Pharmaceutical 3D Printing Beyond Printability: Polymer Functions, Structural Design, and Predictable Drug Release

Abstract

Oral solid dosage forms, due to their mature manufacturing processes and stability, have become the cornerstone of clinical drug therapy. However, fixed dosages, uniform components, and large-scale production may not meet increasingly complex personalized requirements. The emergence of 3D-printed drugs provides a potential solution to this challenge. Drug 3D printing has progressed beyond feasibility verification and is moving toward functional dosage form design. Current research primarily focuses on printability; however, this review integrates printing technology, polymer functionality, structural design, release behavior, and translational requirements, summarizing mainstream printing technologies, including Fused Deposition Modeling (FDM), Direct Ink Writing/Semi-Solid Extrusion (DIW/SSE), Powder Bed Printing (SLS/BJ), and Photopolymerization (SLA/DLP). Polymers are classified according to drug release control functions, illustrating how modulation of porosity, filling density, shell thickness, material partitioning, and spatial drug distribution enables 3D-printed dosage forms with diverse therapeutic functions. These functions include immediate and sustained release, gastric retention, intestinal targeting, and sequential release of multiple components. This review provides guidance for technical selection, structural design, and formulation development of 3D-printed drugs, while highlighting major translational barriers, including limited printable excipients, empirical formulation development, insufficient structure-based release prediction, quality control challenges, and weak clinical evidence. Future progress requires close integration of material, process, structure, and performance, enabling 3D-printed drugs to evolve from individual prototypes into scalable, quality-controllable, and clinically translatable drug delivery systems.

1. Introduction

Oral solid dosage forms remain central to clinical pharmacotherapy due to their manufacturing maturity, stability, and patient acceptability [1]. However, formulations with fixed doses, homogeneous compositions, and large-scale production may be inadequate for specific clinical scenarios, particularly in pediatric and geriatric patients, individuals with dysphagia, patients requiring long-term therapy, and those needing flexible dose adjustment, multi-drug regimens, or tailored release profiles [2,3,4]. Therefore, a major challenge in modern formulation science is how to translate the flexibility of material, process, and structural design into predictable release performance and quality-assured manufacturing [5].

Pharmaceutical 3D printing provides a formulation-manufacturing approach in which digital designs can be directly translated into the geometry and internal architecture of dosage forms [6]. By regulating external morphology, internal density, pore structure, shell thickness, material partitioning, and spatial drug distribution, 3D printing enables the design of dosage forms based on wetting pathways, diffusion distances, exposed surface areas, and release kinetics [7]. In this context, structure serves as an active formulation variable rather than a passive container, as the same material system can exhibit distinct disintegration, dissolution, and release behaviors when fabricated with different geometries, infill patterns, pore networks, or multi-zone architectures [3,8,9,10,11,12].

Over the past decade, pharmaceutical 3D printing has evolved from proof-of-concept demonstrations toward functional formulation development and early-stage translational evaluation [13]. The approval of Spritam®, a porous 3D-printed levetiracetam formulation designed for rapid dispersion, demonstrated the commercial feasibility of printed pharmaceuticals [14]. However, Spritam® mainly highlights the feasibility of producing porous, rapidly dispersible printlets and does not, by itself, address the broader challenge of establishing predictable relationships between complex printed structures and drug-release performance. Recently, printed drug products and manufacturing platforms have been increasingly investigated in preclinical, translational, and regulatory-oriented studies, reflecting growing interest in their clinical and industrial applicability [13].

Despite these advances, the central question in pharmaceutical 3D printing is shifting from whether a formulation can be printed to whether its material composition, process parameters, and structural features can enable predictable, reproducible, and clinically relevant drug-release performance [5]. Each printing technology imposes a distinct material processing window, including requirements for thermoplasticity, rheological properties, powder flowability, energy absorption, or photoreactivity; however, most pharmaceutical excipients were originally developed for conventional processes such as compression, coating, or capsule filling rather than layer-by-layer manufacturing [15,16,17]. Moreover, drug release from printed formulations is governed not only by polymer hydrophilicity, hydration, dissolution, and degradation, but also by structural variables such as infill density, porosity, shell thickness, surface area-to-volume ratio, and multi-material spatial distribution. As structural complexity increases, formulation development often remains empirical, and transferable design principles linking material properties, process parameters, structural features, and release kinetics remain insufficiently established [17,18,19,20].

