3D Printing of Hydrocortisone-loaded Eudragit RS Tablets: Influence of Plasticizers and Their Concentration on the Printability of Filaments

Abstract

Although FDM is one of the prominent 3D printing technologies, and it has been widely investigated in pharmaceutical sciences, the printability of filaments remains a challenge. Therefore, our primary objective was to evaluate the effect of PEG 400, PEG 4000 and triethyl citrate at different concentrations (10%, 15% and 20% w/w) on the printability behavior of hydrocortisone-loaded Eudragit RS filaments. In this study, physical mixtures and their filaments were produced using a hot melt extruder and the properties of the filaments were examined by DSC, XRD, FESEM, FTIR, MFI and mechanical tests. Release behavior and hardness properties of the 3D-printed tablets were also evaluated. DSC and XRD results showed that the drug converted from crystalline to amorphous during hot melt extrusion and remained so during the 3D printing.

FTIR results showed no chemical interactions between the drug and other excipients during hot melt extrusion and 3D printing. FESEM results of filaments showed that triethyl citrate-containing filaments had rougher surfaces, which makes them more suitable for 3D printing, while PEG-contained filaments had smoother surfaces. Mechanical tests showed that filaments containing triethyl citrate were stronger and tougher and had moderate ductility and stiffness. Overall, these filaments showed a good balance between these mechanical characteristics, which makes them a suitable candidate for 3D printing. Release studies showed that regardless of plasticizer type, the concentration of the plasticizer determines the extent of drug release. MFI test showed that formulations containing TEC presented a melt flow closer to 30 g/10 min compared to other formulations. Therefore, it can be deduced that TEC improves printability by enhancing melt flow better than the other two plasticizers (PEG 400 and PEG 4000). Based on the results, it can be concluded that triethyl citrate in 15% concentration is the best plasticizer for the production of hydrocortisone-loaded Eudragit RS tablets.

Introduction

Oral drug administration is the most desirable route of drug delivery due to ease of administration, patient compliance, and non-invasiveness [1]. In recent years, 3D printing, also called additive manufacturing, has emerged as a revolutionary technology in developing oral dosage forms [2]. The utilization of 3D printing in pharmaceuticals is rapidly increasing due to the advantages of 3D printing over conventional methods, such as on-demand preparation, tailored release profiles, and dose personalization [3, 4]. 3D printing is the process of depositing materials in a layer-by-layer manner to form a three-dimensional object based on a computer-aided design (CAD) model. There are three main categories of 3D printing: extrusion-based, powder-based, and laser-based [5, 6]. One of the most investigated and well-known 3D printing technologies is Fused Deposition Modelling (FDM), also called Fused Filament Fabrication (FFF). In this technology, a gear system drives solid polymeric filament into the hot end of the print head; the polymeric filament softens to a semi-solid state in the hot printhead and comes out of the nozzle, and then solidifies on the print bed [7]. FDM has several advantages over other 3D printing technologies, such as lower cost and ease of utilization [8].

Two main methods for producing drug-loaded filaments for FDM are simple soaking in a solution saturated with a drug and hot melt extrusion. In the first method, a commercial filament such as polyvinyl alcohol (PVA) or Polylactic acid (PLA) is soaked in a saturated drug solution, and after several hours, the drug will diffuse into the filament [9]. This technique has several drawbacks, such as low loading efficiency and a limited number of pharmaceutical-grade filaments [9]. Another technique of filament preparation is hot melt extrusion (HME), in which the drug and thermoplastic polymer mixture is blended, melted, and extruded from a nozzle with a standard diameter (1.75 mm) to manufacture drug-loaded filaments. The superiority of this method over the former method is evident due to allowing more consistent products and more polymer choices for different drug delivery approaches [10, 11]. In recent years, HME has been utilized to produce filaments from other thermoplastic polymers such as polymethacrylate polymers (Eudragit™), cellulose-based polymers, and polyvinyl polymers [12,13,14]. Originally, the pharmaceutical industry utilized Eudragit™ polymers as a coating agent to produce conventional and stimuli-triggered solid oral dosage forms [15]. Recently, many studies have unravelled the potential of different Eudragit™ polymers to produce 3D-printed dosage forms [16]. One of the Eudragit™ polymers that is used in time-dependent strategies for controlled release drug delivery systems, particularly for colonic drug delivery, is Eudragit RS which is a copolymer of ethyl acrylate, methyl methacrylate, and a low content of methacrylic acid ester with quaternary ammonium groups. The presence of ammonium groups makes the polymers permeable [17, 18].

The pharmaceutical industry faces several obstacles that hinder the continuous integration of FDM coupled with HME technologies. One of the major obstacles associated with using the FDM-HME combination is the printability of the manufactured filament [19]. There are several drawbacks with the printability of filaments during 3D printing process such as filament Buckling, filament fracture, and irregular extrusion. Nowadays, printability refers to filaments’ capacity to exhibit particular mechanical and rheological characteristics [2, 20]. There are several mechanical and rheological methods to assess the printability of HME filaments. Nasereddin et al. proposed an approach to assess the printability of filaments by evaluating their mechanical properties by simulating the mechanical stresses that a filament undergoes during 3D printing [21]. On a similar note, Xu et al. developed several methods to determine the filaments’ mechanical properties and then leveraged the obtained data to evaluate their printability [22]. Another approach for evaluating the filament’s printability is to assess its melt rheology, which simulates the 3D printing process in which the molten polymer comes out of the nozzle [23]. Therefore, Lee et al. utilized the melt flow index to determine the melt flow of the filaments [24]. Considering the advantages of coupling HME and FDM, these methods are worth further investigation in the preparation of solid oral dosage forms; however, developing a reliable method to establish whether a filament is printable remains challenging.

Plasticizers are chemicals that are added to polymers to enhance their mechanical properties and, hence, their printability [25, 26]. A plasticizer works by positioning itself between the polymer chains, increasing their distance. This results in a decrease in the attractive forces between the chains, thereby enhancing the flexibility of the material. While the presence of the plasticizer may lead to a reduction of the polymer’s strength and stiffness, it makes the material more adaptable in situations where flexibility is a priority [27]. To investigate the effect of different types of plasticizers, two plasticizers were selected based on hydrophilicity (e.g., polyethylene glycols) or hydrophobicity (e.g., triethyl citrate) [28, 29]. Polyethylene glycols (PEGs) as hydrophilic plasticizers and triethyl citrate as hydrophobic plasticizers have been widely used to plasticize Eudragit RS in different studies [30, 31]. Khodaverdi et al. have concluded that the optimum concentration for the plasticization of Eudragit RS by PEG and TEC is between 10 and 20% (w/w), so in the current research, this range was selected [32]. Therefore, in this research, the authors aimed to investigate how the type and concentration of plasticizers influence the printability of Eudragit RS filaments loaded with hydrocortisone as a model drug. To achieve this goal, mechanical, rheological, and morphological analyses were integrated and a comprehensive framework to understand how plasticizer type and concentration affect filament printability in FDM 3D printing was proposed.

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Materials

Hydrocortisone was kindly donated by Aboureihan Pharmaceutical Company (Tehran, Iran). Eudragit RS® was obtained from Evonik (Germany). Triethyl citrate (TEC), HPLC grade acetonitrile and methanol were acquired from Merck (Darmstadt, Germany). Polyethylene glycol (PEG) 400 and PEG 4000 were acquired from Mojallali Ltd (Tehran, Iran).

Hatami, H., Mohammadi, M., Sadeghi, F. et al. 3D Printing of Hydrocortisone-loaded Eudragit RS Tablets: Influence of Plasticizers and Their Concentration on the Printability of Filaments. AAPS PharmSciTech 27, 88 (2026). https://doi.org/10.1208/s12249-025-03302-5