Structure-function correlation and personalized 3D printed tablets using a quality by design (QbD) approach

Abstract

The current investigation aimed to manufacture and evaluate the structure-function relationship of various 3D printed tablets by conjugating hot-melt extrusion (HME) and fused deposition modeling (FDM) based additive manufacturing (AM) technique. Design of experiments (DoE) and formulation optimization studies were performed by using the Box-Behnken design based on the effect of the design parameters and responses which included drug loading, mechanical properties, and in vitro drug release performance. Key parameters such as shell thickness, infill density, and layer height were selected as independent variables. The tablet's weights (as a function of drug loading), hardness tested at 0° and 45° set-up, the amount of drug released by 180 min, and the average drug release rate were measured as responses. The reproducibility of the printing process was also studied by repeating the mid-point of the DoE data set multiple times (n = 3). A series of evaluation and characterization studies, including DSC, XRD, PLM revealed the amorphous solid-state conversion of the crystalline drug, whereas texture analysis showed robust mechanical properties of developed filaments. All FDM compatible filaments with IBU in amorphous states were successfully utilized to manufacture and evaluate 15 batches of tablets. The shell thickness and infill densities were significant (p-value < 0.05) to the tablet's weights and mechanical properties, and the DoE studies on in vitro drug release showed that the selected individual variables had a significant effect on the amount of drug released at a certain time point as well as drug release rate. In summary, conjugating HME with FDM offers a flexible platform for the on-demand personalized drug product development, and the DoE studies provide robust guidance for the optimization and fabrication of patient-focused drug products while adhering to the regulatory expectations.

Keywords: 3D printing; Box-Behnken design; Design of experiments; Fused deposition modeling; Hot-melt extrusion; Ibuprofen; Quality by design.