(M1430-09-59) Electrophotographic 3D Printing of Pharmaceutical Films

Purpose: Laser sintering (LS), also referred to as powder bed fusion – laser beam (PBFLB), offers the production of pharmaceuticals directly from a powder mixture with high geometrical flexibility and adjustable release profiles via three-dimensional printing (3DP). Due to limitations of conventional powder application methods, neither the material composition nor distribution can be tailored within a printed layer. To overcome these restrictions, electrophotographic powder application (EPA), a novel method for selective powder application in combination with powder bed fusion – laser beam of polymers (EPA-PBF-LB/P), was utilized in this study for the first time. Powder blends consisting of Eudragit L 100-55, and different concentrations of acetaminophen, nicotinamide, and caffeine, respectively, were prepared and successfully deposited by EPA.

Methods: Powder characterisation - All drugs and polymer investigated were characterised based on their particle size distribution and electrostatic surface potential to compare their adherence to the printing platform and charge storage potential. Scanning electron microscopy was used to visualise the powder particle shape and identify any surface defects or craters that would influence charging during printing. Powder application process - EPA uses the principle of electrostatic attraction and repelling forces to selectively attract powder particles, also called powder development, or to deposit powder particles. An aluminium plate coated with a photoconductive layer (photoconductive plate) (PCP) was used to transfer the developed powder layers to the build chamber. Powder charging was performed using the gas discharge-based method. The experimental setup included a piezo for increasing the powder deposition efficiency by piezoelectric excitation. For fusing the layers, an optical setup consisting of a CO₂-laser providing a maximum output power of 60 W (Synrad ti60, Novanta Photonics, Seattle, WA, USA) was utilized. Drug content determination - The powder blends and 3D printed samples were analysed on an Agilent 1200 high performance liquid chromatography (HPLC) system equipped with a Phenomenex Gemini NX-C18 110 Å column (250 mm Å~ 4.6 mm, 5 μm) (Phenomenex Inc. Torrance, CA, USA). Mobile phase A consisted of 0.1 % v/v formic acid in water and mobile phase B of 0.1 % v/v formic acid in ACN. The column was operated at 25 °C with the following gradient (min/%B): -5.0/0, 0.0/0, 15.0/90, 18.0/90, flow rate: 2.0 mL/min, injection volume: 10 μl. All samples were dissolved in water:ACN 50:50 (v/v) + 0.1 % formic acid and filtered (0.45 μm) (VWR International GmbH, Darmstadt, Germany) before measurement.

Results: Pure Eudragit L 100-55 consists of spherical particles, with no surface defects such as craters or holes (Figure 1). This decreases the probability for ions, which serve as charge carriers for the powder charging, to be stored on the particle surface. Therefore, the microstructural differences between the polymer and three investigated drugs suggest the particle charging during powder application to vary. Since the powder transfer behaviour of EPA strongly depends on the respective particle charging, an electrostatic separation between polymer and the drugs may occur. The cylindrical single-drug film has a diameter of 23.01 ± 0.02 mm and a thickness of 0.98 ± 0.01 mm, and the cuboidal film has a thickness of 0.98 ± 0.01 mm and an edge length of 25.01 ± 0.01 mm (Figure 2). A predominant electrostatic transfer of acetaminophen is taking place due to its small particle size. Hence, the drug loading of the films increases compared to the drug loading of the powder. The multi-drug film in Figure 3 has a diameter of 46.07 ± 0.09 mm and a thickness of 1.04 ± 0.03 mm. The individual drug contents of the regions of the multi-drug part correspond well to the drug loadings of the respective powder blends. However, in the middle region, a higher caffeine than nicotinamide loading is present, which can be explained by the higher actual drug loading of caffeine in the powder blend compared to nicotinamide. Some contamination of the right region with caffeine is measured, which can be explained by the fact that each caffeine loaded powder portion adhering to the PCP had to pass across the right region of the 3D printed film during EPA-PBF-LB to reach the left region. The printed single- and multi-drug films did not show any evidence of degradation such as colour change of the initially white powders. Additionally, no evidence of degradation could be found by the HPLC analysis of the films.

Conclusion: In the present study, EPA-PBF-LB/P was applied for generating pharmaceutical parts loaded with three different model drugs. Thin layers up to 5 times thinner than in the case of conventional doctor blade- or roller-based powder application methods could be successfully deposited into the build chamber. This allowed a CO₂ laser to be employed for generating pharmaceutical test samples with no evidence of thermal degradation. Finally, a multi-drug film was successfully printed via EPA-PBF-LB, opening the possibility of EPA to selectively as well as precisely apply different powders within one layer into the build chamber.

Figure 1. SEM images of a) pure Eudragit L 100-55 particles; SEM images of b) acetaminophen, c) nicotinamide and d) caffeine, taken from the respective drug particles after mixing 15 wt% of the drug with 85 wt% of Eudragit L 100-55.

Figure 2. a) measured drug loading by HPLC of a powder blend consisting of Eudragit L 100-55 and a theoretical drug loading of 15 wt% acetaminophen; b) drug loading measured by HPLC of the deposited powder layer; c) image of two generated pharmaceutical films and the corresponding drug loading of the cuboidal film.

Figure 3. Position dependant measured drug loading by HPLC of multi-drug 3D printed film.