Hypromellose Acetate Succinates as a Single Mebeverine Hydrochloride Release-Modifying Excipient for Fused Deposition Modeling

Abstract

Background: Three-dimensional (3D) printing has been established in pharmaceutical sciences for preparing customized dosage forms with intricate release profiles. However, realizing this potential requires complex design strategies and the careful use of various excipients. This study was designed to evaluate the utility of hypromellose acetate succinate (HPMC-AS) as a singular release-modifying excipient for manufacturing oral solid dosage forms via fused deposition modeling (FDM) 3D printing.

Methods: The scope of work encompassed comprehensive material characterization, formulation and production of drug-loaded filaments using hot-melt extrusion (HME), subsequent FDM 3D printing of tablet geometries, and in vitro dissolution studies using mebeverine hydrochloride (MebH) as the model drug.

Results: Initial HME processing indicated that the HPMC-AS-based filaments were brittle, presenting technical challenges for direct 3D printing. This issue was successfully overcome by incorporating an additional preheating stage into the FDM printing process, which enabled production of the tablets. Dissolution analysis demonstrated that the 3D-printed mebeverine hydrochloride tablets exhibited delayed and sustained-release characteristics.

Conclusions: These results confirm the viability of HPMC-AS as a standalone functional excipient in FDM 3D printing to produce tailored, complex drug delivery systems.

Introduction

Over the last years, various additive manufacturing methods, more commonly known as three-dimensional (3D) printing, have been introduced into the field of pharmaceutical sciences [1]. Among these methods, fused deposition modeling (FDM) has demonstrated significant potential for preparing dosage forms [2]. Numerous studies conducted by various research groups have demonstrated the applicability of FDM for producing a wide range of dosage forms. This, among others, includes orodispersible films (ODFs), tablets (ODTs), immediate-release and sustained-release tablets, microneedles, and implants [3,4,5,6]. Creating a successful 3D-printed dosage form with specific properties begins with preparing a drug-loaded filament. This filament is a uniform, rod-shaped extrudate typically produced using hot-melt extrusion (HME). In this process, an active pharmaceutical ingredient (API) is homogenized with a polymer in a twin-screw extruder and then pushed through a circular die, usually 1.75 mm in diameter. The resulting filament must have sufficient mechanical strength to withstand the forces in the 3D printer’s printhead. Furthermore, it is crucial that the filament’s diameter is uniform, as this directly affects the reproducibility of the printed drug mass and dose [7,8]. The development of filament extrusion and its characterization methods have not kept pace with the rapid advancement of FDM 3D printing. Most published research concentrates on the 3D printing process and the properties of the final dosage forms. Consequently, there is often a lack of detailed information regarding filament preparation, evaluation methods, and quality attributes. This is a significant gap, as the composition of the polymer matrix and the quality of the filament itself have a profound influence on the properties of the final dosage form [9].

Selecting the right excipients is one of the most crucial steps in developing a dosage form. For 3D-printed dosage forms, the polymer is the primary excipient, and its properties significantly impact both the filament and the final product. While a few pharmaceutical-grade polymers can be used alone for filament production—such as poly(vinyl alcohol), hypromellose, and Kollicoat® IR—most require the addition of other functional excipients. These can include plasticizers, disintegrants, flow enhancers, or stabilizers. One polymer that could expand the applications of 3D printing is hypromellose acetate succinate (HPMC-AS). However, it is rarely used as a standalone material due to its rigidity and temperature sensitivity [10,11]. For example, Goyanes et al. used 5 or 15% of methylparaben as a plasticizer in their paracetamol-loaded HPMC-AS-based filaments, and Shojaie et al. utilized triethyl citrate or sorbitol for the same reason. Both research groups also used magnesium stearate or colloidal silica as lubricants [12,13]. Despite these challenges, its pH-dependent solubility makes it an excellent candidate for creating delayed and sustained-release tablets.

Mebeverine hydrochloride is a freely water-soluble antispasmodic used in the treatment of spasm-associated abdominal pain, especially in the treatment of irritable bowel syndrome and other gastrointestinal conditions. It is usually formulated in the form of tablets or capsules also with modified release. As its therapeutic effect is mainly local, it has to be delivered to the site of action, which is usually the large intestine [14].

This study aimed to evaluate how different grades of hypromellose acetate succinate could be used to modify the release of a highly water-soluble model drug, mebeverine hydrochloride, from tablets produced via fused deposition modeling. The primary objective of this research was to investigate the possibility of using HPMC-AS as an auxiliary substance that does not require the use of any functional additives at the printing stage, which has not been studied to date. The research also included a comprehensive characterization of hot-melt extrusion and 3D-printing processes, as well as of the raw materials and resulting filaments, focusing on their thermostability and mechanical properties. Furthermore, we developed and utilized new jigs specifically for testing the filament’s breaking resistance.

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Materials

Mebeverine hydrochloride (abbreviated as: MebH, 4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butyl 3,4-dimethoxybenzoate; hydrochloride, MOEHS, Lessines, Belgium) was used as the model active substance. Poly(vinyl alcohol) (PVA, Parteck^® MXP 4-88, M_W = 32,000 g/mol, hydrolysis degree 85–89%, Merck^®-KGaA, Darmstadt, Germany) and three medium particle size grades of hydroxypropylmethylcellulose acetate succinates (HPMC-AS), namely, AQOAT^® AS-LMP, AQOAT^® AS-MMP, and AQOAT^® AS-HMP—kindly donated by SE Tylose GmbH & Co., KG (Wiesbaden, Germany)—were used as a matrix-forming polymer for the preparation of the filaments and 3D-printed tablets. Hydrochloric acid solution and trisodium phosphate dodecahydrate (both from Merck^® KGaA, Darmstadt, Germany) were used in the dissolution media. The water used in all experiments was produced by the Elix 15UV Essential reverse osmosis system (Millipore SAS, Molsheim, France).

Kurek, M.; Nunes, M.B.L.; Jamróz, W.; Knapik-Kowalczuk, J.; Paluch, M.; Mendyk, A. Hypromellose Acetate Succinates as a Single Mebeverine Hydrochloride Release-Modifying Excipient for Fused Deposition Modeling. Appl. Sci. 2026, 16, 1237. https://doi.org/10.3390/app16031237