Hot‑Melt Extrusion of Bupropion with Three Ethylcellulose Grades for Pellet Feedstock Preparation and Screw‑Based 3D Printing of Sustained‑Release Tablets

Abstract

3D printing has emerged as a novel technology for producing personalized dosage forms tailored to patients’ therapeutic needs. Hot-melt extrusion (HME) is commonly used to produce filaments for most extrusion-based 3D printers. This study aimed to investigate the effect of three different ethylcellulose (EC) grades (7N, 10N, and 20N) on the physicochemical properties, matrix restructuring, and sustained-release behavior of bupropion hydrochloride (BUP·HCl)-loaded tablets. The extrudates were fabricated using HME, pelletized, and used as feedstock for screw-based 3D printing, thereby overcoming the limitations of filament-based systems. The formulations were evaluated for drug release, hardness, swelling, and porosity before and after dissolution using micro-computed tomography (microCT). The influence of tablet geometry on drug release was also investigated. Morphology, crystallinity, and thermal properties were characterized using scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). All formulations exhibited sustained BUP·HCl release, with drug release decreasing as EC viscosity grade increased. Tablets prepared with higher-viscosity EC showed greater hardness, reduced swelling, and lower post-dissolution porosity. MicroCT analysis revealed raster-related internal pores in all tablets before dissolution. However, initial porosity did not correlate with release behavior; tablets containing EC 20N exhibited the highest initial porosity but the lowest post-dissolution porosity and slowest drug release, whereas EC 7N tablets showed the opposite trend. Larger, thinner tablets released drug faster due to higher surface-area-to-volume ratio. The findings demonstrate that EC molecular weight plays a critical role in governing hydration-driven matrix restructuring and controlling sustained-release behavior of the 3D-printed tablets.

Introduction

Hot-Melt Extrusion (HME) has gained recognition as an innovative processing method for producing molecular dispersions of active pharmaceutical ingredients (APIs) within various polymer and/or lipid matrices [1, 2]. This approach has enabled the development of drug delivery systems with controlled, modified, extended, and targeted release profiles [3]. During the extrusion process, active pharmaceutical ingredients (APIs) are melted and homogeneously dispersed within a polymeric carrier, leading to the formation of amorphous solid dispersions (ASDs) [4, 5]. These systems enhance drug solubility by increasing wettability and reducing crystallinity. Due to its continuous operation, solvent-free nature, which aligns with current environmental and regulatory requirements, and high production efficiency, HME remains the primary industrial method for manufacturing high-quality three-dimensional (3D) printing filaments [6].

3D printing has emerged as one of the most widely adopted platforms for the design and fabrication of personalized pharmaceutical products [7,8,9,10,11,12]. As an additive manufacturing technology, the workflow begins with the generation of a digital model of the target structure using computer-aided design software compatible with 3D printing systems [13,14,15]. This digital file is subsequently converted into a printer-readable format, which guides the deposition of material during fabrication [16,17,18,19]. The object is then constructed through the sequential addition of material in a layer-by-layer manner. Consequently, most 3D printing processes conceptualize and fabricate structures, as a series of discrete two-dimensional cross-sectional layers rather than as a continuous three-dimensional entity [20].

Fused deposition modeling (FDM) is one of the most widely used 3D printing technologies today [21,22,23]. Several studies have investigated the use of FDM 3D printers in the fabrication of tablets [24,25,26,27,28]. For example, Sadia et al. utilized FDM 3D printing to fabricate immediate-release pharmaceutical tablets incorporating multiple model drugs [23], whereas Goyanes et al. used FDM 3D printers to fabricate modified-release budesonide capsule-shaped tablets [29]. Moreover, Chen et al. investigated the feasibility of fabricating gastric floating tablets using FDM 3D printing with low infill percentages and evaluated the influence of infill density on the in vitro performance and physicochemical properties of the resulting dosage forms [30]. Moreover, Buyukgoz et al. aimed to investigate FDM-based 3D printing tablet design strategies for simultaneous control of drug dose and release profiles. Specifically, it was evaluated how variations in tablet geometry and drug distribution influence dissolution behavior independently of drug–polymer interactions [28]. Finally, Tabriz et al. developed immediate‑release, flavored paediatric chewable formulations of diphenhydramine hydrochloride by preparing drug‑loaded filaments via HME and using an FDM 3D printer to fabricate 3D fruit‑chew designs [31].

While FDM relies on thermoplastic filaments for material deposition, direct extrusion 3D printing has attracted considerable interest due to its ability to process pharmaceutical materials under relatively mild conditions [11]. Unlike FDM, direct extrusion enables the use of pellets or powders fed directly through the nozzle, thereby overcoming the limitations associated with filament-based systems [32].

