, Ann Arbor, USA) coupled with PhAT (Pharmaceutical Area Testing) probe was utilized in reflection mode to acquire the spectra of the homogenized powder and tablets. The focal length was 25 cm while spot size was 6 mm. A diode laser source of wavelength of 785 nm and 400 mW was applied. Spectra were collected in the range of 200-1890 cm-1 with a resolution of 4 cm-1.

NIR spectra have been collected by a Bruker Optics MPAâ„¢ FT-NIR (Bruker OPTIK GmbH, Ettlingen, Germany) spectrophotometer. The instrument was run in reflection with the aid of a REFLECTOFLEX SS316L probe. The spectral range was between 4000 and 12500 cm-1. The resolution was 32 cm-1 while the spectrophotometer was averaging 32 scans. The reflected beams arrived to a Te-InGaAs detector.

A process camera (Spark SP-5000M-GE2, JAI A/S, Tokyo, Japan) was applied for the in-line measurements. It was attached to the twin-screw equipment with a custom-made stainless steel mount along with a polished steel chute for the particles. The inclination of the metal chute allows the granules to flow freely, allowing random orientation of the particles to be captured.


Technological development of continuous wet granulation

The starting materials possess weak flowability. Based on our results, granules with excellent flow properties could be obtained on the twin-screw granulator even with low, 3% of PVPK30. Tablets prepared from the granules had good hardness and disintegration time and appropriate friability. The model API (CAR) was pumped to the machine with the PVPK30 in ethanolic solution through a liquid addition port. Two different kinds of pumps were applied: a peristaltic pump and an infusion pump. Due to the pulsation of the peristaltic pump, CAR was not perfectly homogenized in the granules and in tablets based on our HPLC measurements (relative standard deviation was ~8%). This problem could be mitigated by the application of an infusion pump lowering the RSD of API content to ~2% (on a longer term, an HPLC pump could be used in a continuous manner).

PAT developments for monitoring the API content during continuous wet granulation

During this research, the challenge was that the model API was used in an extremely low dose (<0.05%), therefore spectroscopic determination of its content is impossible with limits of detection of today’s spectrophotometers. However, CAR was added to the system along with PVP which has a much higher concentration in the product (3-6%). Our idea was to measure the content of PVP and validate with HPLC measurements that the content of CAR can be estimated based on that. Both NIR and Raman spectroscopies were employed. In this case, the latter was found to be more precise. Naturally, a feedback control strategy could be developed on a long term based on these spectroscopic measurements.

Particle size control based on image analysis

A process camera was used for the in-line determination of particle size in this study. Firstly, the ability of it to determine the particle size was certified by comparing it to a microscope with certain particles. A software was developed in-house for the image analysis. With this system, the particle size enhancement with increasing liquid-to-solid ration could be monitored. With a P controller, it was possible to modify the liquid addition rate after disturbances in order to return to the set point of particle size. In the future, an even more advanced PI controller is planned to be developed.

Continuous melt granulation

Twin-screw melt granulation is a very promising process since it alloys effective bulk density and flowability enhancement (like wet granulation) with being solvent-free providing the possibility to omit drying (like roller compaction). Therefore, melt granulation fits perfectly into continuous manufacturing lines. Our goal was to prepare a directly compressible powder by melt granulation. This was successfully carried out since tablets could be compressed without the addition of any further excipient, the frictional forces did not increase (PEG acted as a lubricant). The process was monitored by thermal and process camera to observe the temperature and the particle size enhancement. This can be a base for controlling the process.

Melt granulation seems very suitable for the downstream processing of amorphous solid dispersions (ASDs). Spray drying and electrospinning as ASD manufacturing technologies usually result in a powder with low bulk density and weak flowability. Melt granulation can be the perfect way to enhance these properties via a solvent-free process. The temperature is the most critical process parameter as it must be elevated above the melting point of the granulating polymer but under the glass transition temperature of the ASD. According to our results, the selection of the granulating agent is of great importance. The amorphous Soluplus® gave better results in terms of dissolution of the subsequently obtained tablets.


Twin-screw granulations are certainly very promising techniques. Development of such processes can open up new ways for downstream processing. The monitoring and controlling of these processes via in-line techniques are of great importance since these are needed to ensure appropriate quality of the obtained product. The presented work showed promising results about monitoring and controlling critical quality attributes such as content uniformity and particle size and certainly can be of industrial interest.


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