Considering Twin-Screw Granulation

October 2, 2018
Jennifer Markarian

Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-10-02-2018, Volume 42, Issue 10
Page Number: 40–42

A twin-screw extruder can be used as a continuous wet granulator.

Twin-screw extruders, which have found commercial use in making amorphous solid-dispersions for improving drug solubility and in loading drugs into polymers that can be shaped into drug-delivery devices, are also emerging as equipment for continuous wet granulation. The same machine can be used for wet granulation as for hot-melt extrusion, but the hot-melt extrusion process requires external barrel heating to raise the temperature above the melting point (Tm) or glass transition temperature (Tg) of the polymeric excipient, while granulation takes place at lower temperatures, below the excipients’ Tor Tg

Twin-screw granulation

The ongoing development and commercialization of continuous manufacturing for oral solid-dosage (OSD) pharmaceuticals is creating a growing opportunity for continuous granulation processes, and twin-screw granulation (TSG) is already being used in commercial continuous manufacturing. Some continuous systems, such as GEA’s ConsiGma and Glatt’s MODCON, for example, use TSG. Twin-screw extruders are available in models designed for pharma processing from manufacturers including Coperion, CW Brabender, Leistritz, Steer, Thermo Fisher Scientific, and others. 

The primary benefit of TSG is that the extruders are intended for continuous manufacturing, notes Dirk Leister, technical marketing manager, process and pharma extruders for Thermo Fisher Scientific. “Extruders are time-based production-the same equipment can be used for different amounts of material. One can potentially use the same extruder for R&D as for production, by simply running longer. Or, the process can be scaled up to a larger extruder for higher throughput.” Thermo Fisher’s Pharma 11 (11-mm diameter) and Pharma 16 (16-mm diameter) twin-screw extruders are designed for both R&D and production. These extruders can be set up for both granulation and hot-melt extrusion, using conversion kits for the necessary hardware modification. Thermo Fisher recently introduced the Thermo Scientific Pharma 24 TSG, a 24-mm diameter twin-screw extruder dedicated for twin-screw granulation with a throughput rate of up to 70 kg/h. The extruder can be either integrated into a continuous production line or used as a standalone instrument for project development or small-scale production using either wet or dry granulation (1). The extruder has a 40:1 ratio of length to diameter that offers flexible adaptation for processing length, screw setup, and introduction of ingredients into the process. Minimal downtime is needed for cleaning, and online monitoring facilitates detection and segregation of out-of-specification product.

In addition to flexibility of scale, continuous processes offer the potential for improved process control compared to batch processes and for on-line, real-time monitoring. The twin-screw extruder is considered a small-volume continuous mixer, and it creates a more uniform mixing history for more homogeneous distribution of drug, excipient, and binder (2).

“Consistency is a big advantage,” notes Michael Thompson, professor in the department of Chemical Engineering at McMaster University in Ontario, Canada. “TSG can reduce lot-to-lot variation of the granulated product and reduces reliance on a specific seasoned operator in order to get the correct product quality by knowing when to stop the batch mixer.” TSG may need less binder or less water to produce equivalent granules to batch systems, which could reduce production cost. 

How the primary variables in the TSG process affect product properties is relatively well understood at this point, although each formulation would need to be optimized. “Just about any formulation based on known pharmaceutical ingredients can be made into granules so long as the formulator has a working knowledge of the different techniques to ‘wet out’ the powders,” says Thompson. “I would always recommend to a company to study the binder-to-powder needs in each new formulation as if starting from scratch, but the initial machine setup and operating conditions can be treated as relatively generic.” Scaling up from a small laboratory machine to larger production equipment poses more challenges, however. “One can’t truly know a process until it has run for several hours, with the machine heated up by mechanical rotation and the feeders having gone through several fill cycles to fully learn the bulk density of the process’s ingredients,” cautions Thompson. “A product made from a 20-minute lab trial doesn’t necessarily translate to a continuously operated production process.”  



