Mechanistic Comparison of Semi-Solid Extrusion 3D-Printed Printlets and Hot-Moulded Tablets: Linking Polymer–API Interactions, Microstructure, and Dissolution of Plant-Based Formulations

Abstract

Background: Three-dimensional printing (3DP) is rapidly advancing personalised medicine, yet systematic performance comparison with conventional manufacturing remains limited, particularly for plant-based formulations.

Methods: This study compared tablets containing plant-based APIs (cannabidiol, apigenin, and luteolin) produced via conventional hot moulding and semi-solid extrusion (SSE) 3DP. The formulations were evaluated for physicochemical, mechanical, rheological, structural, and drug-release properties.

Results: Both manufacturing methods produced tablets with comparable dimensions and mass; however, pronounced formulation-dependent differences were observed in mechanical strength, rheology, and microstructure. The molecular modelling predictions were consistent with the experimental findings. Agar–pectin exhibited the strongest predicted polymer–polymer and polymer–API interactions, including multiple hydrogen bonds, and formed a comparatively dense and cohesive matrix associated with slower API release. In contrast, the weaker interactions predicted for gelatine–pectin were associated with a less cohesive and more porous matrix that facilitated medium penetration, API diffusion, and drug release. SSE printlets generally exhibited greater porosity and more heterogeneous internal architectures than moulded tablets, resulting in enhanced drug release of approximately 95%. Micro-CT analysis provided important structural confirmation; API incorporation increased the void volume of gelatine–pectin printlets from 1.15% to 8.77%, demonstrating that disruption of polymer interactions contributed to pore formation and enhanced molecular diffusion. The observed release behaviour correlated with predicted molecular interactions and experimentally observed microstructural features, where increased porosity and weaker polymer–API interactions facilitated enhanced drug diffusion.

Conclusions: Overall, SSE-3DP outperformed conventional moulding, demonstrating superior tunability and performance. This work provides a mechanistically informed strategy for designing plant-based, personalised natural products using 3DP technologies.

Introduction

Conventional manufacturing techniques like direct compression, dry granulation, and wet granulation have long been the norm for producing tablets because they provide accurate dosing, scalability, reproducibility, cost-effectiveness, and good patient compliance [1,2,3]. However, the concept of large-scale, centralised production using tablet presses has remained fundamentally unchanged for over a century. It curbs flexibility in dose individualisation and the incorporation of complex geometries or multiple release profiles, while also requiring proven long-term stability [4,5]. For regular tablets the most commonly used manufacturing techniques are via pressing and compression or via trituration, produced by forming a mass. Compressed tablets can be divided into direct compression of powder or tablet mixture, wet granulation and dry granulation. For soft, gummy, and gel-based dosage forms that are unsuitable for conventional compression, moulding provides a practical alternative. In hot moulding, a heated, flowable formulation is dispensed into predefined moulds and subsequently cooled or gelled to establish its shape and mechanical stability. Other approaches applicable to soft dosage forms include cold-set moulding, automated material deposition, continuous extrusion followed by cutting, and freeze-drying [6,7]. Although these traditional methods support reproducible and cost-effective large-scale production, their dependence on fixed tooling or mould geometry limits rapid adjustment of dose, shape, internal architecture, and drug-release behaviour, particularly for low-dose or sensitive active pharmaceutical ingredients (APIs) and formulations intended for paediatric, geriatric, or otherwise individualised therapy [8,9].

In contrast, three-dimensional (3D) printing has recently developed as a transformative approach in pharmaceutical manufacturing, providing control over tablet geometry, internal structure, and drug distribution [10,11]. The semi-solid extrusion (SSE) method facilitates layer-by-layer fabrication of tablets with adjustable doses and defined release profiles, allowing on-demand production and patient-specific formulations while reducing excipient loss [12]. By overcoming several challenges of conventional manufacturing, 3D printing offers a radical solution toward the development of personalised medicines. Nonetheless, systematic studies comparing traditionally manufactured with 3D-printed tablets (printlets) are required to evaluate their physical characteristics, mechanical strength, and drug-release profile, thereby providing the evidence needed to support clinical translation and regulatory approval.

