Particle engineering enables laser powder bed fusion of highly loaded metoprolol tablets at room temperature

Abstract

Laser powder bed fusion (LPBF) is a promising additive manufacturing technology for producing personalized pharmaceutical dosage forms at industrial scale. In this process, a laser fuses thin layers of powder composed of an active pharmaceutical ingredient (API) and a binder to build three-dimensional objects layer-by-layer. A key limitation for pharmaceutical application of LPBF is the poor flowability and spreadability of fine and cohesive API powders, especially at high API loadings, which can cause spreading defects and poor process reproducibility. The purpose of this study was to enable LPBF manufacturing of highly loaded metoprolol (MTP) tablets by tailoring powder properties through particle engineering. Tangential spray fluidized bed processing was employed to produce MTP–polymer composite particles with API loadings between 75-90% (w/w).

The engineered particles exhibited narrow particle size distributions, good flowability, and favorable spreadability, as determined by the roughness index of the spread powder layers. Tablets were manufactured without preheating the powder, using the laser as the sole energy source. Stimulated Raman scattering microscopy allowed visualization of the fine distribution of MTP and polymer within the tablets across the different API loadings. This particle engineering approach overcomes key material barriers to LPBF of highly loaded drug products and demonstrates that room-temperature manufacturing of metoprolol tablets is feasible. This strategy provides a foundation for extending LPBF to highly dosed APIs, supporting future development of personalized medicines.

Introduction

Personalized Medicine aims to deliver “tailor-made prevention and treatment strategies” to individual patients.1 Advances in this direction are most prominent with injectable formulations, e.g., for biologics, where dose adjustments via injection volume are straightforward for targeted therapies. However, applying the principles of personalized medicine is also valid for solid oral medication, especially when interindividual differences between patients have been correlated to a lack of therapeutic efficacy or drug safety risks.2, 3, 4, 5 Swen et al. showed that therapy adjustments based on pharmacogenetic testing reduced the incidence of adverse drug reactions by 30%.6 To realize mass-produced personalized solid oral medicines, advanced manufacturing technologies are required. Additive manufacturing (AM), commonly known as 3D printing, enables on-demand fabrication of patient-specific dosage forms with controlled release profiles. Among the AM techniques tested for pharmaceutical applications, laser powder bed fusion (LPBF), also known as selective laser sintering, has demonstrated its potential for large-scale manufacturing while maintaining high accuracy, design flexibility, and compatibility with industrial implementation.

In LPBF, a laser selectively fuses powder particles to build three-dimensional objects layer-by-layer. LPBF is widely applied in metal and polymer industries, primarily for prototyping and manufacturing complex components. The majority of powders used for industrial LPBF applications are single-material powders specifically designed for the process. Typical powders for LPBF require average particle sizes of 15–90 µm, a spherical shape, and excellent flowability to form thin, uniform, and defect-free layers.7 In contrast, pharmaceutical applications employ at least binary systems, consisting of an active pharmaceutical ingredient (API) and a binder, typically a polymer. The binder material should exhibit thermoplastic properties in order to soften upon heating and solidify upon cooling, without undergoing chemical modifications. In its softened state, most binders have low viscosity so that they can coalesce into a fused microstructure. Pure API particles do not meet these requirements, as they are often fine cohesive powders with poor flowability and lack proper thermoplastic properties. Consequently, API-binder mixtures for LPBF typically require a large proportion of binder to enable successful processing, thereby limiting drug loading.8 Low API loading can be problematic as it often results in larger dosage units that are difficult to swallow, particularly for paediatric or geriatric patients. High API loading is also relevant when combining multiple APIs in a single dosage form, such as in polypills for cardiovascular therapy.

To process highly loaded API powders into dosage forms, the particle characteristics must be optimized. Fluidized bed processes are widely used in the pharmaceutical field to co-process composite mixtures to modify the size, shape, flow properties, and functionalities of powder particles. In fluidized bed processes, the primary particles are aerated and kept in constant movement (fluidized) by an upward air flow.9 Granulation or coating liquids are sprayed into the fluidized bed through a nozzle via top-, bottom-, or tangential-spray configurations, resulting in distinct particle properties. Top-spray produces more granular, low-density particles suitable for compaction into tablets, while bottom-spray excels in coating, especially with a Wurster tube insert, and tangential spray generates denser, more spherical granules.10 For tablet compaction processes, optimized particles improve compressibility, prevent segregation, and ensure content uniformity and API distribution.

In this study, we apply fluidized bed granulation to improve the particle characteristics of highly API-loaded formulations to enable LPBF manufacturing of tablets. Metoprolol succinate (MTP) was selected as a model API, given its need for personalized dosing. Its pharmacokinetic variability is inherently high, largely due to polymorphisms in the main metabolizing enzyme CYP2D6.11 MTP particles were granulated by spraying a polyvinylpyrrolidone-vinyl acetate (PVP/VA)–water solution in a tangential spray fluidized bed system with varying drug contents between 75 and 90% (w/w). The engineered MTP-PVP/VA particles were evaluated for particle size distribution, flowability, and spreadability, and compared to the physical mixtures. LPBF was employed to manufacture tablets at ambient temperature. The tablets were thoroughly characterized and analysed using stimulated Raman scattering microscopy to image the spatial distribution of PVP/VA and MTP.

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Materials

Metoprolol succinate (MTP, Zentiva, Slovakia) was used as model API. Colloidal silica (Aerosil® 200, Evonik, Germany), kindly donated by Evonik, was used as glidant. Copovidone (PVP/VA, Kollidon VA 64®, BASF, Germany) was kindly donated by BASF. For the dissolution study, a 50 mM phosphate buffer pH 6.8 was prepared using sodium phosphate monobasic dihydrate, phosphoric acid, and ultrapurified water from a MilliQ purification system (Merck KGaA, Germany). Acetonitrile (HPLC-S gradient grade, Biosolve BV, the Netherlands) was used for UPLC analysis.

Florian Engelsing, Wessel Kooijman, Teemu Tomberg, Clare Strachan, Lukas Vaartjes, Jochen Thies, Annette Grave, Robbert Jan Kok, Julian Quodbach, Particle engineering enables laser powder bed fusion of highly loaded metoprolol tablets at room temperature, Journal of Pharmaceutical Sciences, 2026, 104531, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104531.

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