(34b) Identifying CQAs of 3D Printed Extended-Release Tablets through the Optimization of Formulation and 3D Geometric Variables

Authors: 
Alayoubi, A., U.S. Food and Drug Administration
Zidan, A., U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Ashraf, M., Office of Testing and Research, U.S. Food and Drug Administration
Three-dimensional printing-3D printing (3DP) offers the potential to revolutionize the production of personalized drug delivery systems. In semisolid extrusion, 3D printing (SEP) a drug loaded paste is extruded through a small nozzle and allowed to dry to form a 3D object on build-plate SEP technology. This procedure has numerous advantages that include low cost, use of common excipients, and the capability to print personalized dose formulations with a wide variety of polymeric pastes. This study is aimed at identifying the critical quality attributes (CQA) of 3D printed extended release tablets prepared by this technology. Nineteen drug loaded pastes were prepared according to a fractional factorial design with three replicates of the center point: (1) to manufacture 3D printed round shaped tablets and (2) to evaluate the effect of formulation variability and (3) weaving patterns on the various tablet characteristics.

Diclofenac sodium, an NSAID, was used as a model drug. Drug-loaded carbopol based pastes were prepared by compounding Unguator using Avicel PH101, Avicel PH105 and spray dried lactose as diluents, glycerol as plasticizer and polyplasdone as the disintegrant. The pastes were extruded into 3D printed tablets using EnvisionTec 3D Bioplotter. The formulation variables included percentages incorporated of the drug and various soluble and insoluble excipients. The 3D geometric variables included nozzle diameter, weaving angle and distance between filaments. The 3D printed tablets were characterized in terms of drug assay and content uniformity, disintegration time, percent friability, tensile and axial breaking strengths, porosity, drug release characteristics and the uniformity of dosage units (thickness, weight and diameter).

Changing the formulation variables required variating in printing pressure from 0.5 bars to 4.5 bars to maintain a printing rate of 10 mm/secs for all pastes. Pre-flow and post-flow times of 0.1 seconds were required to avoid gaps in the internal structures and/or contours. The soluble components of the formulations affected the radial strength of the 3D tablets. However, the weaving parameters were more important to control the axial strength. The results indicate that 3D weaving pattern has a minimal influence on the porosity of the filament deposited while printing. Nevertheless, the distance between the printed filaments necessary to create the structure, determined the porosity of tablets. Dissolution results demonstrated that the weaving angle and lactose loading negatively affected the percent of drug release after 8 hours. Conversely, the drug release rate increased from 75% to 95% by increasing the distance between filaments from 0.5 mm to 1.5 mm, respectively.

In summary, this study demonstrated that formulation and weaving parameters should be controlled to produce robust 3D printed extended-release tablets by SEP. This or similar 3D printing (SEP) procedures have significant potential to contribute to personalized therapy and/or preparation-on-demand medications at health care settings.