Building on previous reviews of printing technologies, materials, and personalized medicines, this review links polymer functions and processing constraints to structural variables and experimentally observed drug-release behavior. It examines how these relationships guide formulation design and what evidence is needed for prediction and translation. The primary focus is oral and oral-related dosage forms, with implantable and localized systems considered as extensions. Study selection and evidence interpretation are described below. Literature Search Strategy: To provide a comprehensive narrative overview of pharmaceutical 3D printing, the relevant literature was retrieved from PubMed, Web of Science, and Google Scholar. The search period primarily covered publications from 1990 to April 2026, supplemented by representative high-quality reviews and key original studies. The search terms included, but were not limited to, “3D printing”, “additive manufacturing”, “pharmaceuticals”, “drug delivery”, “polymers”, “fused deposition modeling”, “hot-melt extrusion”, “semi-solid extrusion”, “selective laser sintering”, “binder jetting”, “stereolithography”, “digital light processing”, “printability”, “drug release”, and “personalized medicine”. The selected literature primarily focused on pharmaceutical 3D-printing processes, polymer material selection, formulation structure design, drug-release control mechanisms, and advances in clinical translation. Representative original studies were selected when they provided sufficient information on the printing method, formulation or polymer matrix, model drug, dosage-form design, and experimentally characterized release behavior. Studies were further selected to represent different printing platforms, material systems, structural strategies, and release functions, while avoiding excessive duplication of highly similar formulations. Representative studies were selected when they clearly demonstrated a relationship between defined formulation or structural features and the intended drug-release function, covering immediate/rapid release, sustained/controlled release, gastrointestinal site-specific delivery, and multicomponent or sequential release.

2. Pharmaceutical 3D Printing Technologies: Process Windows and Formulation Compatibility

Pharmaceutical 3D printing should be considered a family of formulation-manufacturing technologies rather than a single preparation method. Each printing process defines a specific material window, including feedstock form, energy input, solidification mechanism, post-processing requirements, and potential quality risks. In pharmaceutical formulations, technology selection is not simply an equipment-related decision but represents the starting point of formulation design. This choice determines whether the drug maintains stability, the material remains processable, the printed structure achieves sufficient integrity, and the intended release profile can be reproducibly obtained. The three major categories of pharmaceutical 3D printing technologies and their representative manufacturing processes are schematically illustrated in Figure 1.

Based on current research and translational progress, pharmaceutical 3D printing can be broadly categorized into material extrusion, powder-bed printing, and photopolymerization-based printing technologies [5]. Material extrusion technologies include FDM and DIW/SSE [3,21]. Powder-bed printing includes binder jetting (BJ) and selective laser sintering (SLS), which are particularly suitable for fabricating porous structures and support-free architectures [22,23]. Photopolymerization-based printing, represented by stereolithography (SLA) and digital light processing (DLP), offers advantages in producing high-resolution microstructures, microneedles, and localized delivery devices [24,25]. The applicability of each technology depends on drug properties, excipient characteristics, target dosage form, and release requirements [15].

2.1. Material Extrusion Printing: FDM and DIW/SSE

Material extrusion is the most extensively studied category of pharmaceutical 3D printing and produces printlets through nozzle-based deposition of softened or flowable drug-containing materials [26,27]. Although FDM and DIW/SSE both rely on path-controlled layer-by-layer deposition, they differ fundamentally in terms of feedstock characteristics, processing stress, and formulation constraints [28]. FDM generally requires drug-loaded thermoplastic filaments prepared by hot-melt extrusion (HME). Therefore, polymer glass transition or melting behavior, melt viscosity, filament mechanical strength, drug thermal stability, and interlayer adhesion collectively determine printability and the quality of final products [16,29]. FDM is particularly suitable for fabricating mechanically robust printlets, controlled-release formulations, gastroretentive systems, polypills, and complex architectures containing shells, channels, or internal compartments [30,31]. However, its application remains limited by thermal processing requirements, potential drug solid-state alterations, filament brittleness, feeding instability, and restricted drug-loading capacity. Fused filament fabrication (FFF) is broadly equivalent to FDM and is also used to describe filament-based material extrusion in pharmaceutical studies. Other related approaches reported in pharmaceutical manufacturing include Arburg Plastic Freeforming–Droplet Deposition Modeling (APF-DDM), a thermal droplet-based freeforming process, and direct extrusion additive manufacturing (DEAM), a filament-free material extrusion approach. Injection volume filling (IVF), although not itself an extrusion-printing process, has also been combined with printed cavities or scaffolds to introduce drug-containing formulations after fabrication.

