(M1030-08-45) Novel 3D Printed Modular Tablets containing Multiple Anti-viral Drugs: High Precision Drop-on-Demand Drug Deposition

Purpose: Binder jetting (BJ) is one of the most widely used 3D printing techniques. Various studies have employed BJ to print drug-loaded tablets[1]–[8]. However, most BJ printers are designed for mass production, which is unsuitable for small-scale dose tailoring for individualized drug delivery. This study designed a novel precise dosing approach on BJ printed muscular concentric cylinder tablets with three compartments (outer shell, mid-layer, core). The high-precision dispersing solution is based on an electro-magnetic deposition platform where a piezoelectric valve was equipped to trigger the printing process. In this case, each module of 3D printed tablets could load with different drug solutions and be assembled after the solutions dried. Moreover, the dose could be tailored by changing the printing area, the number of layers, cycle time, infill density, and nozzle travel speed with ultra-precision control over smaller doses. Therefore, a tablet is produced with a personalized formulation and precise dose. There are four primary aims for this investigation: 1) design and print the modulated tablets via BJ; 2) comprehensively understand the high-precision deposition process by printing on printed tablets; 3) investigate the printing process parameters; 4) design and print with high-precision on the surface of the modulated tablets.

Methods: The solid and concentric cylindrical tablets were printed using BJ technology to load individual drugs in different compartments. The effect of printing parameters, such as pressure, valve open time, cycle time, and shape on printability was investigated to optimize the printing condition. 100 mg/ml Hydroxychloroquine sulfate (HCS)- water solution, 12 mg/ml favipiravir- (FVP-) and 8 mg/ml ritonavir- (RTN-) ethanol solution were marked with red, violet and blue dyes for visualization, respectively. The red HCS solution was applied to the core using a designed g-code file (6 mm x 6 mm x 0.5 mm, cylinder). The violet favipiravir was applied on the middle layer (10 mm x10 mm x 0.5 mm – 6 mm x 6 mm x 0.5 mm hollow cylinder). Moreover, the blue ritonavir was applied on the out layer (14 mm x 14 mm x 0.5 mm -10 mm x10 mm x 0.5 mm hollow cylinder). Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and polarized light microscope (PLM) were used for solid-State characterizations of raw materials. Optical microscopy, scanning electron microscope (SEM) images, and energy-dispersive X-ray (EDX) spectroscopy was applied to examine tablet morphology. In addition, in vitro dissolution studies were performed to assess the drug release profiles of the model drugs.

Results: It was shown that printing pressure was the critical variable that affected the printing quality, among other parameters. The solid-state characterization, including DSC, XRD, and PLM, revealed that all the materials are crystalline. The printing speed and infill density significantly affected the dispersing volume. Additionally, the valve open time and cycle time affected both dispersing volume and the uniformity of the tablets. SEM and EDX indicated that the drugs were successfully dispersed on the tablet surface and changed the morphology. 4.4 mg HCS was loaded on a 144 mg core tablet (3.05 % drug loading), 0.76 mg FVP and 1.1 mg RTN were loaded on a 229 mg middle layer (0.33 % drug loading) and a 340 mg out layer (0.32 % drug loading). For a four-hour in vitro drug release assay, the drug in the outer layer was released over 90%, and the drug incorporated in the middle layer was released over 70%. In contrast, the drug encapsulated in the core was only released about 40%, indicating that the outer and middle layer was suitable for burst release while the core has the potential to be applied for the delayed release.

Conclusion: In this study, modulated tablets were 3D-printed using BJ technology. A high-precision deposition technique has been proved to disperse (water/ethanol-based) drug solution precisely on the surface of the blank cylinder tablets and the modulated tablet compartments. The dose of tablets was determined by the solubility of each drug and the dispersion volume of the printing. Pressure is the crucial variable that affected the printing quality (10 kPa was recommended). In addition, the printing speed and infill density could change the dispersing volume essentially. Furthermore, the open time and cycle time could affect the dispersing volume and the uniformity of the tablets. According to the dissolution data, the drug loaded in the outer layer would be released over 90% after 4 hours, whereas the drug in the core could only be released about 40%. So, the outer and middle layer could be suitable for fast release and the core could be applied for slow release. Overall, this study demonstrated outstanding potential for the development of personalized drug delivery systems by combining different 3D printing techniques where ultra-precision dosing is necessary, such as for high potent drugs or biologics.

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Acknowledgements:This study was supported by CoM3DLtd., under an existing Master Sponsored Research Agreement with the University of Texas at Austin.


Figure 1. A. Schematic illustration of electro-magnetic deposition (EMD) printing on tablets. The EMD printhead can print precisely by controlling valve open time and cycle time with a piezoelectric valve. B. Schematic illustration of EMD printing results when the cycle time is increased with open time at the same ratio. C. Images of tests 11 and 16-22 taken by optical microscopy. T11 and T18-22 showed the actual results when increasing open time and cycle time.


Figure 2. A1. Images of drug-loaded tablet compartments and assembled tablets taken by optical microscope: out layer: blue ritonavir; middle layer: violet favipiravir; core: red HCS. A2.assembled blank tablets versus drug-loaded tablets.
B. Polarized light microscopy (PLM) images of calcium sulfate hemihydrate (CSH), hydroxychloroquine sulfate (HCS), favipiravir (FVP) and ritonavir (RTN) powder.
C. Scanning electron microscope (SEM) images of the blank (CSH) and drug-loaded tablets.


Figure 3. The drug release profile of modulated tablets (n=3). During the dissolution study, it was observed that the tablets deformed after 90 mins and the color faded after 240 mins. Ritonavir, dispersed in the outer layer, has the highest drug released ratio, followed by favipiravir and hydroxychloroquine sulfate (HCS).