Inﬂuence of the Inﬁll Geometry of 3D-Printed Tablets on Drug Dissolution †

: Patient-centric therapy is especially important in pediatrics and may be attained by three-dimensional printing. Filaments containing 30% w / w of theophylline were produced by hot-melt extrusion and printed using fused deposition modelling to produce tablets. Here, preliminary results evaluating the effect of inﬁll geometry (cross, star, grid) on drug content and release are reported.


Introduction
Additive manufacturing, also known as 3D-printing (3DP), is gaining relevance in the manufacturing of personalized medicines, mainly of tablets (TAB), using fused deposition modelling (FDM). This technique requires prior drug incorporation in the matrix (e.g., thermoplastic polymers) and the production of filaments (FIL) through hot-melt extrusion (HME). FIL are in turn fed into the 3D-printer, molten and deposited layer-by-layer to build the dosage form [1]. The extrudability and printability of FIL depend on the raw materials (adjusted qualitatively and quantitatively, as required) and the processing conditions [1]. Since both HME and FDM rely on the fusion of the matrix, the heat stability of the drug is paramount.
The customization of medicines in pediatrics is critical, as one needs to repeatedly adjust the dose according to age, body weight or surface area as the child grows and to achieve well-defined drug release kinetics. This work evaluates how the infill geometry of 3D-printed TAB impacts drug content and release.

Results and Discussion
Initial experiments have shown that the qualitative and quantitative composition of the chosen polymeric matrix possesses adequate plasticity and lubrication, enabling successful HME and FDM 3DP.
The uniformity of drug distribution in the FIL (samples from ends and middle of the extrudate) was ascertained as 98.15 ± 3.35% of the theoretical amount of TEO, also confirming drug stability during HME. Moreover, the heating of TEO at the printing temperature did not reveal degradation peaks in HPLC. TEO suffered partial amorphization caused by HME, a phenomenon strengthened during the FDM printing of the TAB, as ascertained by disappearance of the drug peaks in DSC and XRPD.
To evaluate the impact of geometry on dissolution, TAB of different infill geometry (cross, star, and grid, without a top and bottom; Figure 1) were 3D-printed and characterized (Table 1).

Results and Discussion
Initial experiments have shown that the qualitative and quantitative composition of the chosen polymeric matrix possesses adequate plasticity and lubrication, enabling successful HME and FDM 3DP.
The uniformity of drug distribution in the FIL (samples from ends and middle of the extrudate) was ascertained as 98.15 ± 3.35% of the theoretical amount of TEO, also confirming drug stability during HME. Moreover, the heating of TEO at the printing temperature did not reveal degradation peaks in HPLC. TEO suffered partial amorphization caused by HME, a phenomenon strengthened during the FDM printing of the TAB, as ascertained by disappearance of the drug peaks in DSC and XRPD.
To evaluate the impact of geometry on dissolution, TAB of different infill geometry (cross, star, and grid, without a top and bottom; Figure 1) were 3D-printed and characterized (Table 1). TAB dimensions, mass, and drug content were uniform. The star and grid TAB were equivalent; the cross showed significantly lower mass. Drug content was consistently below the theoretical value, but no degradation or interaction of TEO with the matrix was found by FTIR. Spontaneous micellization of the polymeric matrix (e.g., SOL) may account for the unavailability of the drug for quantitation. In vitro drug release did not reveal significant differences related to infill geometry between the star and grid shapes since the surface area of exposure to the dissolution media did not seem to have a sufficient enough difference to impact the dissolution profile. For the cross geometry, the larger void spaces account for the higher accessibility of water to the structure, as well as slightly faster and more complete drug dissolution (≈100% at 3 h); the star and grid show higher mass and thicker walls, so the matrix effect on slowing drug release is more marked (≈ 95% after 4-5 h).
Further in-depth studies are warranted to fully understand and characterize the systems and to explore the impact of geometry on dissolution.  TAB dimensions, mass, and drug content were uniform. The star and grid TAB were equivalent; the cross showed significantly lower mass. Drug content was consistently below the theoretical value, but no degradation or interaction of TEO with the matrix was found by FTIR. Spontaneous micellization of the polymeric matrix (e.g., SOL) may account for the unavailability of the drug for quantitation.
In vitro drug release did not reveal significant differences related to infill geometry between the star and grid shapes since the surface area of exposure to the dissolution media did not seem to have a sufficient enough difference to impact the dissolution profile. For the cross geometry, the larger void spaces account for the higher accessibility of water to the structure, as well as slightly faster and more complete drug dissolution (≈100% at 3 h); the star and grid show higher mass and thicker walls, so the matrix effect on slowing drug release is more marked (≈95% after 4-5 h).
Further in-depth studies are warranted to fully understand and characterize the systems and to explore the impact of geometry on dissolution.