Scale-up Challenges in Hot-Melt Extrusion - Pharmaceutical Technology

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Scale-up Challenges in Hot-Melt Extrusion
Critical issues that should be considered when scaling up a hot-melt extrusion process.


Pharmaceutical Technology
Volume 36, Issue 4, pp. 88-92

Scale-up considerations

Scale-up in a continuous process from a mid-size to a larger size TSE is actually much more predictable than scale-up of batch mixing, says Gebhardt. Extrusion mixing is more repeatable than batch mixing because the shorter mass transfer inherent with the design of a TSE allows materials to be intimatelymixed, adds Charlie Martin, president of Leistritz.

"In a TSE, the processor must manage residence time distribution using screw design, screw speed (rpm), and degree of screw fill," explains Martin. Matt Shaffer, senior research engineer at Bend Research, adds that to successfully scale up to a larger TSE, the processor should understand how the boundary conditions and process parameters at the smaller scale relate to the quality attributes of the product.


Figure 3: The outer diameter (OD) to inner diameter (ID) of the screw is a key parameter. (FIGURES 3 AND 4 COURTESY OF LEISTRITZ)
In general, 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, as shown in Figure 3, 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.


Figure 4: A set of intermeshing twin screws shows various screw elements.
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 (see Figure 4). In scale-up, the screw profile of the larger extruder should be similar to that of the smaller extruder. A similar profile is only a starting point, however, because adjustments are often needed, notes Gebhardt. Shaffer adds that mass- or heat-transfer limitations can arise at larger scales, therby affecting dispersion and uniformity. "These competing limits can result in lower throughput increases than would be expected theoretically, and require the use of longer process sections, alternative screw designs, or lower screw speeds, which can in turn alter the residence time distribution of the material within the extruder," he explains.

In addition, the tip speed of the rotating screw flights increases as the screw diameter increases, thereby raising the peak shear to which the material is exposed. Processors should aim to maintain peak shear rates, especially because pharmaceutical ingredients are often temperature-sensitive, says Martin.

The effects of high peak shear can be reduced with tight tolerances that improve the self-wiping characteristics of a TSE and with specialized mixing element design, adds Robert Roden, technology manager at Steer America.

Design-of-experiment approaches and process models are useful for defining the process space. Software tools can be used as a first approach to calculate probable scale-up conditions. Current software is limited, however, because it requires raw-material data, which can be difficult to calculate for a mixture of components that changes as it changes from a solid to a non-Newtonian fluid, says Gebhardt.

He notes that more robust software tools are being developed. Equipment and software improvements, however, can only go so far. Skilled operators remain essential to successful scale-up. "You still need experienced people who understand the machines to run the physical tests on the line and adjust as needed," emphasizes Gebhardt.

Upstream processes, especially how materials are fed into the extruder, should also be considered during scale-up. In split feeding, the polymeric excipient and the API are fed separately into the extruder, but in a premix the two are combined in a dry blend and fed to the extruder in one stream.

Commercial extrusion uses either split-fed or premixed feeds, depending on the application. Split-feeding must be used when feeding different physical forms, such as an excipient in pellet form and an API in powdered form. Premixing performs a percentage of the mixing, but in a split-fed system the extruder does 100% of the mixing, which may lead to decreased rates or less mixing, says Martin.

On the other hand, a split feed in which the API is added part way down the extruder, after the excipient is at least partly melted, is useful for limiting the exposure of sensitive APIs to heat and shear.

Laboratories may use a premix feed because small volumes require specialized feeding equipment to meter accurately. Matching the feeding method of the smaller-scale to that of the larger-scale, however, can be a factor in scaling up the process because the feeding method significantly affects mixing. Dosing equipment suppliers, such as K-Tron and Schenck, offer feeders that that are accurate even at low flow rates for use with mid-size extruders.

Downstream processes, including cooling and pelletizing, are sometimes neglected in development timelines, but should be considered as part of scale-up because these aspects can lead to a bottleneck in the overall process.

Considering upstream and downstream operations as well as an extruder's processing parameters are key to successfully scaling up from a mid-size to larger-size extruder.

Jennifer Markarian is the acting manufacturing editor at Pharmaceutical Technology, 485 Route One South, Building F, First Floor, Iselin, NJ 08830 tel. 732.346.3087,
.

Have an equipment or processing troubleshooting concern? Email it to
and we may address the problem in a future column.


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