(M1030-08-52) Revolutionizing Chewable Tablet Fabrication: A Green, Continuous Approach via Hot Melt Extrusion Integrated with Direct Extrusion-Based 3D Printing

Purpose: Chewable tablets are solid oral dosage forms designed to be chewed before being swallowed, offering a patient-friendly alternative that is especially for pediatric and geriatric patients due to ease of administration and improved compliance [1, 2]. With the rise of personalized medicine, 3D printing has emerged as a transformative pharmaceutical technology capable of producing patient-specific dosage forms with tailored drug release profiles [3]. In this study, we present a novel continuous manufacturing platform that integrates hot melt extrusion (HME) with direct extrusion-based 3D printing for the fabrication of chewable tablets. This integrated approach eliminates the need for filament preparation, commonly associated with FDM 3D printing, thereby overcoming filament printability limitations and improving process efficiency. Additionally, it improves how well poorly soluble compounds are absorbed in the body and helps to mask unpleasant tastes, critical quality attributes for pediatric formulations. The study focuses on addressing key pharmaceutical development challenges through a process that is compatible with industrial manufacturing standards, emphasizing scalability, material efficiency, and environmental sustainability.

Methods: Four distinct ibuprofen (ibu) formulations were developed, each comprising varied qualitative and quantitative combinations of pharmaceutical-grade excipients, including EPO ReadyMix, Eudragit EPO, Galen IQ 981, Neusilin US2, Polyplasdone XL, maize starch, xanthan gum, and croscarmellose sodium (CCS). These formulations were processed using a Rondol co-rotating twin-screw extruder operating at 70–90°C, with a screw speed of 100 rpm and a feed rate of 150 g/h. The resulting hot-melt extrudates were pelletized to yield ibuprofen-loaded pellets ranging from 1 to 1.5 mm in size, which were directly fed into a temperature-controlled (80°C) extrusion-based 3D printer to fabricate chewable tablets of varying geometries and with different internal infill densities (100%, 70%, 50%, and 30%), simulating real-world personalization potential. Solid-state characterization was performed using X-ray powder diffraction (XRPD) to assess crystallinity, detect any amorphous transitions, and monitor potential polymorphic changes. Rheological profiling and texture analysis were conducted to evaluate the mechanical and viscoelastic properties critical to the chewability and structural integrity of the printed dosage forms. In vitro drug release was assessed using USP Apparatus II (paddle method) at 37°C and 50 rpm. A biorelevant two-stage pH-shift dissolution protocol was employed: 15 minutes in simulated gastric fluid (pH 1.2), followed by 45 minutes in simulated intestinal fluid (pH 7.4), mimicking gastrointestinal transit. All evaluations adhered to current ICH and USP guidelines, ensuring pharmaceutical relevance and regulatory compliance.

Results: All four ibuprofen (IBU) formulations were successfully processed via hot melt extrusion. The extrudates displayed uniform morphology and were readily pelletized for direct feeding into the 3D printer, eliminating filament-related limitations. Tablets printed at 80°C exhibited consistent weight, dimensional accuracy, and shape fidelity across all geometries and infill densities (100%, 70%, 50%, and 30%). XRPD analysis revealed the complete amorphization of ibu, enhancing its dissolution potential without evidence of drug-excipient incompatibility. Texture analysis confirmed appropriate chewability, with hardness values ranging from 30 to 60 N. Rheological evaluation indicated favorable shear-thinning behavior, ensuring smooth extrusion and print stability. In vitro dissolution studies disclosed minimal drug release in gastric conditions (pH 1.2), followed by >85% release at pH 7.4 for most formulations. Tablets with lower infill densities exhibited faster drug release, attributed to increased surface area and porosity. Notably, tablets printed at 30% infill achieved significantly enhanced release profiles without requiring mastication, suggesting passive disintegration driven by internal structure alone.

Conclusion: The integration of hot melt extrusion with direct extrusion-based 3D printing presents a viable continuous manufacturing strategy for chewable tablets, addressing key formulation challenges such as taste masking, poor solubility, and scalability. This novel approach supports environmentally sustainable practices and aligns with regulatory trends toward personalized, patient-centric dosage forms. It demonstrates strong potential for industrial adoption in pediatric and geriatric therapeutics, fulfilling both quality-by-design (QbD) and green chemistry principles. This cutting-edge platform aligns with the pharmaceutical industry's goals for greener, more scalable, and more precise manufacturing technologies. It offers a long-term solution that meets the current expectations for innovation and patient-centered design in both industry and government.

References: [1] FDA et al., 2018.
[2] Rodríguez-Pombo, L. et al., Pharmaceutics 2022.
[3] Tabriz et al., Molecular Pharmaceutics, 2023.

Ibuprofen four-formulas composition

X-ray powder diffraction (XRPD) of bulk vs formulations

Dissolution profiles of IbuPure vs. F3 100% & 30% infill vs. F4 100% and 30% infills of heart-, round-, and banana-shaped tablet