Preparation of self-dispersible eutectic mixtures for poorly soluble drugs: Hot-melt extrusion vs. melt casting

Abstract

Solid eutectic mixtures of self-dispersible polyethylene glycol-40-stearate with fenofibrate or ibuprofen—prepared by casting or by twin-screw extrusion—were compared in terms of processability and dissolution rate at, below, and above the eutectic concentration. Furthermore, the effects of extruding with two distinct screw configurations—a shear screw and a conveyor screw—were investigated. The eutectic mixtures containing ibuprofen had a poor recrystallization tendency and therefore did not yield the desired solid state in the casting process. In contrast, they could be successfully processed by extrusion due to the initiation of recrystallization by friction and shear forces. Fenofibrate-containing solid mixtures were obtained by both methods. The extrudates of all mixtures showed a decreasing API particle size with increasing API concentration up to a certain threshold (d50 ∼ 6 to 9  µm). For the extrudates containing ibuprofen, smaller API particle sizes were obtained with the conveyor screw; for the fenofibrate extrudates, however, the particle sizes were similar regardless of the screw configuration. Compared to the physical mixtures and the pure API, all cast samples and extrudates exhibited a considerably higher dissolution rate, depending on the excipient to API ratio. Despite the differences in particle size, similar dissolution profiles were observed for the ibuprofen extrudates produced by both conveyor and shear screws. For the fenofibrate mixtures, the dissolution profiles were similar for both screw configurations as well as for the cast references below and at the eutectic concentration. The dissolution rate was superior for the extrudates containing fenofibrate above the eutectic concentration.

Introduction

Extrusion, in general, describes the technique of forcing materials in a plasticizable state through a die. It is a common process in a variety of fields, such as the plastics, food, feed, and metal industry (Al-Salem et al., 2009, Donati et al., 2022, Drew et al., 2007, Hernandez-Izquierdo and Krochta, 2008). Since the early 1980 s, extrusion has also become a promising process in the pharmaceutical field (Crowley et al., 2007). A widely used type of extruder in pharmaceutical technology is the twin-screw extruder. This device facilitates the application of technologies such as the intensively researched hot-melt extrusion (Breitenbach, 2002, Crowley et al., 2007, Li et al., 2024, Repka et al., 2007, Tiwari et al., 2016), as well as wet extrusion (Keleb et al., 2002, Thompson and Sun, 2010) and solid lipid extrusion (Reitz and Kleinebudde, 2007, Vithani and Douroumis, 2019, Windbergs et al., 2010, Windbergs et al., 2009a). Not only the use of different types of excipients (e.g., polymers, lipids), but also the variety of options in terms of variously shaped dies and versatile downstreaming processes allow for the production of a wide range of pharmaceutical products, such as granules, pellets, films, intravaginal rings, implants, and nanoparticles (Bagde et al., 2019, Clark et al., 2012, Dukić-Ott et al., 2009, Even et al., 2015, Even et al., 2014, Koutsamanis et al., 2023, Morales and McConville, 2011, Nandi et al., 2021, Petrovick and Breitkreutz, 2018, Reitz and Kleinebudde, 2009, Sarabu et al., 2021, Sarabu et al., 2019, Seem et al., 2015, Vaassen et al., 2012). Furthermore, extrusion is used for taste masking, modified and controlled drug release, and for enhancing the dissolution rate of poorly water-soluble drugs (Haupt et al., 2013; Hülsmann, S., Backensfeld, T., Keitel, S., Bodmeier, R., 2000; Koutsamanis et al., 2023, Maniruzzaman et al., 2016, Petrovick et al., 2016, Schulze and Winter, 2009, Vaassen et al., 2012, Windbergs et al., 2009b).

A common approach in the field of pharmaceutical extrusion to increase the dissolution rate and, consequently, the bioavailability of poorly water-soluble BCS class II drugs is the formulation of amorphous solid dispersions (ASDs). In ASDs, water-soluble amorphous polymers are used to trap the active pharmaceutical ingredient (API) in the amorphous state, thereby accelerating its rate of dissolution (Baghel et al., 2016).