DIW/SSE uses gels, pastes, slurries, or semi-solid inks that are extruded through a nozzle under pneumatic, piston-driven, or screw-driven pressure. Compared with FDM, DIW/SSE operates under milder processing conditions and provides greater formulation flexibility, making it particularly suitable for heat-sensitive drugs, high drug-loading systems, orodispersible formulations, and small-batch personalized manufacturing [28,32]. However, DIW/SSE shifts the primary formulation challenge from thermoplastic processability to precise rheological regulation. Parameters including ink viscosity, yield stress, shear-thinning behavior, structural recovery, drying shrinkage, and solvent removal critically affect dimensional accuracy, interlayer integrity, dose uniformity, and release reproducibility. Thus, FDM performance is primarily determined by thermal processing parameters and filament properties, whereas DIW/SSE relies more heavily on ink rheology, shape retention, and post-processing stability [33,34].

2.2. Powder-Bed Printing: BJ and SLS

Powder-bed printing fabricates dosage forms by selectively consolidating powder layers through binder-mediated bonding or laser-assisted sintering [35,36]. Unlike extrusion-based printing, powder-bed processes rely on powder spreading and localized consolidation, while the surrounding unsolidified powder can serve as temporary support during fabrication [36,37]. These characteristics make powder-bed printing suitable for producing porous, rapidly wetting, or support-free structures, but also introduce quality challenges associated with powder flowability, layer uniformity, powder removal, powder recovery, dust control, and mechanical robustness [38].

BJ forms printlets by depositing binder droplets onto powder beds, producing highly porous and low-density structures that facilitate rapid medium penetration and disintegration. The commercial example of Spritam® highlights the translational potential of BJ in the development of rapidly dispersing oral formulations [35,39]. However, the dependence of structural integrity on localized binder-particle bonding may result in insufficient mechanical strength, increased friability, uneven binder distribution, and difficulties in maintaining dose uniformity. Therefore, effective management of powder handling, de-dusting, powder recycling, and cross-contamination control remains essential for the scale-up and industrial implementation of the technology [38,39]. SLS consolidates polymer powder beds through localized laser-induced softening, melting, or sintering processes. Compared with BJ, SLS generally achieves higher structural integrity without the use of liquid binders; however, the applied laser energy may also affect powder-bed characteristics, including porosity, drug dispersion, crystallinity, and subsequent release behavior [37,40]. Owing to these features, SLS is suitable for fabricating porous printlets, orodispersible systems, sustained-release structures, and formulations in which controlled powder sintering is exploited to regulate dissolution. Nevertheless, thermal exposure during processing, variations in powder spreading, potential thermal degradation, and the requirement for light-absorbing agents may compromise drug stability, excipient safety, content uniformity, and release reproducibility [40]. Overall, BJ is more advantageous for highly porous and rapidly disintegrating formulations, whereas SLS is more appropriate for solvent-free powder-based structures that require enhanced mechanical integrity or sintering-mediated control of drug release. For both technologies, major barriers to clinical and industrial translation include powder processability, powder recovery, product robustness, batch-to-batch consistency, and control of the manufacturing environment [35,38].

2.3. Photopolymerization Printing

Photopolymerization-based printing, including SLA and DLP, fabricates three-dimensional structures through light-induced polymerization or crosslinking of liquid resins, prepolymers, or hydrogel precursors containing photoreactive groups [41,42]. Compared with material extrusion and powder-bed printing, the primary advantages of photopolymerization-based technologies are their high resolution, excellent surface quality, and strong microstructural fabrication capability. These characteristics make SLA/DLP particularly suitable for applications such as microneedles, ocular inserts, implantable devices, drug-eluting structures, and hydrogel-based localized delivery systems [43,44]. However, their application in high-dose oral solid dosage forms remains limited, mainly because most photopolymerization systems require photoreactive monomers, oligomers, crosslinkers, and photoinitiators. The presence of these components raises concerns regarding residual toxicity, incomplete curing, potential drug instability, and long-term biocompatibility [45].

