Considering Twin-Screw Extruders for Continuous Mixing and Granulation

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Equipment and Processing Report

A twin-screw extruder can be used as a continuous wet granulator or as a continuous mixer for a wet gelatin mass.

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 (i.e., via hot-melt extrusion), are also emerging as equipment for continuous wet granulation, as well as for continuous mixing of wet gelatin mass for soft-gel capsules. 

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.

A twin-screw extruder has a modular design, and different types of screw elements can be arranged on the screw shaft to optimize mixing and to allow ingredients to be added to the machine at multiple locations (i.e., part-way through mixing). 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 (or glass transition temperature) of the polymeric excipient, while granulation takes place at lower temperatures, below the excipients’ melting point or glass transition temperature. 

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 duringsteady-state processing, and can be used in process control, notes Leister. 

Continuous gel-mass mixing 

Twin-screw extruders can also be used for continuous processing of gel mass used in casings for soft-gel capsules. In April 2018, Leistritz introduced a twin-screw extrusion (TSE) system to continuously mix and condition gel-mass formulations. The system, which uses a ZSE-LS model twin screw extruder, replaces batch mixing for gel-mass R&D and production processes, and the continuous process is inherently more consistent and repeatable, says the company. Continuous, real-time monitoring of the TSE process parameters ensures product quality.

“The short residence time inherent with the TSE process section helps avoid degradation of the gel-mass,” explained Leistritz (3). “It is estimated that the residence time in the TSE process section is less than two to three minutes. … Raw ingredients (gelatin, starches, water, plasticizer, and other additives, such as colorants and flavors) are sequentially metered into the extruder process section where they are heated, hydrated, mixed, and pumped to an intermediate filling station.  The intermediate filling station refills two spreader boxes to form thin webs on chilled rolls, which are integrated with die rollers and liquid injection apparatus to produce soft-gel capsules.”  

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, Chllenges, and the Future of Twin-Screw Granulation for Manufacturing Oral Tablets and Capsules,” AAPS News Magazine, March 2018.

3.    Leistritz, “Leistritz Introduces a Continuous Twin Screw Extrusion System That Replaces Batch Mixing for Gel Mass R&D and Production,” Press Release, April 16, 2018.