Category: Formulation and Quality
Purpose: The identification of new treatment options as well as the development of personalized medication are increasingly important and promising research topics in the pharmaceutical field. Innovative solutions aiming at a strong therapy adherence such as patient specific tablets with an individualized dosing regimen or polypills containing several active pharmaceutical ingredients in one single tablet are challenging to realize with conventional pharmaceutical manufacturing techniques. Hence, innovative alternatives, such as 3D printing, are being studied extensively . Fused deposition modeling (FDM) in particular has recently moved into focus as a promising 3D printing technique. This method allows for the fabrication of oral solid dosage forms with high accuracy, flexible shapes and drug release profiles tailorable to individual needs. The shift from bulk production of drug products towards personalized medication and dose tailoring approaches requires a deep understanding of critical process parameters and the identification of suitable materials approved for pharmaceutical applications. The purpose of this study was to evaluate the suitability and application potential of EUDRAGIT® RL as an exemplary poly(meth)acrylate polymer for processing via FDM. The combination with various tablet design principles was investigated as platform for tailoring drug release profiles.
Methods: Pharmaceutical filaments for FDM were produced based on a mixture of EUDRAGIT® RL PO (87.5% w/w) (Evonik Nutrition & Care GmbH, Darmstadt, Germany) and triethyl citrate (7.5% w/w) (Merck KGaA, Darmstadt, Germany). Diprophylline (5.0% w/w) was used as a model drug (NBS Biologicals, Cambridgeshire, UK). A twin-screw extrusion process was chosen to manufacture the filaments (Three Tec extruder ZE 9; Three-Tec GmbH, Seon, Switzerland). The melt extrusion process temperature was kept below 130°C to minimize thermal stress on API and polymer. Optical appearance and surface characteristics of the filaments were determined utilizing an Olympus SZH-ILLD-200 microscope (Olympus Optical Co. Ltd., Tokio, Japan). To study the inner structure of the filament, the samples were cut manually .
For the 3D printing process, the Anycubic i3 Mega FDM printer with bowden tube drive was applied (Shenzhen Anycubic Technology Co., Ltd, Guangdong, China). The nozzle diameter was 0.6 mm and its temperature was kept at 130°C. The bed temperature on the build plate was set at 60°C. The infill was varied between 15 and 75% and the printing speed was kept constant at 20 mm/s (Figure 1). Dissolution experiments were carried out using USP apparatus II (Dissolution Tester DT, ERWEKA GmbH, Langen, Germany) in 0.1N HCl and phosphate buffer pH 6.8.
Results: Polymeric filaments containing Diprophylline could be produced successfully. The microscopic analysis confirmed the uniform cylindrical structure and a smooth surface, two important criteria that indicate good conveying properties in the subsequent FDM process (Figure 2). The filaments were successfully 3D printed to cylindrical tablets. The selected bed temperature allowed for a proper adhesion of the tablet on the build plate. All printed tablets had the same identical geometric dimensions of 10.0 mm x 3.0 mm. The printing process could be performed at a high resolution. The tablet weight was determined by the infill level respectively (15%: 143.1 mg; 45%: 170.2 mg; 75%: 187.7 mg). The dissolution test revealed a sustained release profile over up to 12 h (Figure 3). Furthermore, the release kinetics varied based on the infill level applied.
Conclusion: The FDM 3D printing technology offers new opportunities for the development of versatile pharmaceutical dosage forms. Pharmaceutical functional excipients with adequate physical properties are required for this technique to enable personalized medication, the design of individual dosage forms and the creation of tailored release profiles. Poly(meth)acrylate polymers, such as EUDRAGIT® polymers are in general well-known for their excellent performance in pharmaceutical standard bulk processes like hot melt extrusion and coatings. Beyond that, they display a promising platform for the application in FDM processes. The functional polymer EUDRAGIT® RL was successfully applied with varying infill levels to achieve modifiable sustained release profiles, that are challenging to provide with standard bulk processes. This study successfully demonstrates promising insights into the potential of combining functional polymers with dosage form design principles to tailor release profiles that can be adapted to patients’ specific needs in the future.
 Douroumis, D., 3D Printing of Pharmaceutical and Medical Applications: A New Era, Pharm Res (2019)
 Kempin, W. et al., Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants, Eur. J. Pharm. Biopharm. (2017)
Melanie Liefke– Senior Scientist Drug Delivery, Evonik Nutrition & Care GmbH, Darmstadt, Hessen, Germany
Jessica Huppertz– Scientist Drug Delivery, Evonik Nutrition & Care GmbH, Darmstadt, Hessen, Germany
Peter Niepoth– Head of Applied Technologies Laboratory, Evonik Nutrition & Care GmbH, Darmstadt, Hessen, Germany