Novel On-Demand 3-Dimensional (3-D) Printed Tablets Using Fill Density as an Effective Release-Controlling Tool

Abstract

This research demonstrates the use of fill density as an effective tool for controlling the drug release without changing the formulation composition. The merger of hot-melt extrusion (HME) with fused deposition modeling (FDM)-based 3-dimensional (3-D) printing processes over the last decade has directed pharmaceutical research towards the possibility of printing personalized medication. One key aspect of printing patient-specific dosage forms is controlling the release dynamics based on the patient's needs. The purpose of this research was to understand the impact of fill density and interrelate it with the release of a poorly water-soluble, weakly acidic, active pharmaceutical ingredient (API) from a hydroxypropyl methylcellulose acetate succinate (HPMC-AS) matrix, both mathematically and experimentally. Amorphous solid dispersions (ASDs) of ibuprofen with three grades of AquaSolve^TM HPMC-AS (HG, MG, and LG) were developed using an HME process and evaluated using solid-state characterization techniques. Differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), and polarized light microscopy (PLM) confirmed the amorphous state of the drug in both polymeric filaments and 3D printed tablets. The suitability of the manufactured filaments for FDM processes was investigated using texture analysis (TA) which showed robust mechanical properties of the developed filament compositions. Using FDM, tablets with different fill densities (20-80%) and identical dimensions were printed for each polymer. In vitro pH shift dissolution studies revealed that the fill density has a significant impact (F(11, 24) = 15,271.147, p < 0.0001) and a strong negative correlation (r > -0.99; p < 0.0001) with the release performance, where 20% infill demonstrated the fastest and most complete release, whereas 80% infill depicted a more controlled release. The results obtained from this research can be used to develop a robust formulation strategy to control the drug release from 3D printed dosage forms as a function of fill density.

Keywords: HPMC-AS; additive manufacturing; amorphous solid dispersions; controlled release; fused deposition modeling; hot-melt extrusion; personalized medication.

Figure 1

Screw design was selected for processing of the active pharmaceutical ingredient (API) and polymer physical blends.

Figure 2

Modulated differential scanning calorimetry (mDSC) overlay. (PM = physical mixture, EXT = extruded filaments).

Figure 3

X-ray powder diffraction (pXRD) overlay. (PM = physical mixture, EXT = extruded filaments).

Figure 4

Polarized light microscopy (PLM) of: (A) pure crystalline ibuprofen (530 nm compensator), (B) pure crystalline ibuprofen (Dark background), (C) 20% ibuprofen + HPMC-AS HG extrudates (530 nm compensator), (D) 20% ibuprofen + HPMC-AS HG extrudates (Dark background), (E) 20% ibuprofen + HPMC-AS MG extrudates (530 nm compensator), (F) 20% ibuprofen + HPMC-AS MG extrudates (Dark background), (G) 20% ibuprofen + HPMC-AS LG extrudates (530 nm compensator), and (H) 20% ibuprofen + HPMC-AS LG extrudates (Dark background).

Figure 5

Fourier transform–infrared spectroscopic (FT–IR) spectrum overlay. (PM = physical mixtures, EXT = extruded filaments).

Figure 6

Graphical comparison textural parameters of the test and reference filaments.

Figure 7

Digital microscopy of 20% w/w ibuprofen loaded (A) HPMC-AS HG 3-D printed tablets with 20% infill density (A1), 40% infill density (A2), 60% infill density (A3), and 80% infill density (A4). (B) HPMC-AS MG 3-D printed tablets with 20% infill density (B1), 40% infill density (B2), 60% infill density (B3), 80% infill density (B4). (C) HPMC-AS LG 3-D printed tablets with 20% infill density (C1), 40% infill density (C2), 60% infill density (C3), and 80% infill density (C4).

Figure 8

(A) The in vitro release profiles of 20% w/w ibuprofen loaded HPMC-AS HG 3-D printed tablets with different infill densities. (B) The in vitro release profiles of 20% w/w ibuprofen loaded HPMC-AS MG 3-D printed tablets with different infill densities. (C) The in vitro release profiles of 20% w/w ibuprofen loaded HPMC-AS LG 3-D printed tablets with different infill densities.

Figure 9

(A) pXRD of 20% w/w ibuprofen loaded HPMC-AS HG 3-D printed tablets collected after dissolution testing. (B) PLM of 20% w/w ibuprofen loaded HPMC-AS HG 3-D printed tablet post-dissolution testing with 20% infill density (B1), 40% infill density (B2), 60% infill density (B3), and 80% infill density (B4). (C) Digital microscopic images of 20% w/w ibuprofen loaded HPMC-AS HG 3-D printed tablet post-dissolution testing with 20% infill density (C1), 40% infill density (C2), 60% infill density (C3), and 80% infill density (C4).

Figure 10

Pearson’s correlation between % Infill of the 3D printed tablets and % Release from the tablets for (A) All polymer-infill combinations, (B) HPMC-AS LG, (C) HPMC-AS MG, and (D) HPMC-AS HG).