An additional challenge arises when formulating printlets containing medicinal plant extracts, as these extracts differ from conventional pharmaceutical APIs because of their complex composition, hygroscopicity, and pronounced bitterness. Taste masking is particularly critical for ensuring patient acceptability, especially in paediatric and geriatric populations where palatability and ease of administration strongly influence compliance [12,13]. Traditional methods like coating, β-cyclodextrin/polysaccharides complexation, or the use of sweeteners often deliver partial masking and may reduce drug loading or affect stability [14,15]. SSE printing allows precise loading of bitter plant extracts into polymer matrices along with taste-masking agents, and enables the creation of porous internal structures that enable fast disintegration and rapid release. In contrast to conventional methods, SSE enables on-demand tailoring of dose, size, and flavour within a single process, facilitating the development of patient-friendly, plant-based dosage form with improved compliance and therapeutic outcomes.

Previous studies have widely examined the printlets containing pharmaceutical APIs such as omeprazole [16] and metformin [17]; however, only a few studies have focused on plant-based APIs [18]. This highlights an unmet need for the development of printlets containing plant-based APIs and emphasises the potential of SSE for producing age-specific, patient-centric printlets, importantly in low-resource settings. To date, no comparative framework has been published evaluating comparison of conventional tablets with printlets with respect to visual appearance, texture, and drug-release profiles, and limited studies are available on printlets containing plant extracts.

For the development of such systems, understanding formulation science becomes crucial, as the choice of polymers and their interactions with the drug directly influence performance. Therefore, the selection of optimal polymers is critical for tailoring drug release. Molecular interactions, particularly hydrogen bonding and ionic interactions between drug and polymer, play a crucial role in modulating dissolution and release behaviour. Benko et al. showed that hydrogen bond-based solid-state interactions, identified by FT-IR, significantly enhance drug retention and sustained release in implantable matrices [19]. Similarly, Que et al. reported that hydrogen bonding in amorphous solid dispersions reduces drug release, demonstrating its strong influence on dissolution kinetics [20]. In the case of ionic bonding, a cationic Salecan-g-PMAPTAC hydrogel exhibited a markedly sustained release of diclofenac due to strong ionic affinity, whereas insulin showed faster release [21]. Likewise, Salecan–PNM semi-IPN hydrogels also exhibited pronounced pH-responsive behaviour, with significantly higher DOX release at acidic pH (5.0) than at physiological pH (7.4), due to increased DOX protonation and weakened electrostatic interactions within the network [22]. This finding highlights the importance of assessing the molecular interactions to design the tablets with controlled and predictable drug-release profiles.

This work presents the first comprehensive investigation to test the hypothesis that modelling molecular interactions between polymers and plant-based APIs can help in predicting formulation behaviour and the differences in the release profiles for rationally designed moulded tablets and printlets. The present research also aims for a systematic comparison of conventional moulded tablets formulated through moulding and SSE 3D printing, with emphasis on an advanced structural analysis and drug-release behaviour. Furthermore, the study also explores the incorporation of Artemisia annua L. extract (phytochemicals such as apigenin and luteolin) and cannabidiol (CBD) into SSE-printlets, focusing on the role of different excipient combinations. The insights gained provide a novel molecular–mechanistic correlation, offering a rational design pathway for next-generation, nature-inspired 3D-printed drug delivery systems.

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Materials

The dried Artemisia annua L. herbs were purchased from “Pamario žolynai” (Klaipėda, Lithuania). The chemicals used for this research were crystal CBD purchased from UAB Bioremedium (Vilnius, Lithuania), 96% ethanol (Vilnius, Lithuania), L-Glutathione ≥ 98% (ROTH, Karlsruhe, Germany), gelatine (molecular weight (MW) 50–100 kDa) and citric acid purchased from Sigma-Aldrich (Steinheim, Germany), agar (MW 175 kDa) purchased from Alvo (Panevėžys, Lithuania), pectin (MW 200 kDa) from citrus purchased from TCI (Zwijndrecht, Belgium), hydroxypropyl-methylcellulose (HPMC) “Methocel K15M” (viscosity of 15,000 cP, MW 575 kDa) purchased from IFF (New York, NY, USA), and sugar purchased from AB Nordic Sugar (Kėdainiai, Lithuania).

Nemickaite, E.; Todke, P.; Cicenas, V.; Jasiūnienė, E.; Marksa, M.; Bernatoniene, J. Mechanistic Comparison of Semi-Solid Extrusion 3D-Printed Printlets and Hot-Moulded Tablets: Linking Polymer–API Interactions, Microstructure, and Dissolution of Plant-Based Formulations. Pharmaceutics 2026, 18, 1035. https://doi.org/10.3390/pharmaceutics18081035

Read also our introduction article on 3D Printing here: