(T1030-09-49) Analyzing the Characteristics of HME Extruded Material in Pharmaceutical 3D Printing: Formulation, Printability, and Dissolution Study

Purpose: Three-dimensional (3D) printing has provided additional options to the pharmaceutical industry for formulating innovative drug products using non-traditional manufacturing methods. Because the 3D printing process needs an elevated temperature and the filaments need to pass through the narrow nozzle tips, suitable thermal and mechanical properties of formulation blend, such as flexibility, brittleness, melt viscosity, and printability, are required for successful printing. This study examines the suitability of various synthetic polymers for pharmaceutical 3D printing. The thermal and mechanical properties of various polymers for successful 3D printing are evaluated and assessed for their ability to successfully manufacture the tablet dosage form with desired drug-release characteristics.

Methods: Theophylline, caffeine, and pharma-grade polymers were obtained from BASF. Various excipient blends were processed through the Thermo Scientific PHARMA 11 hot melt extruder to form the flexible filament. The filaments were then subjected to MakerBot Method X for 3D printing (Fused deposition modelling, FDM 3D printing). The process temperature was summarized in Table 1. The printed API-containing tablet (F3) was characterized for dissolution using deionized water (DI) using USP dissolution apparatus 2, 50 rpm at 37°C.

Results: Water soluble polyethylene glycol (PEG)-polyvinyl alcohol (PVA) graft copolymer (polymer KIR; Kollicoat^® IR, BASF) is specially developed for instant release film coating of tablets and capsules. It can also be used as binder for the granulation process and as a hot melt extrusion (HME) aid in combination with other excipients. The polymer formed solid dispersions with APIs using HME and the extruded filaments exhibited flexibility (Figure 1A). The filament could be fed directly into the gear chamber in the 3D printer directly and printed as round tablets at 200^oC using the default settings in MakerBot Print (USA). The printed tablet is clear and can be fully dissolved in DI water within 1h. Another a water-soluble polymer consisting of 55-65% PVA-PEG graft copolymer, 35-45% PVA and 0.1-0.3% silicon dioxide as a processing aid (polymer KP;  Kollicoat^® Protect) was used as a matrixing polymer for drug delivery. After hot melt extrusion, the extruded filament of polymer 2 showed good flexibility and optimum mechanical strength (Figure 1B). Hence, it can be directly employed in FDM 3D printing to create diverse types of dosage forms and shapes, such as hearts or kidneys, based on their therapeutic purpose (Figure 1 A and 1B). For stable amorphous solid disperse (ASD) system, innovative polymers with high glass temperature (Tg) were evaluated. Among them, two polymers: polymer SPLUS (polyvinyl caprolactam (PVCL)-polyvinyl acetate (PVAc)-polyethylene glycol (PEG) graft copolymer (Soluplus^®; Tg ~70 ºC) and polymer KVA64 (Kollidon^® VA 64; Tg ~ 104 ºC, a copolymer vinylpyrrolidone (VP)-vinyl acetate (VC) in a ratio of 6:4 by mass) were utilized in the 3D printing. However, pure polymer filaments were challenging to print with a regular FDM 3D printer because they are very brittle after extrusion, causing failure in the feeding process. To improve the flexibility and mechanical strength of the filaments, a screening process was conducted by adding water-soluble plasticizer like PEG 3350 and/or water insoluble polymer with a low glass transition temperature material such as coprocessed povidone and polyvinyl acetate polymer (polymer KSR; Kollidon^® SR, Tg 39 ºC). The resulted properties of filaments for FDM 3D printing were categorized into four grades: brittle, optimum, soft, and very soft. The brittle grade exhibited good strength but lacked flexibility, while the soft and very soft grades were flexible but lacked strength. The optimum grade demonstrated the desired balance of flexibility and strength properties for 3D printing (Figure 2).  The optimum polymer 3 and plasticizer blend were further screened by adding two kinds of drugs: theophylline and caffeine, and the optimized composition, HME process, and 3D printer setting were summarized (Table 1), the results of which showed enhanced flexibility and good strength (Figure 1C-1E). Finally, dissolution performance of printed ASD tablets containing theophylline (formulation F3) was carried out, demonstrating a controlled-release profile of drug up to 3h (data not shown).

Conclusion: The utilization of water-soluble, water-insoluble with release-modifying properties, and drug solubilizing/ stabilizing polymers enables the 3D printing of various dosage forms. However, the flexibility and strength of the polymer can be adjusted by optimizing the hot melt extrusion process using different combinations of polymer weight ratios, plasticizers, and active pharmaceutical ingredients (APIs). This research highlights the potential of 3D printing in the pharmaceutical industry for personalized medicine and controlled drug release. Further exploration of the applications of existing excipients on the market is necessary to identify the most suitable polymers or formulations. Advanced technologies like data mining and machine learning can be employed to predict printable excipients or formulas with desired thermodynamic, mechanical, and release profile characteristics.

Figure 1. Images of HME filaments and 3D printed tablets.

Figure 2. Printability optimization for A) polymer SPLUS; B) polymer KVA64; and C) polymer KSR.

Table 1. Hot melt extrusion and FDM 3D printing conditions for the successful formulations.