Semisolid extrusion 3D printing for pharmaceutical compounding: influence of active ingredients on alginate-based inks and tailored-dosage forms properties

Abstract

The most relevant challenge concerning the semi-solid extrusion 3D printing (SSE) pharmaceutical application is the development of versatile inks that can bypass the limitations of drug-matrix combinations. The present study aims to elucidate how physicochemical properties of different Active Pharmaceutical Ingredients (APIs) influence the performance of an alginate hydrogel-ink, as a function of drug concentrations (5 or 10% w/V). Precrosslinked alginate was used as matrix, while different NSAIDs (i.e., Ibuprofen, Ketoprofen, and Ketoprofen lysine salt) were used as model drugs, exploiting their differences in water solubility to obtain solubilized or dispersed drug. The match of FT-IR and rheological characterizations highlighted how drug solubilization in polymer matrix can generate chemical interaction leading to alteration of hydrogel entanglement, greater at higher drug concentration. Nevertheless, it was possible to reach optimal printability for all developed inks (tablet mass variation less than 10%), ensuring high encapsulation efficiency (>90%) for all matrices except for the ink loaded with 10% w/V of solubilized drug because the excessive entanglement disruption led to matrix leakage during post-printing. Release studies showed that all tablets had similar release behavior governed by the polymer matrix with a Super Case II transport. These results underlined the potentialities of the developed alginate matrix as a versatile SSE ink for compounding applications.

Introduction

The new paradigm of personalized medicine aims to provide a differentiation of healthcare services based on patients’ individual characteristics and needs, strengthening the patient-physician-pharmacist triad in clinical decision-making (Lopalco & Denora, 2026). This ongoing transition has introduced new challenges, especially in the pharmaceutical field. In this context, the investigation of new technologies for pharmaceutical development is crucial to fill the gap toward personalized medicine, enabling the preparation of tailored medicines (Aquino et al., 2018). Among technologies recently introduced in the pharmaceutical field, 3D printing (3DP) is certainly the most interesting for compounding (Murugan et al., 2024; Zema et al., 2017). In detail, 3D printing is a subset of techniques that vary in function of the physical or chemical phenomenon used to construct the model (i.e., material fusion, UV radiation, laser sintering, and others) (Seoane-Viaño et al., 2021).

Among these, semisolid extrusion 3D printing (SSE) is nowadays the most attractive for personalized medicine applications (Auriemma et al., 2022). SSE process involves a semisolid starting material (in the form of gel or paste) that is extruded through an orifice by compressed air pressure, a syringe plunger, or a screw, depending on the specific equipment used. SSE better fits pharma requirements in comparison to other 3DP techniques (such as stereolithography or fused filament fabrication) because starting materials are well established for clinical use since they can be easily obtained by excipients commonly employed in the pharmaceutical industry, and the production process involves mild working conditions, allowing the possibility to use thermosensitive or photosensitive Active Pharmaceutical Ingredients (APIs) or excipients (Cerveto et al., 2024).

One of the first examples of SSE pharmaceutical application dates back to 2014 successfully showed the possibility to produce tablets using two different matrices, i.e., hydroxypropyl methylcellulose and poly(acrylic acid), either alone or in combination, to deliver guaifenesin. They also highlighted the effectiveness of SSE to obtain printed products with technological performance comparable to market products but with potentialities to customize release properties (Khaled et al., 2014). Since that time, the number of scientific articles about the optimization of SSE for pharma application has grown exponentially, confirming potentialities to produce personalized dosage forms with tailorable properties (Lyousoufi et al., 2023; Tracy et al., 2023) (i.e., swallowable tablets (Lopez-Vidal et al., 2022; Roche et al., 2023), chewable tablets (Holkunde et al., 2025; Zhu et al., 2022), gastroretentive tablets (Falcone et al., 2021), orodispersable dosage forms (Yan et al., 2020), muchoadesive films (Abdella et al., 2022), microneedles (L. Zhang et al., 2024), suppositories (Munoz-Perez et al., 2024), and skin patches (Pérez Gutiérrez et al., 2023).

