(M1430-03-18) Optimizing Semi-Solid Extrusion 3D Printed Hydrochlorothiazide Tablets: The Role of Rheological Properties and Drying Methods on Structure and Appearance

Purpose: Three-dimensional printing (3DP) has revolutionized manufacturing, allowing objects to be built layer by layer from a digital file. This technology is especially transformative in the pharmaceutical industry, further enabling personalized medicine. Semisolid extrusion (SSE) is a 3DP method that uses syringe-based printheads to extrude gels or pastes, simplifying material preparation and allowing for diverse excipient use. This technique supports multi-drug incorporation. Pre-filled, disposable syringes also prevent cross-contamination, making SSE suitable for decentralized settings like hospitals and community pharmacies.[1] Rheological measurements are critical to SSE 3DP, because rheological properties dictate the material's extrudability through the nozzle and its structural integrity post-extrusion. For instance, materials with low viscosity are easily extruded but may lack the structural stability needed to prevent collapse of the final object. Conversely, materials with high viscosity might not flow adequately through the nozzle without the application of high mechanical force or heating, especially if their viscosity is temperature sensitive. These adjustments are crucial for managing the printability and quality of the final product; for example, to avoid variability in print weight and consistency. Hydrochlorothiazide (HCT) came into the market in 1957 for hypertension treatment. However, the dosage-related adverse effects of HCT, such as hypokalemia, hyponatremia, hyperglycemia, and hyperuricemia, highlight the need for precise dosing. In our research, HCT was utilized as the model drug. The goal of this study was to use rheological data, collected using a rheometer, to assist in the optimization of the printing parameters. Using these data, we optimized printing parameters to improve tablet quality and consistency.

Methods: FABRX M3DIMAKER2 (FabRx Ltd., London, UK) with the SSE print head was used to print the HCT tablets. The formulation contained alpha-D-Lactose monohydrate, sodium carboxymethyl cellulose (CMC-Na), and polyvinylpyrrolidone K90 (PVP k90). The HCT was mixed at 0%, 20%, 30%, and 40% (w/w) drug loading. The powder was mixed with deionized water at a ratio of 3:8 (water:powder) to prepare the different pastes for rheology testing or printing[2]. Rheological properties of paste samples were determined via the use of rheometer (TA instruments, DE) with 40-mm diameter plate with cone angles of 1°; the gap between the two plates was set at 25μm. Rheology of static and temperature sweep (25℃~80℃) of pastes were measured. Ambient-air drying, vacuum drying, and lyophilization were used to dry the printed tablets. Scanning electron microscope (SEM) was used to study the surface and internal structure of the tablets.

Results: To optimize 3DP quality and tablet appearance, we analyzed the key rheological parameters-yield stress, viscosity, and thixotropy[3]-of pastes with different HCT loadings. Pastes with higher water content are easier to extrude due to lower viscosity but are prone to collapse before drying, require longer drying times, and make controlling the final product's appearance more challenging due to shrinkage and creep. To minimize water content, the viscosity of pastes was reduced by increasing the temperature during printing. A fixed water ratio (wpowder: wH2O =3:8) was used across all pastes to maintain consistency in preparation. Viscosity temperature sweep revealed a significant viscosity drop from 25°C to 40°C, with 40°C identified as the optimal printing temperature to balance paste viscosity and drug stability (Figure 1A). The constant temperature viscosity curves indicate that viscosity decreases with increased drug loading, due to the relatively lower polymer content (Figure 1B). All pastes exhibited pseudoplastic behavior (shear-thinning). Yield point and yield stress decreased with higher drug loading (Figure 1C, 1D), varying with the polymer content. This phenomenon is also observed in the time-stress curve for the printing process (Figure 1E). After extrusion, the material must have sufficiently high yield stress to maintain the shape stability by supporting its own weight[4]. This may also explain why 0% HCT tablets collapsed least after printing. To cope with the extrusion difficulty caused by high yield stress at the beginning of printing, pre-extrusion is necessary. The 0% and 20% HCT curves in Figure 2D show that in the region of high shear rate, the structure of the paste is destroyed, and cracks generated. This indicates that in actual printing processes, the extrusion speed of the nozzle must not be too fast, as it can lead to inconsistent and broken filaments. Figure 2A and 2B show that the tablet can maintain good appearance during printing. To enhance tablets’ appearance retention during drying, three drying methods were evaluated. Lyophilization keeps the tablets’ shape best, whereas vacuum dried tablets and ambient-air dried tablets collapsed (Figure 2C). SEM analysis of tablet fracture plane and surfaces showed similar surface morphologies across all methods, though the lyophilized tablets' internal porous structure helped maintain their structure and appearance during dehydration.

Conclusion: The role of rheological properties in optimizing SSE 3D printed HCT tablets was studied. Adjusting viscosity through temperature control, as well as selecting an optimized printing speed and drying method proved essential for enhancing tablet appearance and minimizing flaws.

References: 1. van Kampen, E.E.M., et al., The Quest for Child-Friendly Carrier Materials Used in the 3D Semi-Solid Extrusion Printing of Medicines. Pharmaceutics, 2023. 15(1): p. 28.
2. Díaz-Torres, E., et al., Characterization and Validation of a New 3D Printing Ink for Reducing Therapeutic Gap in Pediatrics through Individualized Medicines. Pharmaceutics, 2023. 15(6): p. 1642.
3. Jayathilakage, R., P. Rajeev, and J. Sanjayan, Rheometry for Concrete 3D Printing: A Review and an Experimental Comparison. Buildings, 2022. 12(8): p. 1190.
4. Wangler, T., et al., Digital Concrete: Opportunities and Challenges. RILEM Technical Letters, 2016. 1(0): p. 67-75.

Acknowledgements: Acknowledgements, disclaimers, funding: The authors gratefully acknowledge funding from SBIR Phase II funding from NIST, grant # 70NANB23H209.


Figure 1. Rheological parameters of different HCT loaded pastes: (A) Viscosity temperature sweep of different HCT loaded pastes; (B) Viscosity versus shear rate for different HCT loaded pastes; (C) Yield stress measurement of different HCT loaded pastes based on the viscosity maximum method in a stress ramp; (D) Thixotropy of different HCT loaded pastes (stress ramps at 40°C); (E) Time-stress curve in printing process.


Figure 2. Pictures of SSE 3D printed HCT tablets before and after drying with different methods (A) Tablets in the printing process; (B) Tablets before drying; (C) Tablets after drying by ambient-air drying, vacuum drying, and lyophilizing (front and back side).


Figure 3 SEM images of SSE 40% HCT tablets dried by different methods (A) SEM image of lyophilized dry tablet fracture plane surface; (B) SEM image of vacuum dry tablet fracture plane; (C) SEM image of ambient-air dry tablet fracture plane; (D) SEM image of lyophilized dry tablet surface; (E) SEM image of vacuum dry tablet surface; (F) SEM image of ambient-air dry tablet surface.