Effects of excipient particle size range on the performance of selective laser sintered pharmaceutical printlets

Abstract

This study investigates how the particle size range (PSR) of the polymeric component in a powder mixture affects the structural strength and drug release rate of additively manufactured pharmaceutical tablets (printlets). These printlets were fabricated via Selective Laser Sintering (SLS) of a powder mixture that was comprised of Carbamazepine (drug), Kollidon SR (excipient/polymer) and Candurin sheen (laser absorbing agent). In this study, three PSR of the polymer were evaluated for their manufacturability, microstructure, and their eventual influence on performance (tablet hardness and drug release rate). The results indicated that the mixtures having the larger median particle sizes (among those studied) exhibited higher crushing resistance and drug release rates within the initial 12 h.

Introduction

Additive manufacturing has expanded in prevalence across different industries, and more recently for its potential for “Just-In-Time” production of solid pharmaceutical formulations (tablets). It lends flexibility to the manufacturing process and aids customization of drugs/dosages [1]. Drugs in a powder form can be made into tablets using the selective laser sintering (SLS) technique which uses a laser to selectively melt and fuse particles in a layer-by-layer fashion [2]. The manufacturability, properties and performance of such tablets fabricated using SLS is governed by several factors related to material composition, powder particle characteristics, process parameters, etc., among a plethora of other parameters and their complex interactions [3], [4], [5], [6]. More recently, pharmaceutical manufacturing using SLS has progressed on several fronts. For instance, there have been studies that investigated the effects of varying drug concentrations on the manufacturability and properties of the printed tablets (printlets) [7], [8]. Other efforts have focused on understanding the influence of different process parameters on the manufacturability, drug degradation, structural integrity, and dissolution dynamics of these tablets [9], [10]. Furthermore, researchers have used SLS to customize tablets, such as embossing Braille letters to help the blind [11], printing lattices to alter drug release rates [12], and formulating tablets with different drugs to target multiple therapeutic actions simultaneously [13], among others.

In earlier studies on sintering an organic polymer with a maximum particle size < 180 μm, it was noticed that the flowability and spreadability of the powder was generally improved for certain smaller particle size ranges (up to a limit). Particle sizes/shapes can result in different laser energy absorption rates, resulting in a differing part density and mechanical strength [14]. Most literature affirms that lowering particle size in SLS can be beneficial for processing and performance until a limit. However, depending on the application, the recommendation for the lower limit of particle size can differ [15]. A more recent study showed that tablets manufactured with lower drug particle sizes (<5 μm) showed higher dissolution rates than that for larger drug particle sizes [16]. Although many studies have been conducted in the manufacturing of pharmaceutical printlets using SLS, no prior work has explored the effects of varying the excipient PSR in a CBZ-involved drug formulation.

This paper highlights the impact of excipient PSR on the structure/properties and performance of certain SLS-manufactured printlets. Note that this work is part of a larger investigation involving different drugs, excipients, compositions, scan strategies and process parameters, among others. The scope of this paper is however limited to how a certain excipient PSR affects its melting (the only ‘melting’ component within the powder mixture), and hence certain printlet performance metrics.

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Materials and methods

Carbamazepine (CBZ) (C15H12N2O) (Hangzhou Starshine Pharmaceuticals Co., Ltd., Hangzhou, China), an anticonvulsant to treat seizures and bipolar disorders [17] was chosen as the active pharmaceutical ingredient (API). This drug is a white crystalline powder with a melting point of 189–192 ºC. CBZ has strong UV-Visible absorption characteristics, but it has limited-to-none absorption of visible spectra including the blue diode laser wavelength of 445 nm [18]. The biocompatible excipient suitable for the extended release of this drug is Kollidon SR (KDSR) (BASF, Germany). This polymer consists of a ∼80% polyvinyl acetone component which is insoluble in water and 20% soluble povidone, hence facilitating an extended (delayed) release of the drug. KDSR is an amorphous polymer with a glass transition temperature of 35 ºC. It generally possesses a small angle of repose (30º) which is advantageous in terms of flowability for powder bed fusion processes. Additionally, it is known that KDSR has poor laser absorptivity under a blue or red diode laser, wherein it is typically used in conjunction with a laser ‘absorbing’ agent (sheen) for laser powder bed usage [19].

