Scale-up Challenges in Hot-Melt Extrusion

Hot-melt extrusion (HME) using twin-screw extruders (TSEs) is increasingly being used to make solid dispersions of drugs in a polymer matrix. The process is useful for poorly soluble drugs and for alternative dosage forms such as controlled-release drug devices. Small, benchtop TSEs are available for formulation development, but these are typically not appropriate for process development. Mid-size TSEs, however, can be used for process development and scale-up.

Benchtop TSEs

In the past, laboratories had only small-scale batch mixers for formulation development, but during the past few years, several extruder manufacturers have introduced laboratory-scale TSEs suitable for API quantities as small as 5–20 g, thus enabling pharmaceutical manufacturers to test new drug candidates on a TSE.

A TSE has shorter residence time and exposes the material to lower thermal stress than a small-scale batch mixer, notes Andrew Loxley, director of new technologies at Particle Sciences, a company providing drug-development services. Particle Sciences uses either a small-scale, batch mixer or a benchtop, laboratory-scale TSE (MiniLab, Thermo Scientific), as shown in Figure 1, to prepare proof-of-concept materials and identifyearly-lead formulations before running process experiments on a 12-mm or 18-mm mid-size extruder at rates from 1–15 kg/h. While benchtop extruders are useful as a screening tool, they do not scale up to larger-volume extruders because equipment-design attributes are fundamentally different.

Mid-size TSEs

Mid-size extruders in the range of 12–20 mm in diameter that have similar design attributes to larger extruders can be used for process development in preparation for scale-up to pilot-size or small commercial-size TSE in the range of 26–32 mm and perhaps eventually to larger commercial-size TSE in the range of 40–70 mm. Extruder manufacturers, such as Coperion, C.W. Brabender, Leistritz, Steer America, and Thermo Scientific, offer extruders for the pharmaceutical industry in the mid-size range that can be used for process development and clinical-scale trials as well as small-scale commercial runs. In some cases, drug manufacturers may even choose to use these mid-size extruders for commercial production.

Throughputs on Coperion's 18-mm ZSK, for example, range from 500 g/h to 4 kg/h, with a minimum batch size of 1 kg (see Figure 2). CDMO Bend Research uses an 18-mm extruder that runs up to 3 kg/h and has run batch sizes as small as 300 g. Bend Research has scaled up from an 18-mm extruder to throughputs as high as 10 kg/h on its 27-mm extruder, and from a 27-mm to a 50-mm extruder, all of which have similar equipment attributes. Brabender's 12-mm TSE runs batches in the 25–100 g range for product and process development, up to 1.5 kg maximum. The 12-mm scales up to Brabender's 20-mm TSE, which can be used for further process development.

Mid-size extruders are useful for determining the "extrudability" of a formulation and identifying the extrusion conditions needed for good mixing, says Stefan Gebhardt, head of extrusion systems for pharma and food at Coperion. Parameters can include the extruder's screw design, temperature profile, shear rate, and throughput.

The processing window for pharmaceutical excipients is narrow, and in some cases, a few degrees in temperature change can have a dramatic affect on material viscosity, says Gebhardt. In addition, excipients and APIs may be sensitive to degradation from heat or shear.

Determining the appropriate temperature profile in a TSE, therefore, is an important parameter in running process experiments. In the processing laboratory, researchers may want to run multiple temperature profiles in a short period of time and without shutting down the extruder to minimize the amount of experimental material needed. To enable this approach, Coperion recently developed an improved temperature-control system using cartridge heaters and a water-cooling system that allows its mid-size extruder to reach stable temperature conditions more quickly.

Processing laboratories also have a need to be able to quickly clean the screw or change the screw profiles of an extruder between experiments. Several mid-size extruders have a clamshell barrel design in which the barrel cover opens on a hinge to allow easy access for cleaning and screw changes.