(M0930-01-07) Three-Dimensional Extrusion Based Bioprinting of Metronidazole Immediate Release Tablets; Impact of Processing Parameters on In Vitro Evaluation

Purpose: The current study was designed to investigate the suitability and applicability of a 3-Dimensional extrusion-based bioprinter in developing the 3D-printed tablet as a single-step process. Metronidazole was used as a model drug, Soluplus® was used as a matrix forming polymer and Eudragit^® EPO as a taste-masking polymer for formulating taste-masked tablets. Processing parameters were optimized for the nozzle's printing speed, a printhead's heating temperature, and pressure. Single step direct powder-based extrusion 3D printing method helps overcome limitations associated with FDM 3D printing¹. This technique eliminates the additional processing steps involved with FDM 3D printing. Also, it allows the use of polymers having low glass transition temperatures. Thus, it does not require prior preparation of filaments with Hot melt extrusion. Moreover, post-processing steps could be eliminated by creating mechanically robust tablets. Extrusion-based 3D printing thus facilitates the installation of desktop 3D printers in medical facilities and pharmacies for the decentralized production of personalized dosage forms². Overall, 3-Dimensional extrusion-based printing provides the combined effect of hot-melt extrusion and fused deposition modeling techniques in a single-step process and needs to be explored further to establish an attractive alternative method to fused deposition modeling 3D printing technique.

Methods: The BIO X™ bioprinter (CELLINK AB, Gothenburg, SE 41346, Sweden) was used in this study to print the metronidazole tablets (Figure 1). Different formulations were made, as given in Table 1. The oval shape of the tablet was designed using Autodesk Tinkercad software (Tinkercad, Autodesk Inc, CA, USA) and exported as a stereolithography file (.stl). The dimensions of the tablet were 22mm*10mm*5.92mm. The tablet was printed with a nozzle diameter of 0.4mm. Further processing parameters were optimized. The heating temperature was set to 140< ![if !msEquation] >< ![if !vml] >< ![endif] >< ![endif] >. A rectilinear pattern was chosen as a printing pattern for the tablet. Printhead speed was set to 6mm/s with a pressure of 250 kPa. 3D-printed tablets were characterized by Differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and Scanning electron microscopy (SEM). The in vitro release study was carried out using a USP dissolution apparatus I in 900 mL 0.1 N HCl, with the temperature maintained at 37 ± 0.5℃ and a basket rotation speed set at 100 rpm. Further, the lead formulation was evaluated for taste masking ability in 900 ml artificial salivary media pH 6.8.

Results: Taste-masked tablets of 500 mg weight containing 100 mg of metronidazole dose were successfully formulated with a 3-dimension extrusion-based bioprinter. Three formulations with different percent compositions of Eudragit and Soluplus were evaluated for drug release. The lead formulation showed the desired immediate drug release profile in gastric pH per USP specifications. Tablet shape and infill density influenced the release profile of the tablet to acquire more than 85% drug release within 60 minutes, as shown in Figure 2. Taste masking was achieved with Eudragit® EPO as the tablet showed less drug release than metronidazole's tasting threshold after 1 min in simulated artificial saliva.

Conclusion: In conclusion, The BIO X™ bioprinter technique was successfully demonstrated the feasibility of single-step 3D printing to prepare the tablets. It also overcomes the need for pre formulated filaments associated with hot melt extrusion and fused deposition modeling 3D printing.

References: 1. Goyanes, A., Allahham, N., Trenfield, S.J., Stoyanov, E., Gaisford, S., Basit, A.W., 2019. Direct powder extrusion 3D printing: Fabrication of drug products using a novel single-step process. International Journal of Pharmaceutics 567, 118471. https://doi.org/10.1016/j.ijpharm.2019.118471
2. Fanous, M., Gold, S., Muller, S., Hirsch, S., Ogorka, J., Imanidis, G., 2020. Simplification of fused deposition modeling 3D-printing paradigm: Feasibility of 1-step direct powder printing for immediate release dosage form production. International Journal of Pharmaceutics 578, 119124. https://doi.org/10.1016/j.ijpharm.2020.119124

Formulation Compositions

Bio Printer

Dissolution Profiles of the study