Evaluating Swellable Cross-Linked Biopolymer Impact on Ink Rheology and Mechanical Properties of Drug-Contained 3D-Printed Thin Film

Abstract

Background/Objectives: Interest in 3D printing oral thin films (OTFs) has increased substantially. The challenge of 3D printing is film printability, which is strongly affected by the rheological properties of the ink and having suitable mechanical properties. This research assesses the suitability of sodium starch glycolate (SSG), a swellable cross-linked biopolymer, on ink rheology and the film’s mechanical properties.

Methods: A water-based ink comprising sodium alginate (SA), the drug fenofibrate (FNB), SSG, glycerin, and polyvinylpyrrolidone (PVP) was formulated, and its rheology was assessed through flow, amplitude sweeps, and thixotropy tests. Films (10 mm × 15 mm × 0.35 mm) were 3D-printed using a 410 µm nozzle, 50% infill density, 60 kPa pressure, and 10 mm/s speed, with mechanical properties (Young’s modulus, tensile strength, and elongation at break) analyzed using a TA-XT Plus C texture analyzer.

Results: The rheology showed SSG-based ink has suitable properties (shear-thinning behavior, high viscosity, higher modulus, and quick recovery) for 3D printing. SSG enhanced the rheology (viscosity and modulus) of ink but not the mechanical properties of film. XRD and DSC confirmed preserved FNB crystallinity without polymorphic changes. SEM images showed surface morphology and particle distribution across the film. The film demonstrated a drug loading of 44.28% (RSD 5.62%) and a dissolution rate of ~77% within 30 min.

Conclusions: SSG improves ink rheology, makes it compatible with 3D printing, and enhances drug dissolution (formulation F-5). Plasticizer glycerin is essential with SSG to achieve the film’s required mechanical properties. The study confirms SSG’s suitability for 3D printing of OTFs.

Introduction

Oral thin films (OTFs) have emerged as a promising and prominent dosage form in the pharmaceutical industry, traditionally dominated by tablets and capsules [1]. OTFs are particularly beneficial for patients with swallowing difficulties, such as children, the elderly, and those with dysphagia [2,3]. OTFs also provide other advantages, including more accurate dosing, enhanced oral absorption, improved bioavailability through minimization of drug degradation, better stability, dose tunability, portability, etc. [4]. Three-dimensional (3D) printing has become increasingly important in drug delivery since it offers a safer and more effective method for administering potent therapeutics [5,6]. Recent advancements have expanded 3D printing in oral drug delivery, leading to innovative pharmaceutical dosage forms, including OTFs [7]. 3D printing presents a promising alternative for developing and manufacturing OTFs, overcoming the limitations of traditional techniques such as solvent casting or hot-melt extrusion. Unlike solvent casting, 3D printing allows for more customization of solid dosage forms for end-stage personalization [8,9].

Extrusion-based 3D printing, such as fused deposition modeling (FDM) and pressure-assisted microsyringe (PAM), has been widely studied in pharmaceutical manufacturing, including the development of OTFs [10,11,12,13]. These techniques construct 3D structures with precise composition and architecture by depositing materials layer by layer under the control of a computer [13]. Furthermore, these techniques are cost-effective and flexible when using various polymers, with or without drugs. Moreover, extrusion-based 3D printing helps control drug release by adjusting the geometry and polymer of the film [14]. In FDM 3D printing, the thermoplastic filament is melted or softened, then extruded and deposited layer by layer to form a 3D object [13]. In PAM printing, semi-solids like gels or pastes are continuously extruded through a syringe-based print head, typically using pneumatic, mechanical, or solenoid pistons [10,15]. PAM is ideal for thermally sensitive drugs and polypills and offers higher drug loading than FDM [16,17]. Although PAM does not require high temperatures like FDM, post-processing drying is necessary after printing, which can cause shrinking or deformation. The printed object may also collapse if the layers do not solidify enough to support the weight of subsequent layers [18]. Additionally, the rectilinear, hexagonal, or honeycomb infill pattern affects the printed structure’s mechanical strength (i.e., flexural strength) in 3D printing [10].

The key challenge with PAM 3D printing is developing a polymer-based ink with the appropriate rheological properties to ensure smooth extrusion through the print head and maintain its shape after deposition [12]. Inadequate rheological properties can lead to nozzle clogging or defective prints [19]. Proper printing parameters, tailored to the ink’s rheology, are also essential for achieving good printability and reproducibility [20]. Thus, it is crucial to formulate a polymer-based ink tailored for PAM-type 3D printing. Semi-solids require an optimal mixture of polymer, solvent, and other excipients to achieve the necessary rheological properties for successful printing [10]. The polymers can be natural or synthetic, with natural polymers being the most prevalent in the biomedical and pharmaceutical industries [21,22].

