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Improved characterization of twin-screw extrusion enables increasing use in pharmaceutical manufacturing.
Twin-screw extrusion, a continuous mixing process, is gaining acceptance for producing solid-dosage drugs as developers deepen their understanding of how the process can be applied in pharmaceutical manufacturing. One commercial use today employs the well-established extrusion of plastic parts (e.g., fiber, tubing, or rods) and blends in a drug to produce a combination drug–device product. Another application, often called hot-melt extrusion (HME), uses a twin-screw extruder to combine excipients with APIs to improve bioavailability or for controlled release or taste masking. In addition, an emerging use of the twin-screw extruder is as a continuous granulator, which is an alternative to a batch granulator for agglomerating and homogenizing particles to improve powder-compaction properties for tablet pressing. Over the past decade, much has been learned about optimizing equipment set up and processing conditions for these applications, and research continues to develop further understanding and promote use.
Although twin-screw extruders have been used in the plastics industry for decades and are well understood, using the equipment for granulation is relatively new. However, "a broad scientific community is investigating the specific requirements of pharmaceutical applications and their implementation with twin-screw granulation. So the level of understanding is growing quite rapidly," notes Dirk Leister, technical marketing leader, material characterization products, Thermo Fisher Scientific. A powerful aspect of the twin-screw extruder is its modular design; screw segments can be combined in various shapes and orders on the screw shaft to make a unique design that has a significant effect on product quality. The segments include conveying elements for moving material; mixing elements for shearing, mixing, or dispersing; and distributive flow elements for distribution of small quantities of additives or shear-sensitive APIs, explained Leister in a webinar (1). Although most research to date has been based on specific formulations, "There is already momentum around gaining a more universal understanding of how conveying, mixing, and distribution screw elements are influencing the granule formation and quality," noted Leister in an interview with Pharmaceutical Technology.
Some general screw designs have been determined for granulation. For example, mixing zones in granulation tend to be shorter and less intense compared to those used in HME, and a compaction section at the end of the screw (close to the discharge) should be avoided, says Leister. In addition to screw design, important parameters that affect the level of fines and porosity in granulation include feed rate, liquid/solid ratio, and screw speed. Barrel set-up and total length of the barrel, which is the reaction chamber of the granulator, also have an impact on the process, says Leister.
An advantage of a twin-screw granulator is that it is easy to control, and parameters can be changed without stopping the process, which aids performing a designed experiment to define a process window. "Parameters like overall torque, temperature along the barrel, screw speed, and feed-rate can be monitored and adjusted quickly and precisely, and the twin-screw granulator will return to steady-state quickly," says Leister.
"Industry and academia are aggressively tackling issues related to commercialization of this process," added Michael Thompson, professor in the Chemical Engineering Department at McMaster University in Canada, in a presentation at the Leistritz Pharmaceutical Extrusion Seminar (2). Researchers have come a long way in characterizing the mechanisms occurring inside the extruder. "Screw design is the single most important factor in affecting the granulation process," said Thompson, who showed how placement and pitch of kneading blocks and conveying elements, as well as wetting methods, affect the granules. Twin-screw granulation has matured so that it can be used effectively to eliminate downstream milling, but researchers have not been able to eliminate downstream drying, concluded Thompson.
A benefit of twin-screw granulation that is driving its use is its flexibility, comments Leister. As a continuous, time-based (rather than volume-based) process, twin-screw granulation can process small or large volumes of material as needed. Although existing batch granulation equipment for validated processes and products is not likely to see wide-scale replacement at this point with twin-screw granulation, manufacturers are considering the continuous process for new products, concludes Leister, "We expect a significant growth in commercial twin-screw granulator projects within the next 3-5 years."
Evaluating screw design for hot-melt extrusion
Hot-melt extrusion uses the same basic extruder equipment as twin-screw granulation but with a different screw setup. Several presenters at the Leistritz Pharmaceutical Extrusion Seminar described the influence of screw design (i.e., the type and placement of different screw segments on the shaft) on the mixing process and the properties of the end product.
Researchers at the University of Maryland (UMD), led by David Bigio, associate professor in the Mechanical Engineering Department, have developed a new tool to further evaluate the effect of twin-screw extruder design on product properties. Although many models use residence time distribution (RTD) as a way to characterize the effect of mixing, the group's experiments show that RTD does not directly correlate to the stress the material experiences. They have developed an approach to create a residence stress distribution (RSD) as a function of operating conditions. The approach employs polymeric beads that rupture at a specific stress. The percent break-up of beads quantifies the amount of material that experiences that stress and has been shown to be a function of screw speed and specific throughput. Masters student Ben Dryer presented his work in developing an equation for percent break-up and relating it to the final product properties of degradation, bioavailability, and residual moisture.
"A single, three-dimensional equation that better predicts material behavior in the extruder could be powerful for computer modeling and improved understanding of twin-screw extrusion for pharma as well as other applications," concluded Bigio in an interview with Pharmaceutical Technology.
Researchers from Merck; the Research Center for Pharmaceutical Engineering in Graz, Austria; and simulation software company ANSYS presented work to model a HME process using one- and three-dimensional commercial modeling software (4). Improvements in such models enable software to be used to evaluate screw design and process conditions in silico to reduce laboratory experiments.
Barriers to use of HME have been limited laboratory-scale equipment capability and the fact that not all APIs- depending on physicochemical properties such as melting point and organic solubility-are suited to HME. As a result, most early formulation work has been performed with spray drying, said Jim DiNunzio, head of the HME Technology Development Team at Merck, in a presentation (5). Recent modeling work and an improved process understanding are being used, however, to identify optimal processing conditions and move formulations developed in spray drying to HME. "We are now able to link characteristics assessed at small-scale to interactions in the melt state influenced by processing parameters, which facilitates using HME earlier in the development process. Eventually we hope to use HME earlier in development by utilizing small-scale predictive technologies supplemented with modeling and simulation to extrapolate at-scale performance," explained DiNunzio in an interview with Pharmaceutical Technology.
1. D. Leister, "A Modular Approach to Continuous Granulation," webinar (June 24, 2015).
2. M. Thompson, "Progress in Continuous Granulation by Twin Screw Extrusion," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
3. B. Dryer, et al. "Pharmaceutical Application of the Residence Stress Distribution," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
4. D. Johnson, et al., "Hot Melt Extrusion Modeling," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).
5. J. DiNunzio, "Formulation and Process Design of Melt Extruded Dispersions," presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, June 18, 2015).