Screw-based 3D printing, which is a direct extrusion 3D printing represents a variant of FDM technology [33,34,35]. Unlike conventional filament-based FDM systems, screw-based extrusion can directly process bulk materials, such as powders, pellets, or granules, which are melted and conveyed through the nozzle [36]. This approach accommodates higher-viscosity formulations and provides enhanced control over material flow and homogeneity, making it particularly well-suited for pharmaceutical and biomedical applications [37]. The combination of HME with Screw-based 3D printing enables a unified, continuous, and adaptable manufacturing platform that is particularly suitable for point-of-care applications. This approach facilitates the on-demand fabrication of patient-specific dosage forms without requiring intermediate filament production or sophisticated infrastructure. Consequently, it promotes decentralized manufacturing by improving flexibility, enabling rapid production, and reducing reliance on complex supply networks [38,39,40].

BUP·HCl is a class I drug in the biopharmaceutical classification system (BCS) [41, 42]. It is available in all three different release rates: Immediate release (IR), Sustained release (SR) and Extended release (ER). The IR is available in 75 mg and 100 mg tablets, the SR 100 or 150 mg and ER 150 or 300 mg [41]. However, IR formulations of BUP·HCl are characterized by rapid drug dissolution and absorption, resulting in high peak plasma concentrations shortly after administration. While this can be advantageous for achieving a quick onset of action, it also leads to pronounced fluctuations in systemic exposure, with distinct peak and trough levels over the dosing interval. Consequently, IR products require multiple daily dosing, typically two to three administrations per day, which may negatively affect patient adherence, particularly in long-term therapies. In addition, the sharp increase in plasma concentration associated with IR delivery has been linked to a higher incidence of concentration-dependent adverse effects, including insomnia, agitation, and an increased risk of seizures at higher doses. In contrast, SR and ER formulations are designed to modulate the release of BUP·HCl over an extended period, thereby reducing peak plasma concentrations and providing a more stable pharmacokinetic profile. This controlled release results in improved tolerability, reduced fluctuation in drug levels, and simplified dosing regimens, often once or twice daily, which significantly enhances patient compliance. Overall, compared with modified-release systems, IR formulations of BUP·HCl are less suitable for chronic therapeutic use due to their pharmacokinetic variability, increased dosing frequency, and less favorable safety-tolerability profile.

BUP·HCl is an unconventional antidepressant commonly used for a range of therapeutic purposes, including smoking cessation, weight control, management of attention-deficit/hyperactivity disorder (ADHD), treatment of seasonal affective disorder (SAD), and support in amphetamine dependence therapy [43,44,45,46]. Despite its extensive clinical use, BUP·HCl is characterized by a narrow therapeutic index, which poses a significant risk of severe adverse effects in cases of overdose [46, 47]. Previous studies have reported that this limited therapeutic window substantially increases the likelihood of seizure occurrence, even when the drug is administered within the recommended dosing ranges [48]. Furthermore, pronounced interindividual variability in BUP·HCl metabolism, influenced by physiological factors, such as body weight, body surface area, and age, as well as pharmacokinetic parameters including metabolic capacity, drug clearance, and organ function, can lead to up to a 5.5-fold difference in safe dosage requirements amongst patients receiving identical doses [49].

Given the pronounced interindividual variability in BUP·HCl metabolism, exposure, and tolerability, fixed-dose treatment may not provide optimal therapy for all patients [50, 51]. This makes BUP·HCl a relevant model drug for personalized sustained-release dosage forms, in which both the dose and release rate can be adjusted through formulation and design variables to reduce the risks associated with overdose or underdosing, improve treatment efficacy, and ensure safe and efficient drug utilization [52]. In this context, 3D printing offers a practical route to tailor tablet geometry and mass while maintaining a controlled-release matrix [53].

In the present study, BUP·HCl-loaded HME extrudates containing three EC viscosity grades (7N, 10 N and 20 N) were pelletized and used as feedstock for screw-based 3D printing of tablets in two geometries. The aim was to investigate the potential of 3D printing in enabling personalized medicine of BUP·HCl and to determine how EC grade and tablet geometry influence printability, mechanical strength, swelling, microstructural evolution before and after dissolution, and BUP·HCl release. By combining hardness, friability, swelling, dissolution and microCT data, we sought to identify the formulation variables governing matrix integrity and sustained-release performance.

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Materials/Methods

The active ingredient BUP·HCl in the form of its hydrochloride salt, was kindly donated by Gattefossé (Lyon, France). The excipients EC 7 N, 10 N and 20 N were kindly donated by Ashland (Bradford, United Kingdom) and the Xanthan gum was purchased from Jordanian Pharmaceutical Manufacturing Company (Amman, Jordan).

Protopapa, C., Junqueira, L.A., Kolipaka, S.S. et al. Hot-Melt Extrusion of Bupropion with Three Ethylcellulose Grades for Pellet Feedstock Preparation and Screw-Based 3D Printing of Sustained-Release Tablets. AAPS PharmSciTech 27, 251 (2026). https://doi.org/10.1208/s12249-026-03494-4