Sodium alginate (SA), a sodium salt of an anionic linear polysaccharide composed of β-d-mannuronic acid and its epimer α-l-guluronic acid, is widely used in the pharmaceutical industry and is generally recognized as safe (GRAS) [23,24]. Recent studies have explored the use of sodium alginate in ink formulations to see if it is suitable for extrusion-based 3D printing [25,26,27,28]. SA films typically lack the desirable mechanical properties [29]. To improve these mechanical properties, plasticizers are added to the polymer mix. A plasticizer is a small, miscible molecule that interacts with the film-forming polymer, moderates the polymer-polymer interactions, and increases polymer chain mobility [9]. This leads to a lower glass transition temperature, reduced tensile strength, and enhanced film flexibility [30]. Thus, plasticizers are crucial in formulating film-based drug delivery systems, as they increase polymer flexibility by reducing intermolecular forces, resulting in better patient compliance and adherence to pharmacotherapy mobility [9]. An effective plasticizer must be compatible with the drugs, solvents, and polymers. Commonly used plasticizers include sorbitol, mannitol, glycerin, diethyl phthalate, triethyl citrate, tributyl citrate, macrogol, propylene glycol, and citric acid esters, whereas glycerin is the most used plasticizer for alginate films [2,31].

Another key excipient in OTF formulations is swellable cross-linked biopolymers known as disintegrants, which promote disintegration through the synergistic action of water absorption and swelling [32]. Swellable disintegrant agents speed up the process by absorbing water and swelling, thus enhancing the bioavailability and disintegration properties of OTF. Common swellable disintegrants are sodium starch glycolate (SSG), croscarmellose sodium (CCS), and crospovidone (CP) [2]. Notably, SSG stands out for its ability to uptake water rapidly, followed by fast and massive swelling while remaining insoluble in water [33]. The SSG swellable disintegrant outperforms traditional high molecular weight viscosity agents like guar gum, xanthan gum, and pectin in improving film drug content uniformity, especially for poorly water-soluble drugs such as griseofulvin, fenofibrate, and fexofenadine [34,35,36].

It is also noted that SSG is a superior dispersant compared to traditional dispersants such as sugar (sucrose) and sugar alcohols (mannitol, sorbitol) [37]. A significantly lower amount of the SSG compared to traditional dispersants provides a similar range of rheological properties of ink suitable for 3D printing [38,39]. In addition to its lower quantity utilization compared to typical dispersants, SSG’s natural origin, biodegradability, and compatibility with pharmaceutical applications support the industry’s transition to more sustainable, environmentally friendly, and effective drug delivery methods [40,41]. A few articles have used SSG as a swellable disintegrator and viscosity enhancer of polymer paste formulations [32,34,35,42]. However, there is currently no research on how the addition of SSG affects the rheological properties of SA polymer inks, its role in 3D printing thin films, and its impact on the mechanical properties of films.

This study explores how incorporating SSG, a swellable crosslinked biopolymer, into SA film-forming polymer ink enhances the ink’s rheological properties, such as viscosity, shear-thinning behavior, and viscoelasticity, leading to successful 3D printing using a PAM printer with accurate shape fidelity. We also assess how SSG influences the film’s mechanical properties and further improve these properties by adding glycerin as a plasticizer. Glycerin is used as a plasticizer because it is widely used and commonly found in pharmaceutical formulations [7,43,44]. Fenofibrate (FNB), which is used to treat high cholesterol levels, was used as a model drug in this study.

Download the full article as PDF here Evaluating Swellable Cross-Linked Biopolymer Impact on Ink Rheology and Mechanical Properties of Drug-Contained 3D-Printed Thin Film

or read it here

Materials

Alginic acid sodium salt (SA) was purchased from Acros Organics (Morris Plains, NJ, USA). Fenofibrate and polyvinylpyrrolidone K 30 (PVP K30) were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Cross-linked biopolymer sodium starch glycolate (Explotab) was donated by JRS PHARMA GmbH & Co. Kg (Rosenberg, Germany). As-received SSG was sieved using mesh openings of 75, 63, 45, and 25 µm nominal size. Particles smaller than 45 µm were used in this study. The sieving was performed to minimize clogging of the nozzle of the printing head because SSG particles swell significantly in water [45]. Polyethylene glycol 6000 (PEG 6000) and D-mannitol 97%+ were purchased from Alfa Aesar (Thermo Fisher Scientific, Ward Hill, MA, USA). Refined glycerin (99.7% vegetable grade) was purchased from Twin Rivers Technologies (Quincy, MA, USA).

Rony, F.K.; Appiah, J.; Alawbali, A.; Clay, D.; Ilias, S.; Azad, M.A. Evaluating Swellable Cross-Linked Biopolymer Impact on Ink Rheology and Mechanical Properties of Drug-Contained 3D-Printed Thin Film. Pharmaceutics 2025, 17, 183. https://doi.org/10.3390/pharmaceutics17020183

Read also our introduction article on Mannitol here: