Hot-melt extruded-FDM 3D-printed polyethylene oxide tablets: Dissolution imaging analysis of swelling and drug release
Abstract
Recent developments in pharmacogenetics have emphasised the importance of customised medication, driving interest in technologies like FDM 3D-printing for tailored drug delivery. FDM 3D-printing is a promising technique for the on-demand manufacturing of customised oral dosage forms, providing flexibility in terms of shape and size, dose and drug release profiles.
Highlights
- Filaments from PEO polymer successfully extruded with propranolol hydrochloride using hot-melt extrusion.
- Filaments with appropriate flexural stress successfully 3D-printed into tablets.
- Sal and Str parameters from focus variation microscopy reveals the surfaces of the tablets to associated with roughness and correlated to API content.
- 3D-printed tablets are assessed using dissolution imaging
This study investigates the fabrication and characterisation of 3D-printed oral dosage forms using PEO as the primary polymer and PEG 6 K as a plasticiser. Firstly, the printability of the PEO filaments with different propranolol hydrochloride concentrations was explored using the hot-melt extrusion technology. The influence of the propranolol hydrochloride concentrations on the mechanical properties of the filaments was examined was then examined after which surface characteristics, including roughness and wettability, were evaluated. Dissolution imaging was used to visualise the effects of drug content on the swelling and dissolution characteristics of the PEO-based 3D-printed tablets. Results showed a reduction in the flexural stress of the filaments with increasing drug load.
It was also observed that increasing the drug load led to higher surface roughness and lower contact angles of the 3D-printed PEO tablets, implying increased surface hydrophilicity. The swelling behaviour of the tablets increased with higher drug concentrations, resulting in a larger gel layer formation. When comparing the drug release percentages, the release rate was higher in the 10 mg propranolol tablets, suggesting that a lower drug content led to a faster release. The greater gel layer of the 40 mg PPN tablets hindered the drug release by acting as a diffusion barrier, while the 10 mg PPN tablets, with less swelling and gel formation, experienced a faster drug release.
These findings show the importance of drug content in modifying the surface properties, swelling behaviour, and drug release profiles of 3D-printed PEO tablets. The study also demonstrates the novel use of dissolution imaging for 3D-printed dosage forms, providing valuable quantitative and qualitative insights into swelling dynamics and channel formation to optimise 3D-printed tablets for drug delivery systems.
Introduction
The connection between a person’s genome, their inherent susceptibility to developing certain diseases, and their reaction to particular medications is becoming increasingly clear due to recent developments in pharmacogenetics [1].
As the interest in patient-centred and stratified treatments continues to grow, there is a demand for technological solutions to give patients safe and reliable personalised therapeutics. Additive manufacturing has emerged in recent years as a promising approach for the on-demand production of personalised dosage forms, allowing flexibility in the design, size, dose and drug release profiles [2], [3]. The drug content of the dosage form can be adjusted according to the weight and physiological requirements of the patient [4]. One effective approach is fused deposition modelling (FDM) 3D-printing, which has several advantages when compared to other commercially available technologies, such as selective laser sintering (SLS), stereolithography (SLA), digital light processing (DLP), inkjet 3D-printing and binder deposition. These advantages include the low cost of the printer, the elimination of finishing processes, and the fact that no powder handling facilities are required. These features make FDM 3D-printing a popular option for small-scale personalisation of solid dosage forms [5], [6], [7]. At the beginning of the FDM process, the thermoplastic filament is fed into the printer as shown in Fig. 1. The extruder gear grabs the filament and pushes it down until it reaches the hot end. The nozzle of the printer is heated to melt the filament, and it begins to move along the x, y, and z axes according to a specific design. The design is built layer by layer as the material hardens following extrusion. It’s important to optimise printing parameters such as printing temperature and deposition speed, as they affect the printing quality [8], [9], [10]. In recent years, several studies have reported the use of FDM 3D-printing to produce immediate, delayed, and extended-release drug formulations [11], [12], [13], [14], [15]. Pietrzak et al. demonstrated how the active dose in various immediate and extended-release polymers can be precisely adjusted using the FDM technique [16]. However, further research is necessary to fully understand the potential of the process and to assess how any modifications or variations might affect the efficiency and performance of the products.
To optimise the material for FDM 3D-printing, filaments are often fabricated using hot-melt extrusion (HME). Research has explored the development of these filaments through HME using single or combined polymers with other excipients, such as plasticisers [8], [17], [18]. When combined with HME, FDM provides many benefits over traditional tablet manufacturing, including increased drug loading capacity [10]. Studies have revealed the adaptability of different polymers in the FDM process, including hydroxypropyl cellulose (HPC) [19], hydroxypropyl methylcellulose acetate succinate (HPMCAS) [20], ethyl cellulose (EC) [21], hydroxypropyl methylcellulose (HPMC) [22], [23], polyethylene oxide (PEO) [24], and Eudragit EPO, a methacrylate-based polymer [25]. Solid dosage forms have also been produced using FDM 3D-printing with polymers like cellulose, methacrylate, acrylic acid, or PVP derivatives [26], [27].
PEO is one of the most widely used polymers in the pharmaceutical industry. It is a synthetic linear homopolymer produced through the heterogeneous catalytic polymerisation of ethylene oxide monomers [28] and is commercially available in a broad range of molecular weights, from 100 K to 10,000 Kg/mol, and viscosity grades [29]. This range makes PEO highly adaptable for a variety of pharmaceutical formulations [30]. PEO has been used in many pharmaceutical applications, including hydrogels [31], matrix tablets [32], buccal films [33] and nanofibers [34].
