Laser powder bed fusion of amitriptyline tablets via eutectic mixtures using sugar alcohols as binders

Abstract

Laser powder bed fusion is an additive manufacturing technique with a big potential for producing personalized pharmaceutical dosage forms on an industrial scale. To date, primarily thermoplastic polymers have been used as binding excipients in investigations. This work demonstrates that sugar alcohols erythritol, mannitol, and xylitol are excellent alternatives as binding excipients for laser powder bed fusion in terms of processability, content uniformity, and tablet strength. A robust dose calibration strategy demonstrates that tablets can be compounded with precise and accurate mass by powder bed fusion utilizing a laser as the only source of energy.

Manufacturing without preheating reduces energy costs and reduces the risks of thermal degradation of API and excipients, which potentially improves the recyclability of residual powder. Amitriptyline hydrochloride was used as the model drug, as personalized medication of this compound is valuable for therapeutic dosing regimens in the treatment of depressive disorders. Phase diagrams showed that amitriptyline forms eutectic mixtures with sugar alcohols. We show that the formation of eutectic mixtures affords reduction of the laser energy density, thus further lowering the risk of thermal degradation. We demonstrate the great potential of sugar alcohols as binders in laser powder bed fusion with exploitable interactions with amitriptyline hydrochloride.

Introduction

A wide variety of genetic, biological, and lifestyle factors influence how medicines are absorbed, distributed, metabolized, and excreted by the body, affecting their safety and efficacy [1], [2], [3], [4], [5], [6], [7]. The personalized medicine concept states that medical therapies should be tailored to patient characteristics, hence affording the proper dosing regimen tailored to optimal pharmacotherapeutic outcome. Manufacturing personalized medicine to supply a larger part of society would require a paradigm shift in industrial manufacturing of oral solid-dose medicines from producing large amounts of “one size fits all” to a variety of different dose strengths. Tablet compression is an optimized process for large-scale tablet production, but it lacks the flexibility needed for compounding such personalized dosage forms. Pharmacies can personalize medication through means of capsule filling or other compounding technologies. However, while effective, these methods are labor-intensive and not scalable for widespread personalization. Recently, additive manufacturing has emerged as a technique for the production of personalized dosage forms [8], [9], [10], [11]. Powder bed fusion – laser beam (PBF-LB) has shown particular promise for the scalable production of personalized dosage forms, offering high precision, design flexibility, and suitability for industrial implementation. In the pharmaceutical field, this technique is also known as selective laser sintering (SLS) or laser powder bed fusion (LPBF).

PBF-LB utilizes a laser to fuse powder particles according to a computer model. It operates in a layer-by-layer fashion and is typically used in industry for prototyping or small-scale production of complex parts. A PBF-LB formulation requires two basic components: the active pharmaceutical ingredient (API) and a binder. A variety of polymers, such as copovidone, polyvinyl alcohol, and polyethylene glycol, commonly used as coatings, dissolution modifiers, stabilizers, or hot-melt extrusion binders, have also shown potential as PBF-LB binders [12], [13]. They are thermoplastic, cost-effective, possess suitable glass transition temperatures and melting points, and do not undergo chemical changes during processing, making them suitable as binders in PBF-LB. Despite the advantages of these polymers, commonly used thermoplastic polymers have high melt viscosities, limiting coalescence of the material resulting in brittle and weakly bound tablets [14], [15], [16]. Additionally, thermoplastic polymers are often processed at elevated temperatures, which alters the material properties leading to reduced recyclability [17]. Expanding the excipient toolbox to include materials with different physicochemical properties would give more options and flexibility in formulation development. Sugar alcohols are promising candidates due to their safety, favorable thermal properties, and pharmaceutical relevance and availability.

Sugar alcohols are derived from monosaccharides or disaccharides through the reduction of carbonyl group(s). Sugar alcohols exhibit a broad melting temperature range (~95–225 °C) and are well suited for PBF-LB [18]. Their melt viscosity (10−2 -100 Pa·s) is significantly lower than that of commonly used thermoplastic polymers (103–106 Pa·s), suggesting that the molten sugar alcohols have improved coalescence and material flow to densify and bind powder particles during PBF-LB [14], [15], [16], [19]. Mannitol’s potential as a binder in PBF-LB has been demonstrated by Gotoh et al., while Allahham et al. and Stanojevic et al. have investigated its use as a filler [20], [21], [22]. Horváth et al. showed that sorbitol can function as a melt binder in twin-screw melt granulation [23]. Sugar alcohols are also commonly used as binders/fillers in tablet compression [24], [25].

Sugar alcohols are commonly used as food additives and can be found in various products such as cereal bars, toothpaste, and baby formula. Naturally, they also occur in many foods, for example mushrooms, cauliflower, and cheese. Sugar alcohols provide a similar level of sweetness to sugar but with a reduced caloric value. Their safety was established in 1994 by the European Parliament and Council, which has assigned them an acceptable daily intake of “quantum satis”, which means that usual levels of food additives do not represent a health concern [26]. Erythritol has recently been reevaluated by the European Food Safety Authority, and an acceptable daily intake of 0.5 g/kg was established to prevent immediate laxative effects and potential chronic effects [27].

