Hot-melt extrusion (HME) using twin-screw extruders (TSE) 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. Bench-top TSE can be used to develop formulations, and mid-size TSE can be used for process development and scale-up.
While in the past, laboratories had only small-scale batch mixers for formulation development, during the last few years, several extruder manufacturers have introduced laboratory bench-top TSE suitable for API quantities as small as 5–20 g, which enables pharmaceutical manufacturers to test new drug candidates using the HME process. A TSE has shorter residence time and exposes the material to lower thermal exposure than a batch mixer, notes Andrew Loxley, PhD, director of new technologies at Particle Sciences, a contract organization providing drug-development services. Particle Sciences uses either small-scale batch mixer or a TSE (Thermo Scientific MiniLab) to prepare proof-of-concept materials and identify early-lead formulations before running process experiments on its 18 mm mid-size extruder. While bench-top 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 extruders in the range of 12–18 mm in diameter 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. 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. CDMO Bend Research uses an 18-mm extruder that runs up to 3 kg/h and has used batch sizes as small as 300 g. Bend Research has scaled up from its 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.
To scale up well, the basic geometry of the smaller extruder should match that of the larger extruder. The ratio of the outer diameter (OD) to the inner diameter (ID) of the screw is a key parameter. The Coperion 18-mm extruder, for example, has the same OD/ID ratio of 1.55 that is found on the larger Coperion extruders. The screw elements of a TSE (i.e.: feeding, conveying, melting, mixing, venting, and pumping) are modular and can be easily changed to optimize the screw profile. Although the same screw profiles and an appropriately scaled length to diameter (L/D) of the process section can be used during scale-up, adjustments are often needed, notes Richard Steiner, sales engineer for pharma and food at Coperion. The surface area to volume ratio is reduced as the size of the extruder increases, which can affect temperature convection and influence mixing characteristics, so that more mixing sections may be needed, says Robert Roden, technology manager at Steer America. Matt Shaffer, senior research engineer at Bend Research, adds that mass- or heat-transfer limitations can arise at larger scales. He says these limitations can affect dispersion and throughput and must be compensated for by changing the process section length, adjusting screw design, or changing screw speeds. Software tools can be used as a first approach to calculate probable scale-up conditions. Skilled operators, however, are key. Steiner concludes, “You still need experienced people who understand the machines to run the physical tests on the line and adjust as needed.”