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As new analytical technologies advance, insight into the twin-screw granulation process is growing.
The range of applications for twin-screw extruders as pharmaceutical manufacturing equipment—either as a stand-alone, continuous unit operation or integrated into a continuous manufacturing line—is growing. Hot-melt extrusion (HME), which involves melting and mixing polymeric excipients with APIs in a twin-screw extruder to produce an amorphous solid dispersion, is used commercially in multiple applications, including drug-loaded devices or as a solvent-free alternative to spray drying. Twin-screw granulation (TSG) uses a twin-screw extruder to make granules using dry granulation, wet granulation followed by drying either continuously or in a separate fluid-bed batch process, or melt granulation using a highly viscous binder.TSG was used in early powder-to-tablet continuous manufacturing lines, and commercial use continues to grow. Although direct compression can be used for some formulas in continuous manufacturing lines, TSG is important for others where direct compression isn’t suitable.
“In recent years, TSG processes have been advancing rapidly, particularly towards continuous manufacturing processes becoming standard in the pharmaceutical industry because of the potential benefits TSG offers,” says Hemlata Patil, senior manager for hot melt extrusion technology at Catalent. “Consequently, a thorough understanding of the impact of formulation and process variables on granule quality has become crucial.”
Researchers continue to create new process analytical technology (PAT) for TSG that provides process insight and helps advance the science needed for product and process development using quality by design (QbD). QbD techniques will be especially helpful because the modular design of twin-screw extruders widens the range of possible variables.
“TSG and HME technologies provide a lot of promise for formulations, such as controlled release or poorly soluble drugs,” says Doug Hausner, senior manager of business development for continuous manufacturing at Thermo Fisher Scientific. “There is a large knowledge base in twin-screw granulation, but there is also a large design space. There are many options for screw configuration in the equipment, along with other input variables such as liquid-to-solid ratio. Process design requires know-how as well as statistical analysis for optimization.”
This knowledge is important for both individual and integrated operations. Hausner adds that while Thermo does not currently use TSG or HME in its integrated continuous process for final dosage forms, the continuous manufacturing team provides expertise in feeding and PAT for individual TSG and HME operations. “A multi-step continuous process will require a good stand-alone development activity on the TSG or HME step,” Hausner says.
Patil points out that Catalent can use TSG to create granules with various profiles, such as immediate release, sustained release, delayed release, and taste masking. Twin-screw dry granulation (TSDG) is effective for moisture-sensitive materials and useful for APIs that are not suitable for roller compaction, such as molecules that require higher shear for mixing and agglomeration, she adds. “In addition, TSDG has a unique application for APIs with needle-shaped crystal habit, which have low flow rate and bulk density. These poor physical and mechanical properties make them difficult to process via conventional methods such as roller compaction and slugging. The kneading action of the twin-screw extruder enhances consolidation of powders with needle-shaped API, resulting in better flow and compressibility. For high drug-loading products, this process yields superior granule quality and bulk density.”
TSG is beneficial for both high- and low-dose APIs. “In low-dose products, it is feasible to increase the uniformity by forming granules and preventing demixing,” explains Robin Meier, scientific director at equipment maker L.B. Bohle. In high-dose APIs, TSG offers the ability to improve compressibility. Meier says that a stable and compressible granule can be formed with minimal amounts of binder, in the range of 5%. He reports that compressible granules could be produced with all APIs tested so far on the company’s equipment, once a suitable binder was identified, depending on API solubility, particle size distribution, and partition coefficient.
To build the knowledge base regarding the behavior of materials in twin-screw extrusion equipment, Leistritz Extrusion Technology formed a consortium in 2019 of pharma companies, the University of Texas at Austin, and McMaster University.
“Equipment variables include the ratio of the outer diameter of the screw to the inner diameter, the length-to-diameter ratio, and the screw design,” says Stephen Post, product manager for Life Sciences at Leistritz. “We’re working on gaining more knowledge of the fundamental behaviors of materials and equipment, and we’re looking for trends in material behavior that can be extrapolated to similar formulations.”
For example, consortium researchers have investigated how screw design affects particle size distribution (PSD). Researchers are also performing scale-up experiments to replicate the PSD obtained from an 18-mm diameter screw on a 27-mm diameter screw. Although some drug manufacturers may choose to scale-out by using multiple 18-mm extruders, there are advantages to using a larger extruder to scale-up, such as lower facility footprint and lower utilities cost, explains Post. Better scale-up data are needed, he says.