Mannitol and xylitol are part of the same series of evaluations, but these evaluations are still ongoing as of the writing of this publication [28]. Excessive intake of mannitol and xylitol (> 20 g per day) can cause gastrointestinal discomfort, most notably laxation [29], [30]. The established daily intake limits are well above the quantities that would be present in tablets, confirming their safe applicability in this context. More recently, Hazen et al. reported a correlation between xylitol and erythritol intake and an increased risk of major adverse cardiovascular events [31], [32]. No direct causation was shown but new findings on the long-term safety of xylitol and erythritol should be taken into account in regard to this work.

The safety and versatile applicability of sugar alcohols leads to a high demand in the food and pharmaceutical industries, resulting in a wide range of chemical and physical grades available on the market. This diversity is advantageous for PBF-LB, which requires binders with specific melting temperatures and particle sizes. Additionally, their varying levels of sweetness can serve as effective taste masking agents. Sugar alcohols are also highly water-soluble, making them ideal for immediate-release dosage forms. To investigate the practical application of sugar alcohols as binders in PBF-LB, this study investigates their use in formulations for the delivery of the API amitriptyline hydrochloride (AMT).

AMT is a tricyclic antidepressant used in psychiatric disorders. It works through inhibition of serotonin and norepinephrine transporters, thus prolonging the activation of serotonergic and adrenergic neurons. There are numerous indications for which AMT is prescribed, such as depression, chronic pain management, including obsessive–compulsive disorder, panic attacks, generalized anxiety disorder, post-traumatic stress disorder, bulimia nervosa, smoking cessation, or enuresis [33]. Depending on the indication and patient, tablet dosages can vary between 10 and 150 mg for patients [34]. The available tablet dosages are 10, 25, 50, 75, and 100 mg [35].

Due to the risk of withdrawal, antidepressants like AMT often require careful tapering when medication is changed or discontinued. Changing the drug dose in a hyperbolic tapering method, with daily dose reductions averaging around 4.5% (a few mg), has been shown to significantly reduce withdrawal symptoms [36], [37]. The required variety in different doses is challenging to produce with conventional manufacturing and additive manufacturing would be an ideal manufacturing method to produce them. Additionally, AMT is considered to be a narrow therapeutic index drug, meaning that its dosing and the resulting drug levels in each patient need to be guided by therapeutic drug monitoring (TDM), in which individual blood concentrations are leading in the personalized dosing regimen in order to avoid therapeutic failure or adverse drug reactions [38]. The small therapeutic window and need for patient-specific dosages underline the potential for additive manufacturing to prepare these personalized dosages of AMT and other tricyclic antidepressants like nortriptyline and doxepin.

The goal of this study is to investigate the capability of sugar alcohols to act as binding excipients in PBF-LB without preheating. AMT was formulated with erythritol, mannitol, and xylitol in three formulations, which were then manufactured in five clinically relevant doses (5, 15, 25, 35, 45 mg). The dosage forms were evaluated using the following pharmacopeial tests: content uniformity, friability, tensile strength, disintegration, and dissolution testing. Furthermore, the influence of the thermal and solid-state properties of the sugar alcohols on their behavior during PBF-LB and the structure of the final dosage forms was investigated. DSC, TGA, XRPD, and IR imaging were utilized to characterize these properties and their relationships.

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Materials

d-mannitol (Pearlitol® 100SD Mannitol, Roquette, France), xylitol (Xylisorb® 90 Xylitol, Roquette), and erythritol (non-disclosed) were used as binders. AMT (Amitriptyline HCl, Duchefa, the Netherlands) was used as a model API, while colloidal silica (Aerosil 200, Evonik, Germany) was added as a glidant. The ratio of the components can be found in Table 1. All materials were sieved through a 200 μm sieve to remove agglomerates and large particles. The mannitol formulation was prepared by mixing mannitol and AMT for 10 min at 72 rpm, after which the blend was sieved through a 315 μm mesh. The xylitol and erythritol formulations were prepared by mixing the erythritol or xylitol with AMT for 10 min at 72 rpm, after which the colloidal silica was mixed in for 10 min at 49 rpm. The resulting blend was sieved over a 315 μm sieve. The particle size distribution of the final blends can be found in Fig. S1. To clearly distinguish between the pure substances and the formulations, the mixtures containing erythritol, mannitol, and xylitol with 15 wt% AMT are referred to as ERY-A, MAN-A, and XYL-A, respectively. MAN75-A refers to the formulation used to study the manufacturing behavior of eutectic mixtures.

Wessel Kooijman, Florian Engelsing, Robbert Jan Kok, Julian Quodbach, Laser powder bed fusion of amitriptyline tablets via eutectic mixtures using sugar alcohols as binders, Journal of Manufacturing Processes, Volume 165, 2026, Pages 1-14, ISSN 1526-6125, https://doi.org/10.1016/j.jmapro.2026.02.076.

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