Furthermore, PEO has been employed in new technologies such as hot-melt extrusion [28], 3D-printing [24], [35], electrospinning [36] and injection moulding [37] for the creation of complex dosage forms. PEO has the ability to regulate the release of both highly soluble and poorly soluble drugs from hydrophilic matrix systems [38]. This control is mainly accomplished by the swelling of the polymer as it encounters the dissolution media. A gel layer forms around the PEO tablet, which regulates the diffusion of the drug from the structure. The erosion of the gel layer also influences the rate of drug release. The erosion of the gel layer is dependent on the specific polymer grade and formulation parameters [30], [39]. In one example, PEO was combined with other additives to make thin oral films [40]. PEO was also added to methacrylate polymer to facilitate tablet 3D-printing [41]. A study by Chung et al. [42] focused on achieving immediate release of ibuprofen using FDM 3D-printing with PEO (Polyox WSR N80) as the main matrix. Polyox WSR N80, known for its water-solubility and suitable mechanical properties, was effective in forming Ibuprofen filaments even at high drug loading (40 % w/w). The use of various release modifiers, including Kollidon VA64 and Kollidon 12PF, was also investigated in enhancing the drug release. Another study by Nashed et al. [43] focused on the use of PEO with molecular weights of 7 M and 0.9 M, in combination with low-viscosity polymers like hydroxypropyl cellulose (HPC) and ethyl cellulose (EC), through the use of different manufacturing methods, including FDM 3D-printing. The study found that PEO/HPC formulations prepared by 3D- printing had a higher dissolution efficiency compared to direct compression, while PEO/EC formulations displayed reduced dissolution efficiency when prepared by 3D-printing compared to direct compression. PEO’s versatile characteristics make it an ideal candidate for 3D-printing customised oral dosage forms.
However, there is limited research on this widely used polymer in FDM 3D-printing. To further enhance the performance of polymers in formulations, plasticisers can be added to modify their mechanical and thermal properties [44]. Plasticisation increases the flexibility of the polymer by enhancing the mobility of the polymer chain. This is useful in situations where higher flexibility or lower processing temperatures for the polymer are required. The filaments used for 3D-printing need to be sufficiently flexible. Very hard and stiff materials can benefit from plasticisation, but it can also make the filaments too soft to print. The 3-point bend test is often employed to assess the flexibility and mechanical properties of filaments and has been used to determine their mechanical resilience [45].
In the context of evaluating drug release profiles, dissolution imaging has gained attention as a valuable analytical technique in pharmaceutical research, as it offers temporally and spatially resolved absorbance data, which are important in understanding drug release dynamics. Since the introduction of this technology, it has been used to investigate a range of phenomena, including intrinsic dissolution rates [46], [47], drug permeation across synthetic membranes [48] transdermal patches [49], and the swelling behaviour of hydrophilic matrices [50], [51], [52]. The instrument provides real-time insights into drug release profiles and enables the visualisation of swelling and erosion.
This makes it useful for correlating dissolution characteristics with the structural features of 3D-printed tablets, including the effects of drug loading on release rates. Such correlation is important in optimising formulation designs to ensure that the printed dosage forms achieve the intended therapeutic outcome. This study aimed to investigate the fabrication of 3D-printed oral dosage forms using PEO as the main polymer of choice, combined with polyethylene glycol (PEG 6 K) as a plasticiser and propranolol hydrochloride (PPN) as the model soluble drug. Filaments were produced through the HME process. The primary goal was to evaluate the impact of varying drug content (PPN at 10, 20, and 40 mg) on the mechanical properties, surface characteristics (surface roughness and wettability), swelling behaviour, and drug release profiles of the printed tablets. Additionally, the application of the UV dissolution imaging instrumentation offered a novel approach by visualising the effects of drug content on the dissolution characteristics (swelling behaviour, gel layer formation, drug release) of the PEO-based 3D-printed tablets thus providing both qualitative and quantitative insights. This study focuses on the behaviour of 3D −printed tablets, differentiating them from conventional compressed compacts previously studied and reported [53].
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Materials
Polyethylene oxide (PEO) MW 300,000 Da (POLYOX™ WSR N-750) was a kind gift from Colorcon (Dartford, UK). The active ingredient, propranolol hydrochloride (PPN), was obtained from TCI Chemicals (UK). Polyethylene glycol (PEG) 6000 (Polyglykol ® 6000P) was kindly provided by Clariant (Frankfurt, Germany). Potassium phosphate monobasic, sodium hydroxide (NaOH), hydrochloric acid (HCl), and potassium chloride (KCl) used to prepare the 0.2 M phosphate buffer dissolution media with a pH of 6.8 and the 0.1 M hydrochloric acid (HCl) dissolution media with a pH of 1.2, were all obtained from Fisher (UK).
Haja Muhamad, Abdul Basit Bashir, James Charlton-Harrison, Rand Abdulhussain, Nihad Mawla, Krishan Patel, James Williamson, Liam Blunt, Karl Walton, Barbara Conway, Kofi Asare-Addo, Hot-melt extruded-FDM 3D-printed polyethylene oxide tablets: Dissolution imaging analysis of swelling and drug release, European Journal of Pharmaceutics and Biopharmaceutics, 2025, 114636, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2025.114636.
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