Influence of Print Settings on the Critical Quality Attributes of Extrusion-Based 3D-Printed Caplets: A Quality-by-Design Approach

Abstract

Extrusion-based 3D-printing is an easy-to-use, cheap manufacturing technique that could be used to produce tailored precision medicines. The technique has an almost unlimited versatility since a multitude of print parameters can easily be adapted. Unfortunately, little is known of the effect of these print parameters on the critical quality attributes of the resulting printlets. In this study, practical guidelines and means to adapt certain parameters in order to achieve the desired outcome (e.g., acceptable visual quality and flexible dosing) are stipulated for medical 3D-printing using a design-of-experiments approach. The current study aims at elucidating the effect of five print parameters (infill, overlap, number of shells, layer height and layer pattern) on the mechanical properties, dimensions, weight, porosity and dissolution characteristics of a fixed-size caplet consisting of Eudragit EPO (69.3%), Polyox WSR N10 (29.7%) and zolpidem hemitartrate (1%). In terms of the mechanical properties, 3D-printed caplets possessed anisotropy where the vertical compression strength and Brinell hardness exceeded the diametral strength. In general, all 3D-printed caplets possessed acceptable mechanical strength except for a small region of the knowledge space. Dimensional analysis revealed small, statistical significant differences between different runs, although the clinical relevance of this variation is likely negligible. The weight or dose of a caplet can be varied mainly using the infill and overlap and, to a lesser extent, via the layer height and number of shells. The impact on porosity was complicated as this was influenced by many factors and their interactions. Infill was the only statistically relevant factor influencing the dissolution rate of the current formulation. This study unravels the importance of the print parameter overlap, which is a regularly neglected parameter. We also discovered that small dose variations while maintaining the same dissolution profile were possible via modifying the overlap or number of shells. However, large dose variations without affecting the dissolution behaviour could only be accomplished by size modifications of the printlet.

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“…Conventional hardness testing does not seem to be suitable for our HME-FDM 3DP tablets as they did not break, but due to their flexible nature, they did bend a little. HME-FDM prepared tablets usually have an excellent hardness, in some cases even better compared to directly compressed tablets (Ilyés et al, 2019;Zhang et al, 2017;Henry et al, 2021). FDM-HME tablet hardness is influenced by infill-density, choice of excipients, structural geometry, layer-height and layer-to-layer adhesion (Karalia et al, 2021;Zhang et al, 2020).…”

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“…While interest in pharmaceutical 3DP continues to grow, with pharmaceutical companies such as Aprecia and Triastek investing in the technology, progress is arguably hampered by the empirical process of formulation development ( Elbadawi et al, 2021b ; Seoane-Viaño et al, 2021 ). The entire process of HME and FDM 3DP typically involves iterative adjustments to the formulation composition and/or numerous printing parameters such as the extrusion speed and temperature, the printing speed and temperature, the layer height, the percentage infill, and the platform temperature ( Đuranović et al, 2021 ; Govender et al, 2021 ; Henry et al, 2021 ; Zhang et al, 2021 ). Given the multifactorial nature of HME and FDM 3DP, conventional systemic methods of evaluating each input variable on printing success (i.e., based on design of experiments) can be time-consuming.…”

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“…Finally, the printing speed will be adjusted. The slower the printing, the better the resolution, but the process can be very long in time [ 37 ]. The most common excipients used in FDM are polylactic acid (PLA), polyvinyl alcohol (PVA), Soluplus, ethylcellulose (EC), Eudragit, hydroxymethyl cellulose (HMPC), hydroxypropyl cellulose (HPC), and polycaprolactone (PCL) [ 38 ].…”