Process analytical technology (PAT) is a crucial part of understanding and controlling a continuous process, and in-line measurements are used in advanced process control strategies and in quality-by-design studies. Innopharma Technology’s Eyecon2, for example, is a direct optical imaging system that captures images of the granule particles and analyzes them in real-time. “In continuous processing, the particle analyzer can be used to monitor particle size after a twin-screw, a continuous drier, or a mill,” says Chris O’Callaghan, senior product manager at Innopharma.

In a continuous system, data are needed for both feed-forward and feed-back control to maintain key parameters and attributes as close to an ideal setpoint as possible, despite some variation in the inputs and outputs of each process stage. “While feed-back control is critical in ensuring that deviations do not continue to grow unchecked, feed-forward control can enable compensation of upstream variations in subsequent processing steps to ensure that variations introduced in early stages can be partially or fully corrected in the final output material,” explains O’Callaghan.

“By measuring particles after granulation, deviations in the measured size can be used to alter parameters of the twin-screw (e.g., liquid addition and screw speed) to correct for the variation in particle size, while the speed of a downstream milling step may be temporarily increased or decreased to more finely or coarsely mill the granulate currently entering, thereby maintaining a more consistent output particle size.”

More work is needed to further develop different types of PAT for TSG, says Thompson. In the McMaster University laboratory, researchers are looking at ultrasonic acoustic sensors to see what information about properties exiting the twin-screw granulator, such as granule size and moisture content, can be measured. Eventually, the researchers hope to also identify technology that can monitor incoming powders, which can also have a significant effect on end properties. For example, the size of a binder particle is known to affect granule size in hot-melt granulation, but a supplier of binder material might not measure or report binder particle size or changes in grinding because they wouldn’t affect chemical properties, notes Thompson. It would be difficult to track a problem with off-spec granules back to the feed materials, and a formulator might mistakenly assume something inside the extruder had gone wrong. 

Sensors that are already built into extruders can also be used as PAT signals. The torque of the extruder drive motor, for example, should stay constant during steady-state processing, and can be used in process control, notes Leister. 

Handling poorly flowing material

TSG has been found to be a useful unit operation for high drug load formulations that inherently have poor flow properties. These formulations would not be suitable for traditional dry granulation, explained Steve Pafiakis, senior research scientist at Bristol-Myers Squibb, in a presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (3). Pafiakis is researching TSG for his doctoral thesis at the New Jersey Institute of Technology in close collaboration with the Polymer Processing Institute (PPI). For the formulations Pafiakis is studying, challenges include high drug loading, low bulk density, and cohesive blends that result in extremely poor flowing input material. These material properties have beenshown to affect the manufacturability of the TSG process by causing build-up inside the extruder. To mitigate these effects, several screw configurations were evaluated to investigate whether the formulation could be successfully processed over an extended period of time, which is a requirement for any continuous manufacturing process. An initial screw design imposed high shear and lead to barrel fouling, but a less shear-intensive screw configuration, along with barrel cooling near the kneading zones was found to be acceptable. Pafiakis explained that understanding the fundamental mechanism for TSG-that frictional energy dissipation (FED) is the driver for granule growth in the extruder and the heat generated is from the relentless rubbing of particles in the compacted state in the kneading section-was important. This set-up controlled the heat generated by FED and led to the desired granule attributes.

Learning from other industries

The food and polymer industries successfully transitioned from batch to continuous processing using twin-screw extruders fifty years ago, and use of TSG is expected to continue to evolve in the pharma industry, say experts (2). 


1. Thermo Scientific, “New Twin-screw Granulator Helps Maximize Throughput in Continuous Drug Manufacturing,” Press Release, June 25, 2018.

2. N. Kittikunakorn, et al., “Processes, Challenges, and the Future of Twin-Screw Granulation for Manufacturing Oral Tablets and Capsules,” AAPS News Magazine, March 2018. 

3.  S. Pafiakis, “Twin Screw Granulation: A Case Study for Enabling an Adaptive Study Plan,” presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (Clinton, NJ, 2018). 

Article Details

Pharmaceutical Technology
Vol. 42, No. 10
Pages: 40–42


When referring to this article, please cite it as J. Markarian, "Considering Twin-Screw Granulation," Pharmaceutical Technology 42 (10) 2018.

About the Author

Jennifer Markarian is manufacturing editor for Pharmaceutical Technology.

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