However, there are few examples of studies aimed to test the clinical compounding application of 3D printed platforms, suggesting that the shift from laboratory to real application is still far away(Parramon-Teixido et al., 2025; Rodríguez-Pombo et al., 2024). The major limit of these studies is the unavoidable relationship between APIs and carrier matrix (B. Zhang et al., 2024) to develop 3D printable inks, a lack of understanding of the role of each ink component, and the potential effect of API or excipient variation on both printability as well as technological properties of printed platforms (Elbadawi et al., 2020; Naghieh & Chen, 2021). This limitation constrains to one by one products characterization, requiring the pharmacist to possess technical knowledge about materials science and the purchase of expensive equipment, thus precluding the real expansion of SSE in compounding (Aina et al., 2025; Cerveto et al., 2024). At this stage, the path toward the clinical application of SSE involves overcoming the specificity of the drug-matrix combination, highlighting the role of excipients or APIs to develop flexible inks ready to use in compounding (Alzhrani et al., 2025; Cooley et al., 2025; Heltmann-Meyer et al., 2025). A large variety of polymeric materials were tested in the form of hydrogels as a primary component for 3D printable inks development (Li et al., 2020). Among those materials, alginate is certainly one of the most attractive for application to 3D printing for biomedical and pharmaceutical fields (Mallakpour et al., 2021).

However, its application in 3D printing for drug delivery is strongly limited by mechanical strength and the high degree of spreading after extrusion, which leads to long post-printing processes such as curing or poor shape fidelity (Yadav et al., 2025). In a previous study, the possibility to develop printable alginate hydrogel by modulating its unique gelation properties through ionic crosslinking via pre-crosslinking procedure, was demonstrated (Falcone et al., 2022). Moreover, it was investigated the feasibility to modify this procedure to add in the hydrogel functional excipient, speculating the possibility to predict technological performance of printouts by adapting matrix composition. In detail, it was demonstrated the possibility to add sorbitol as a plasticizer agent to produce easy-to-swallow tablets (Falcone et al., 2023).

In this context, the present work reports a case study on the evaluation and optimization of an alginate-based ink enabling the incorporation of multiple drugs, ensuring a predictable performance profile. Attention was placed on non-steroidal anti-inflammatory drugs (NSAIDs), a specific subset of drugs widely used in routine practices against different pathologies to reduce inflammation and fever and alleviate pain despite gastrointestinal and kidney-related adverse effects (Drosopoulou et al., 2025). Among NSAIDs, ibuprofen (IBU), ketoprofen (KETO), and ketoprofen lysine salt (KLS) have been selected based on their different characteristics, i.e., solubility, pKa, and pharmacokinetic properties. In detail, the aim was to elucidate how physicochemical properties of different APIs influence characteristics of the alginate matrix, establishing a relationship between these properties and both printability and performance of printed formulations. This approach ultimately aims to support a more rational and efficient design of printable inks, leveraging a limited number of key parameters to optimize the printing process for the extemporaneous preparation of personalized dosage forms containing small drugs as active ingredients.

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Materials

Main components of carrier matrix are: sodium alginate (CAS: 9005-38-3, Mw> 200 KDa, β-D-mannuronic, β-L-glucuronic ration 1.33) obtained from Carlo Erba (Carlo Erba, Milan, Italy) calcium chloride dehydrate (CAS: 10035-04-8, Mw= 147.01 g/mol, purity >99%) provided by VWR International (Milan, Italy), and sorbitol 70% water solution (CAS 50-70-4,) purchased by Sigma-Aldrich (Sigma-Aldrich, Milan, Italy). NSAIDs used to perform this investigation are: ibuprofen (Mw=206,28 g/mol, CAS=15687-27-1) purchased by FarmaLabor (Milan, Italy), ketoprofen (Mw= 254.28 g/mol, CAS= 22071-15-4), and ketoprofen lysine salt (Mw= 400.5g/mol, CAS= 57469-78-0), both kindly donated by Dompè (L’Aquila, Italy).

Giovanni Falcone, Chiara Amante, Carla Sardo, Pasquale Del Gaudio, Rita P. Aquino, Paola Russo, Semisolid extrusion 3D printing for pharmaceutical compounding: influence of active ingredients on alginate-based inks and tailored-dosage forms properties, Carbohydrate Polymer Technologies and Applications, 2026, 101230, ISSN 2666-8939, https://doi.org/10.1016/j.carpta.2026.101230.

Read also our introduction article on Alginate here: