Continuous 3D printing of medicines via a directly coupled twin-screw hot-melt extrusion printing system

Abstract

3D printing drug formulations for personalized medicine is a growing research field and offers many opportunities to improve patient therapy. Downsides of pharmaceutical 3D printing include increased manufacturing costs, lower throughput, potentially high production temperatures, or a lack of suitable excipients. This is especially true for fused deposition modeling, a melt-based technology that involves two heating steps: hot-melt extrusion of the intermediate feedstock material and the actual printing process. This study presents a solution to this issue, the integrated HME3D system consisting of a twin-screw extruder directly coupled with a 3D printing system. This allows the creation of solid dosage forms directly from the extrusion process. The print head is connected to the extruder and enables printing on a conveyor-belt. Four materials, two polymers and two lipid excipients, were processed, printed, and evaluated for mass consistency. To one polymer and one lipid, ritonavir was added to assess content uniformity. Additionally, a solid lipid-based formulation (sLBF) was printed with the HME3D system and compared to 3D printed sLBFs from two semisolid extrusion (SSE) systems. Mass and content uniformity were best for the HME3D system, and the dissolution profiles of the sLBF printed via the HME3D system show smaller fluctuation within the first 8 h of release compared to the SSE printed samples. This study successfully demonstrates the capabilities of a directly coupled twin-screw extrusion-3D printing system and expands the excipient space to previously unprintable materials, such as conventional solid lipids.

Introduction

The field of personalized medicine is growing as the understanding of interindividual differences in drug metabolism (pharmacogenomics), the impact of environmental conditions, or simply age are improving continuously. This has led to an increasing need for individualized medicines over the recent years (Drăgănescu et al., 2019; Sun and Soh, 2015; Hsiao et al., 2018; Trenfield et al., 2018). Additive manufacturing (AM), also known as 3D-printing, is a manufacturing method where individual objects of different shapes, sizes, and densities are built up layer-by-layer. It is a promising technique to realize the requirements of personalized medicine (Trenfield et al., 2018; Chen et al., 2020; Zhang et al., 2018). While several manufacturing methods exist for AM, fused deposition modeling (FDM) is frequently investigated method for pharmaceutical use (Quodbach et al., 2021; Abdul Aleem Mohammed et al., 2021; Vithani et al., 2018; Auel et al., 2025). In FDM, flexible filaments of thermoplastic polymers are heated until the material is melted. Subsequently, the melt is extruded through the printing nozzle to form the desired object (Vithani et al., 2018). Many authors showed that FDM printing is not only a suitable technique to produce pharmaceutical dosage forms, but also to influence drug release kinetics (Goyanes et al., 2014). Jamróz et al. produced aripiprazole-loaded orodispersible films, where the dissolution rate was increased due to a larger surface area and drug amorphization (Jamróz et al., 2017). Windolf et al. accurately predicted different release kinetics via the dosage form surface-area-to-volume ratio and developed a method to enable dose-independent release kinetics (Windolf et al., 2021; Windolf et al., 2022). Researchers also developed dosage forms containing multiple APIs (Maroni et al., 2017; Gioumouxouzis et al., 2018), which may increase patient adherence due to a reduced pill burden.

On the other hand, the application of FDM printing has several challenges (Jonathan Goole, 2016; Goyanes et al., 2015; Narkevich et al., 2018; Johanna Aho et al., 2019). High process temperatures during filament manufacturing and printing can result in drug degradation (Hoffmann et al., 2022; Hoffmann et al., 2023). On the other hand, polymers with lower extrusion temperatures are frequently not usable for FDM as the filaments are too brittle or too flexible for printing. Lipids, which have lower melting points than most polymers, could be one part of overcoming the problem of thermal degradation of the API. They could also be used to increase bioavailability as lipid-based formulations (LBFs). Unfortunately, conventional solid lipids are too brittle after extrusion, which is why they are also not suitable for FDM printing. One exception are synthetic lipids, as they were used by Abdelhamid et al. They used polyglycerol esters of fatty acids (PGFAs) to produce solid lipid-based formulations via FDM printing (Abdelhamid et al., 2023; Abdelhamid et al., 2022). However, the formulations only contained a small amount of API (3.2 %) and required high amounts of plasticizer (polyglycerol monoesters and polyglycerine) to enable 3D printing. In addition to that, the use of FDM printing suffers from low printing speeds and increased costs. Continuous printing processes, envisioned for a long time, as the coupling of 3D printing and twin-screw extrusion may overcome some of the disadvantages listed above. The benefit of coupling extrusion to FDM printing was already suggested by many authors and first demonstrated by Zheng et al. (Zheng et al., 2021), who developed the first directly coupled 3D-printing hot-melt extrusion device.

In this study, we introduce the HME3D system, which combines a twin-screw extruder with a temperature-controlled printing nozzle, and a continuous conveyor belt, which is mounted to a two-axis system as print bed. The printing nozzle contains three different heating zones to control the temperature with 0.1 °C accuracy. The HME3D system combines the benefits of 3D printing and twin-screw extrusion in one manufacturing process, without the challenging step of filament development. We demonstrate that it can create individual dosage forms as part of a continuous manufacturing process, which may increase the production rate and reduce the costs of 3D printing, which is still a main problem for most 3D printing techniques (Jonathan Goole, 2016; Ayyoubi et al., 2025). Besides the reduction of the thermal load, which is important for many drugs (Goyanes et al., 2015; Narkevich et al., 2018; Johanna Aho et al., 2019), those systems can provide access to a broader range of excipients. This includes materials that are not processable into printable filament for FDM, such as most lipids (Korte and Quodbach, 2018), which are rarely found in 3D printing. This can be mostly explained by specific issues with these formulations, e.g., reproducibility and appearance (Vithani et al., 2018). In our study, we successfully printed four different materials, two polymers and two lipids. This is the first time lipids were printed using a directly coupled extrusion-3D printing process. In addition, the printing system was used to print a ritonavir-loaded solid LBF (sLBF), to show the suitability of melt-printing for sLBFs. The printed sLBF was also compared to the same formulation printed by semisolid extrusion (SSE) to investigate the advantages of coupled 3D printing over regular 3D printing processes.

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Materials

Witepsol® E85 and Imwitor® 491 were kindly provided by IOI Oleo (Hamburg, Germany). Gelucire® 48/16 was provided from Gattefossé (Saint-Priest, France). Kollidon® VA64, Soluplus® and Amaranth 85 E123 were kindly donated by BASF (Ludwigshafen, Germany) and Shinetsu. Polyglykol 3350S was obtained from Clariant (Duisburg, Germany). Ritonavir (> 99 %) was purchased from Shanghai Desano Pharmaceuticals (Shanghai, China). Methanol HiPerSolv Chromanorm (> 99 %) and Chloroform HiPerSolv Chromanorm (> 99 %), hydrochloric acid 1 M AVS Tritonorm were purchased from VWR Chemicals. FaSSIF/FeSSIF/FaSSGF powder were purchased from biorelevant.com (London, UK). For all experiments, Micropure UV water from a direct water purification system (Thermo Electron LED, Langenselbold, Germany) was used. Abbreviations of the used excipients are shown in Table 1.

Arne Blume, Stefan Klinken-Uth, Jannis Niesbach, Paul Klauke, Ines Haase, Renz van Ee, Jörg Breitkreutz, Fabian Loose, Tilmann Spitz, Julian Quodbach, Continuous 3D printing of medicines via a directly coupled twin-screw hot-melt extrusion printing system, European Journal of Pharmaceutical Sciences, Volume 221, 2026, 107521, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2026.107521.

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