“We are also developing material-sparing methodologies to assess the feasibility of TSG using various screening tools without running the twin-screw extruder” says Feng Zhang, associate professor in the College of Pharmacy at the University of Texas. “One of the key challenges in TSG is the process-induced chemical degradation and physicochemical transformation during processing.We have developed an in-depth understanding of how these undesired changes can be inhibited via rational selection of formulation composition and process design.”
PAT is being used in TSG processes to measure critical parameters in real-time. Moisture content and PSD, for example, are critical quality attributes (CQAs) of the intermediate product that affect CQAs of the final product.
Near-infrared (NIR) PAT has been evaluated to replace time-consuming loss-on-drying measurements to quantify moisture content in granules, says Patil. “NIR analysis allows for the adjustment of process parameters in real-time, resulting in significantly less material waste and improved process optimization within a shorter timeframe, even during the same extrusion run,” she says.
For PSD, direct imaging is well established, but other PAT types are also being investigated.
“The discrete nature of moving particles makes it harder to understand what’s going on in the machine, because standard monitoring techniques like pressure and temperature monitoring are unreliable as indicators of deviating product specifications,” says Michael Thompson, associate dean and professor of Chemical Engineering at McMaster University, whose research group has studied twin-screw granulation for more than a decade. He adds that while batch granulation often produces a Gaussian PSD, twin-screw granulation typically has a bimodal PSD, which makes real-time analysis even more important. Thompson’s lab has developed an inline particle size analysis PAT using acoustic emissions (AE). The researchers created a digital signal filter to ensure that particles of any size would be represented (1). Next, they created a filter that would also account for inelastic forces by training an artificial intelligence model with an elastoplastic (Walton-Braun) contact force model and a dataset of acoustic emission spectra collected from a broad range of granulated pharmaceutical formulations. The prediction error was as low as 2%, demonstrating its applicability to monitoring particle size distributions in continuous twin-screw granulation (2).“I see the existing optical [imaging] methods and this acoustic method as complementary approaches to particle size analysis,” concludes Thompson. “Both have their strengths and weaknesses in a dusty production environment like the exit chute of a twin-screw granulator.”
In a continuous granulation and drying set-up, such as L.B. Bohle’s QbCon 1, Meier indicates it is most meaningful to measure the residual moisture after the drying process (rather than after granulation) to be able to control and feedback the dryer process parameters. “In this case, we usually apply NIR or microwave resonance measurements. The latter allows univariate calibration,” he says. In the granulation step, Meier explains that solid feeding rate and liquid feeding rate are the crucial parameters used to control mean granule size. He suggests that controlling these rates is more reliable than a method that measures in-line PSD and adjusts liquid addition. Meier reports that the QbCon 1 equipment, as part of a complete continuous manufacturing line, was recently delivered to a large German pharma company for clinical supply of new entities. This line is designed for small-scale throughputs up to 4 kg/h and is capable of handling APIs in occupational exposure band 5.
Researchers at Rutgers University are using a twin-screw extruder as a hot-melt coater and granulator in a unique, patent-pending solution to the ongoing challenge of manufacturing drug products with high doses of poorly soluble APIs. “Poorly soluble drugs are poorly soluble because they dissolve less, but this also is often because they are hydrophobic; they are difficult to wet and so they dissolve more slowly,” says Fernando Muzzio, distinguished professor of Chemical and Biochemical Engineering at Rutgers University. “We solved this problem by using a twin- screw extruder to coat the drug substance particles with a surfactant, which improves solubility. The particles are mixed with a low-melting point surfactant and fed into a twin-screw extruder operating at a temperature low enough to avoid decomposing the API but high enough to partially melt the surfactant and allow it to coat the API particles. The resulting granules flow and compress well, allowing us to make a high-dose (approximately 80% API), immediate release tablet.”
Muzzio says that this twin-screw granulation process is potentially less expensive to operate than more complex processes for high-dose, poorly soluble APIs, such as HME, nanomilling, or spray drying. The innovation is a result of understanding what happens to materials when their surface is modified, combined with an understanding of the twin-screw granulation process that allows accurate control of mechanical and thermal variables, says Muzzio.
Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.