Candurin® NXT Ruby Red Sheen (Merck, Darmstadt, Germany) was used in the mixture owing to its high laser absorption capability unlike the drug and the polymer [20]. The as-received CBZ particles were large and irregular in shape; therefore, they were ball milled and sieved to a PSR of < 106 μm (Fig. 1a), while the fairly-spherical polymer particles (Fig. 1b) were sieved into PSR groups of 0–53, 53–106, and 0–106 μm. Each mixture contained 40% CBZ, 57% KDSR and 3% sheen by weight (Fig. 1c). All three powders were then thoroughly mixed (Fig. 1d). Both the individual powders and the multi-component mixtures were subject to particle size analysis using an Anton Paar PSA 1190 laser diffraction particle size analyzer. D50 values (median diameters) were analyzed for each set, whereby the polymer (KDSR) groups of 0–53, 53–106, and 0–106 μm exhibited values of 48.4 ± 4.5, 83.3 ± 1.5 and 67.5 ± 7.0 μm, respectively. Similarly, CBZ with PSR of 0–106 μm revealed a D50 size of 61.1 ± 9.1 μm. The measured average particle size of the sheen was ∼10 μm. The final powder mixtures for the polymer size groups of 0–53, 53–106, and 0–106 μm exhibited D50 values of 38.9 ± 2.5, 67.4 ± 6.2 and 45.9 ± 6.7 μm, respectively. Note that the combination of the comparatively smaller particle sizes of the sheen along with the high number of sheen particles tend to bring down the overall D50 values of the mixture. The spans of the 0–53, 53–106, and 0–106 μm mixtures were observed to be 4.8, 1.5, and 4.0, respectively. Such a division into three broad particle size intervals is expected to provide a first look at their significance in processing, structure, properties and performance. Note that each powder type possesses distinct characteristics such as mechanical properties, thermal properties, and laser absorption capacities, among others. Assessing the impact of these parameter combinations on the structural strength and dissolution rate of the printlets can provide insight into their resistance to crushing (essential for handling and packaging suitability) and drug release kinetics – these are beyond the scope of this paper but is noted here to highlight the complex interplay of the parameters involved.

Printlets were additively manufactured using a Sintratec kit (Sintratec, Brugg, Switzerland) with a uniform layer thickness (100 μm), hatch spacing (250 μm) and scanning speed (100 mm/s). The laser power was fixed at 2.3 W, with supplemental heating provided through surface and chamber temperatures maintained at 90 ºC and 75 ºC, respectively. Cylindrical tablets (10 mm diameter, 3 mm height) from each PSR group were produced (Fig. 1e) and tested for crushing resistance (“hardness,” as termed in the pharmaceutical industry) using a TA.XT Plus (Stable Micro Systems, Surrey, UK); average tablets weights across the three PSR groups was quite comparable at 105.9 ± 12.9 mg. Further, dissolution tests were conducted in an Agilent 708-DS apparatus (Agilent, Santa Clara, CA, USA), and drug release rates were calculated with the aid of an Agilent 1260 Infinity II High Performance Liquid Chromatography (HPLC) System (Agilent, Santa Clara, CA, USA). The printlets were subjected to dissolution tests in a 900 mL water medium and stirred at 100 rpm using a basket apparatus according to the United States Pharmacopeia (USP) standards, during which the amounts of drug released at each relevant timestamp was recorded, i.e., 3 hr, 6 hr, 12 hr, and 24 hr. Using the HPLC system the drug release of 3 printlets per formulation was evaluated. A C18 column was utilized with dimensions 250 × 4.6 mm, and the mobile phase composition consisted of 65% methanol and 35% de-ionized water with 0.01% (of water) glacial acetic acid (Fischer Scientific, Asheville, NC, USA).

Amrutha Dinesh, Abdelrahman Ahmed, Cyrus Funkhouser, Ziyaur Rahman, Mansoor Khan, Mathew Kuttolamadom, Effects of excipient particle size range on the performance of selective laser sintered pharmaceutical printlets, Next Materials, Volume 13, 2026, 103188, ISSN 2949-8228,  https://doi.org/10.1016/j.nxmate.2026.103188.

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