For drug-containing systems, photopolymerization enables the regulation of drug release through adjustments in crosslinking density, network pore size, hydrogel composition, and device geometry. This feature makes photopolymerization-based printing particularly suitable for localized or microstructured delivery systems, in which drug release is primarily controlled by diffusion through a crosslinked network. Nevertheless, factors including drug loading, light penetration, resin viscosity, oxygen inhibition, curing shrinkage, post-curing treatment, and residue removal can significantly affect product quality and release reproducibility [42,46]. Emerging technologies such as CLIP and TPP may further enhance printing speed or microscale resolution; however, their pharmaceutical applications remain largely limited to research-stage microstructures and localized delivery devices [41,47,48,49]. Volumetric additive manufacturing (VAM), particularly tomographic volumetric printing, represents another emerging photopolymerization approach with potential relevance to pharmaceutical manufacturing. Unlike SLA and DLP, which construct objects sequentially layer by layer, VAM generates three-dimensional structures within a photosensitive resin by delivering multiple angular light projections that collectively exceed the polymerization threshold only within the target volume. This layerless fabrication strategy can substantially reduce manufacturing time; drug-loaded printlets have been produced within seconds, and simultaneous fabrication of multiple tablets has also been demonstrated. Such rapid processing may be advantageous for on-demand or point-of-care production of personalized medicines, while the absence of sequential layering may reduce layer-associated defects and broaden the processing window for certain viscous formulations [50,51]. However, pharmaceutical applications remain at an early stage and are constrained by requirements for optically suitable and photoreactive formulations, limited availability of pharmaceutically acceptable resin systems, light scattering or absorption by drugs and excipients, residual monomers and photoinitiators, and the need to establish reproducible relationships among light dose, drug loading, mechanical properties, and release behavior. Therefore, although VAM offers a promising route toward high-speed fabrication of personalized drug products and drug-delivery devices, further advances in pharmaceutical-grade materials, formulation optimization, and quality-control strategies are required before broader clinical translation.

2.4. Matching Printing Technologies with Dosage-Form Functions

The suitability of a pharmaceutical 3D printing technology should not be evaluated solely based on resolution, printing speed, or geometric complexity. Instead, it should be determined by whether the material window, processing stress, post-processing requirements, and potential quality risks of the technology are compatible with the intended dosage-form function and release mechanism [52,53]. For oral printlets and programmable release systems, extrusion-based printing should be considered as a broad platform that includes both FDM and DIW/SSE. Although these approaches differ in material state and processing requirements, they share similar structural-programming capabilities because both rely on nozzle-based deposition along digitally defined paths. Accordingly, parameters such as infill density, shell thickness, pore architecture, channel design, multilayer organization, and spatial material distribution can be used in both systems to regulate water uptake, diffusion distance, exposed surface area, and release kinetics [54,55]. The main difference between FDM and DIW/SSE lies not in the types of structures that can be produced, but in process-specific limitations associated with their respective material systems. FDM is mainly limited by thermal exposure, melt processability, filament or feedstock properties, and drug thermal stability [56,57], whereas DIW/SSE is mainly affected by ink rheology, solvent removal, drying shrinkage, residual solvent control, drug migration, and post-printing structural retention [33,34].

For immediate-release or orally disintegrating formulations, powder-bed printing and DIW/SSE are useful because they can promote rapid medium penetration, high porosity, and fast disintegration. In contrast, FDM typically requires additional design strategies, such as hydrophilic matrices, low infill density, internal channels, disintegrants, or pore-forming excipients, to achieve accelerated drug release. For sustained-release, delayed-release, gastrointestinal-targeted, and multi-drug formulations, extrusion-based printing plays a particularly important role because shell structures, barrier layers, internal channels, and compartmentalized architectures can be directly incorporated into the dosage form during printing [55]. SLS may also contribute to these applications through porosity regulation and sintering-induced solid-state modification, whereas BJ is more commonly associated with highly porous, rapid-disintegration systems [58]. Compared with these technologies, photopolymerization-based printing is more relevant to microneedles, ocular inserts, hydrogel devices, and localized implants than to high-dose oral printlets. This formulation-driven selection principle also provides a basis for polymer selection, as polymers must simultaneously meet the requirements of processability, structural retention, drug compatibility, and release regulation [52,54]. The processing characteristics, pharmaceutical applications, and formulation constraints of the major 3D printing technologies are summarized in Table 1.

Table 1. Representative processing characteristics, pharmaceutical applications, and formulation constraints of major 3D-printing technologies.

Note: BJ, binder jetting; DIW, direct ink writing; EC, ethyl cellulose; FDM, fused deposition modeling; GelMA, gelatin methacryloyl; HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PCL, polycaprolactone; PEGDA, poly(ethylene glycol) diacrylate; PEO, polyethylene oxide; PLA, polylactic acid; PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; SLA, stereolithography; SLS, selective laser sintering; TPU, thermoplastic polyurethane.

Download the full article as PDF here: Pharmaceutical 3D Printing Beyond Printability: Polymer Functions, Structural Design, and Predictable Drug Release

or read it here

Liu, Z.; Huang, Y.; Liu, Y.; Huang, R.; Xie, P.; Ma, X.; Chen, P.; Li, X. Pharmaceutical 3D Printing Beyond Printability: Polymer Functions, Structural Design, and Predictable Drug Release. Pharmaceutics 2026, 18, 1330.
https://doi.org/10.3390/pharmaceutics18101330

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