(139f) Innovative Manufacturing Strategy Enabling Filament-Based 3D-Printing of Lipid-Based Advanced Dosage Forms

In the last decade, additive manufacturing, commonly known as 3D printing, has captured significant attention in the pharmaceutical industry for its ability to transform the production pipeline. The technological advancement offered by 3D-printing made the transition from large-scale production toward a more personalized model possible. Therefore, 3D-printing has the potential to fulfill the requirements of personalized therapies by enabling on-demand adjustable dosage form production that cannot be afforded using traditional large-scale manufacturing technologies such as tableting. However, many complications can impact and limit the applications of 3D printing in the pharmaceutical sector. For example, the relatively limited number of excipients, mainly polymer-based, that are employed for pharmaceutical 3D-printing diminish its capabilities. Therefore, extending the portfolio of excipients with advanced functionality is necessary. For certain 3D-printing technologies, such as fused deposition modeling (FDM^TM), the lack of printing-associated properties of the intermediate product (filament) is another challenging complication. Hence, developing more effective and advanced technologies to produce printable filaments is required. This study demonstrates the optimization of the extrusion step to develop high-quality drug-loaded lipid-based filaments with desired printing properties and provide accurate and more efficient active pharmaceutical ingredient (API) loading in the lipid matrix.

Materials

Polyglycerol ester of fatty acids, specifically PG6-C16 partial ester (PG6C16p), composed of six glycerol moieties partially esterified with palmitic acid and commercially available as Witepsol® PMF166 was selected as the lipid-based excipient for the embedding of API.

Methods:

Extrusion: A lab-scale twin-screw extruder equipped with two co-rotating screws and three heating barrels was used to produce the filaments. A conveyor belt was used to provide a controlled movement of the produced filament and to adjust its diameter. Besides, extrusion process parameters such as screw speed and nozzle diameter were adjusted to reach the targeted filament dimensions suitable for 3D-printing. Two different feeding strategies during extrusion were screened and compared with each other:

A. Separate feeding of molten lipid and solid API

PG6C16p was fed in its molten state using a liquid pump, while API was fed using the standard powder feeder. The feeding rates of both the liquid pump and the powder feeder were adapted to reach the desired loading inside the filament. In this approach, both materials meet at the extruder inlet. The mixing step and extrusion happen inside the extruder barrels (semi-cold extrusion).

B. Feeding a single molten mixture of lipid and API

The second feeding approach was feeding both materials together as a single molten mixture. A mixture of PG6C16p and API (8% w/w) was prepared by weighing, mixing, and melting. The molten mixture was solidified and used afterwards as the feeding mixture for extrusion. The feeding mixture was again molten and fed to the extruder at 90 °C using the liquid pump. The extrusion temperature was set at the onset of crystallization (cold extrusion).

3D-Printing: A conventional, low-cost filament-based 3D-printer was customized and used for the 3D-printing of lipid-based API-loaded tablets from the manufactured filaments.

Characterization of filaments and 3D-printed dosage forms: The flexibility of filaments was screened by measuring their critical bending diameter. The solid-state of the lipid and the API as well as the alteration in the crystallinity of the API were assessed in the filament and the 3D-printed tablets via DSC and SWAXS.

Results

Filament manufacturing using the first strategy in which the excipient and the API are fed separately was feasible, yet impractical for many reasons. The fine API powder showed poor flowability and hence inaccurate dose loading in the filaments. Mixing of the API powder with molten lipid before reaching the extruder inlet resulted in bridging and interrupted process. The produced filaments displayed peeling resulting in a rough surface and, therefore, unprintable due to the lack of transportability via the driving wheels of the 3D-printer. On the other hand, the second strategy was very efficient. Only one feeding approach (liquid pump) was employed to feed both materials, ensuring a less complex process. The feeding rate was controlled effectively, allowing accurate dosage loading. Neat filaments with smooth surfaces were produced. Melting of API and PG6C16p mixture before feeding to the extruder was also advantageous. For example, the API is amorphized completely before extrusion and dispersed within the lipid matrix. While in amorphous form, the API has a glass transition very close to the onset of melting of the lipid, which allows the mixture to be completely liquid at low temperatures and ready for feeding at 90 °C, below the melting point of the raw API. The glass-forming ability of some APIs becomes effective when fed using this approach, which eventually contributes to a more flexible filament. In this work, the API-loaded filament was found at least 30 times more flexible than the blank lipid filament when produced using the later approach. Furthermore, API peaks in SWAXS and endothermic peaks in DSC were not detected in the freshly prepared filaments and 3D-printed tablets, confirming that it was completely amorphous in the lipid system. After one month, the API remains amorphous in the 3D-printed tablets under long-term conditions (25 °C /60% RH). Signs of recrystallization were observed in the tablets stored under accelerated conditions (40 °C /75% RH). The solid-state of the lipid content of the tablet was found stable upon storage with no polymorphic change.

Conclusion

This work demonstrates effective manufacturing and 3D-printing of drug-loaded lipid-based filaments. It is an essential step toward extending the portfolio of 3D-printing excipients. The advanced extrusion approach opens the door to overcome problems such as poor powder flowability without the need of glidants or the lack of mechanical properties in some approved pharmaceutical polymers without relying on plasticizers. This work is a strong step forward toward the personalization of medicine.

Acknowledgments

This work was funded through the COMET programme which is operated by the Austrian Research Promotion Agency (FFG) on behalf of the Federal Ministry for Transport, Innovation and Technology (BMVIT) and the Federal Ministry for Digital and Economic Affairs (BMDW). It is also funded by Land Steiermark and the Styrian Business Development Agency (SFG).