An alternative approach to increase the availability of BCS class II drugs is the formulation of lipid-based drug delivery systems (Feeney et al., 2016, Porter et al., 2007, Pouton, 2006, Pouton and Porter, 2008). Lipid-based drug delivery systems may consist of self-dispersible materials that can spontaneously form micelles and solubilize poorly water-soluble drugs upon contact with water. Efforts towards the extrusion-based formulation of lipid-based solid drug delivery systems with the aim of improving dissolution have been described. This is achieved by adding self-dispersible systems to a solid carrier or by combined use of lipids and polymers (Maji et al., 2021, Sarabu et al., 2021, Silva et al., 2018, Uttreja et al., 2024, Zupančič et al., 2022). However, to the best of our knowledge, there have been no investigations into the extrusion of two-component systems consisting of an API and solid self-dispersible solubilizers aimed at increasing the dissolution rate of poorly water-soluble drugs.

Crystalline excipients, such as solid self-dispersible polyethylene glycol ethers and polyethylene glycol esters, may form eutectics when co-melted and recrystallized with crystalline solid API (Schlosser and Bunjes, 2025). Upon recrystallization, these eutectics form a finely dispersed solid system that releases API particles with sizes in the lower micrometer range upon contact with water. Compared to conventional drug powders, such micron-sized API particles exhibit a higher dissolution rate due to their increased specific surface area (Law et al., 2003). When developing eutectics containing a self-dispersible surfactant, the benefits of micronizing the API particle size may be combined with the solubilization effect of the excipient. As early as 1980, Kaur et al. demonstrated the superior dissolution properties of tolbutamide from eutectics based on polyethylene glycol-40-stearate compared to those prepared with polyethylene glycol (Kaur et al., 1980a, Kaur et al., 1980b).

As recently shown, polyethylene glycols, polyethylene glycol stearates, and polyethylene glycol esters exhibit an increasing eutectic concentration with increasing temperature of fusion of the excipient when co-melted and recrystallized with ibuprofen (IBU) or fenofibrate (FEN) (Schlosser and Bunjes, 2025). However, not all of the respective mixtures appear suitable for the production of solid self-dispersible eutectics as there may be a low tendency to recrystallize with an API and a considerable melting point depression. Interestingly, in the corresponding study, the smallest API particles were observed close to the eutectic concentration whereas above as well as below the eutectic concentration the API particles size increased again.

The current study was initiated to investigate the effect of processing method and composition on the processing behavior and the properties of the resulting eutectic mixtures. Extrudates produced by twin-screw extrusion were compared with samples prepared by conventional casting in terms of processability, the size of API particles in the solid mixtures and their dissolution rate. For this purpose, mixtures of the poorly water-soluble model drugs FEN and IBU were prepared with a self-dispersible polyethylene glycol stearate. The excipients were selected based on their recrystallization tendency (Schlosser and Bunjes, 2025) as well as due to their solubilization capacity. Two distinct screw configurations were designed for extrusion and investigated regarding their impact on the API particle size of the eutectic mixtures produced at various API concentrations. As an approximation to the casting method, the first screw design was based on low-shearing conveyor elements, while the second design included additional kneading elements with the aim to further reduce the API particle size.

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Materials

Table 1 provides an overview of all excipients (including their HLB values as stated by the manufacturer) and the APIs used in this study. Polyethylene glycol-20–stearate (MyrjTM S20, flakes), polyethylene glycol-40–stearate (MyrjTM S40, powder), polyethylene glycol-100-stearate (MyrjTM S100, flakes), polyethylene glycol-20-stearyl ether (BrijTM S20, powder), polyethylene glycol-100-stearyl ether (BrijTM S100, flakes), polyethylene glycol 1500 (RenexTM PEG 1500, flakes) and polyethylene glycol 4000 (RenexTM PEG 4000, flakes) were a kind gift from Croda GmbH (Nettetal, Germany). HLB values were assumed to be as specified by the manufacturer. Ibuprofen was purchased from Euro OTC Pharma GmbH (Bönen, Germany), fenofibrate 98 % and ethanol 99.8 % (HPLC grade) from Fisher Scientific GmbH (Schwerte, Germany), sodium lauryl sulphate ≥ 85 % (SLS, Ph. Eur.), acetonitrile ≥ 99.95 % (LC-MS grade) and hydrochloric acid 37 % from Carl Roth GmbH & Co. KG (Karlsruhe, Germany), fenofibric acid ≥ 97.5 % from Thermo Fisher Scientific (Waltham, Massachusetts, USA). Purified water was produced with a Barnstead EASYpure LF system (Fisher Scientific GmbH, Schwerte, Germany).

Table 1. Overview of excipients and APIs

Peter Schlosser, Heike Bunjes, Preparation of self-dispersible eutectic mixtures for poorly soluble drugs: Hot-melt extrusion vs. melt casting, International Journal of Pharmaceutics, 2025, 125637, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125637.

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