Key factors influencing twin-screw extrusion scale-up in pharmaceutical manufacturing

Scaling a twin-screw extrusion process is generally thought of as a proportional adjustment that involves increasing screw diameter, increasing feed rate, and maintaining temperature. Although these modifications are important, they are insufficient to ensure process equivalence.

Extrusion scaling depends on maintaining comparable mechanical, thermal, and residence-time histories at a larger scale than during development; it does not scale by geometric enlargement alone. Mechanical energy input determines shear exposure, while shear affects melting and distributive mixing.

Residence-time distribution influences the duration of material exposure to thermal and mechanical stress. Thermal balance governs whether such exposure promotes controlled transformation or results in degradation. Variations in these conditions can alter the final product’s material history and critical quality attributes.

Image Credit: Thermo Fisher Scientific – Production Process & Analytics

Geometric similarity enables physical equivalence

Twin-screw extrusion is dictated by both geometry and parameter settings. The relationships between outer screw diameter (D₀), inner diameter (D_i), barrel length (L), and screw configuration determine the transport and mixing regime within the barrel.

To maintain comparable physics across scales, geometric relationships must be preserved across instruments, from small to large scales:

• Consistent L/D ratio
• Consistent D₀/Di ratio
• Comparable free volume per unit length
• Equivalent screw configuration philosophy

The internal shear field, fill behavior, and transport mechanisms are defined by these relationships. When preserved, material undergoes comparable shear rates, distributive mixing, and residence patterns. Changes in these relationships result in different transport and mixing conditions, even when screw speed and feed rate are scaled proportionally.

Volumetric scale-up strategies assume that geometric similarity across instruments maintains filling levels and shear conditions.¹ Differences in geometry can therefore reduce the predictive value of scaling relationships. This principle is supported by processing literature.

Mixing efficiency and material transport are integral to screw configuration and barrel geometry.² Although geometric similarity cannot guarantee successful scale-up, it does help establish the foundation for achieving predictable scale-up.

Surface-to-volume constraints and thermal balance

An increase in extruder diameter causes volume to scale proportionally to the cube of the diameter (D³), whereas surface area scales only in relation to the square of the diameter (D²). As a result, the relative heat-transfer surface available per unit material decreases with larger scale.³ Larger systems dissipate heat less efficiently relative to throughput, and viscous dissipation becomes a more substantial contributor to melt temperature.

Regression-based scale research across 11 mm, 16 mm, and 24 mm systems shows that feed rate adjustment by itself does not maintain material experience at larger diameters.³

Preserving comparable specific mechanical energy consumption requires adjustments to screw speed as diameter increases. The operating window expands with scale, but its position and boundaries shift.

Development procedures that rely substantially on external heat extraction introduce thermal conditions that may be difficult to reproduce at larger diameters. More scalable operation requires mechanical energy input and stable fill behavior to establish thermal equilibrium. Processes that approximate adiabatic behavior during development facilitate more predictable translation across scales.¹

Steady state as a prerequisite for transfer

Increasing diameter cannot correct instability observed at the laboratory scale. When feed rates are especially low, specific feed load (SFL) may fall below representative fill levels. This can result in a reduced residence time distribution, the development of plug-flow tendencies, and material transport dominated by feed displacement rather than controlled mixing.¹

While these conditions may seem stable, they do not reflect the regime required at a larger scale. Research analyzing volumetric scale-up under low-throughput conditions demonstrates that residence-time equivalence diminishes when fill level is insufficient.¹ Regimes governed by plug-flow tendencies at the development scale can result in mismatched specific mechanical energy behavior and altered axial mixing during transfer.

For this reason, processes that appear stable at smaller laboratory scales pose a greater risk during transfer. Predictable scale-up requires stable steady-state operation at representative fill levels.

What scaling actually changes

Figure 1. These operating windows were derived from experimental runs across 11 mm, 16 mm, and 24 mm extruders. Image Credit: Thermo Fisher Scientific – Production Process & Analytics

The shape and position of each window illustrate a critical constraint: increasing diameter decreases heat-transfer efficiency relative to material volume. To maintain material experience, screw speed must be modified alongside feed rate.

Consequently, development teams must first verify energy input and residence behavior at the next scale before laboratory-scale conditions can be translated proportionally. Rather than being a simple translation, scale-up is an adjustment that requires recalibration within physical constraints.

References and further reading

1. Jeroen Van Renterghem, et al. (2019). Assessment of volumetric scale-up law for processing of a sustained release formulation on co-rotating hot-melt extruders. International journal of pharmaceutics, 569, pp.118587–118587. DOI:10.1016/j.ijpharm.2019.118587. https://www.sciencedirect.com/science/article/abs/pii/S0378517319306325
2. Paulsen, K., Leister, D. and Gryczke, A. (2018) Investigating process parameter mechanism for successful scale-up of a hot-melt extrusion process. Application Note LR71. Karlsruhe: Thermo Fisher Scientific. Available at: https://documents.thermofisher.com/TFS-Assets/CAD/Application-Notes/LR71-e-Investigating-Process-Parameter-Mechanism.pdf.
3. Jakob, B. and Geilen, T. (2012) Relevant process parameters for twin-screw compounding. Application Note LR70. Karlsruhe: Thermo Fisher Scientific. Available at: https://documents.thermofisher.com/TFS-Assets/MSD/Application-Notes/LR70-relevant-process-parameters-twin-screw-compounding.pdf.
4. Wesholowski, J., et al. (2019). Scale-up of pharmaceutical hot-melt-extrusion: Process optimization and transfer. European Journal of Pharmaceutics and Biopharmaceutics, 142, pp.396–404. DOI:10.1016/j.ejpb.2019.07.009. https://www.sciencedirect.com/science/article/abs/pii/S0939641119300475?via%3Dihub

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