Polymeric Matrix Mini-Tablets Based on Eudragit® S 100 and HPMC for Controlled Release of Pantoprazole

Abstract

Background: Pantoprazole is a widely used proton pump inhibitor that is highly unstable under acidic conditions. This limits the performance of conventional formulations and typically requires enteric-coated dosage forms or alternative modified-release approaches. This study reports the development of polymeric matrix mini-tablets designed to protect pantoprazole during gastric exposure and to enable pH-dependent release under intestinal conditions. The formulations combine Eudragit^® S 100, a pH-dependent polymer, with HPMC, a hydrophilic matrix former that modulates drug release through hydration and swelling.

Methods: Matrix mini-tablets were prepared by blending pantoprazole with selected excipients at optimised proportions and compressing the blends by direct compression using an eccentric tablet press. Powder blends and mini-tablets were characterised according to pharmacopoeial specifications. Analytical techniques—including High-Performance Liquid Chromatography (HPLC), Differential Scanning Calorimetry (DSC), Fourier-Transform Infrared Absorption Spectroscopy (FT-IR), Powder X-Ray Diffraction (PXRD), and Scanning Electron Microscopy (SEM)—were employed to evaluate drug content uniformity, thermal behaviour, and potential drug–excipient interactions. In vitro dissolution studies were performed under sequential pH conditions, and the release kinetics were analysed using mathematical models.

Results: Dissolution testing identified formulations F2 and F6 as providing the most suitable gastro-resistant performance in the acidic stage, together with sustained release up to 24 h. Kinetic modelling supported formulation-dependent release mechanisms, and multivariate analysis (PCA) highlighted relationships between physico-mechanical attributes and drug-release behaviour.

Conclusions: The proposed matrix system shows potential as a robust, coating-free platform for the modified delivery of acid-labile drugs using direct compression, simplifying manufacturing. These findings support the rational design of oral modified-release formulations based on polymeric matrices.

Introduction

Pantoprazole is a proton pump inhibitor that is highly susceptible to degradation under acidic conditions. Therefore, formulation strategies focus on protecting the drug in the stomach and ensuring its release under the near-neutral pH conditions of the small intestine [1,2].

The oral route remains the most widely used approach for drug administration due to its convenience and high patient acceptance. Solid dosage forms are particularly preferred because they are easy to administer and support self-medication, thereby improving adherence. Among solid manufacturing methods, direct compression is especially attractive owing to its simplicity, cost-effectiveness, and avoidance of organic solvents and complex processing steps that require special coating equipment [2,3]. However, conventional immediate-release formulations may lead to pronounced plasma concentration peaks of the active pharmaceutical ingredient (API) followed by sub-therapeutic levels. Controlled-release systems have, therefore, been developed to reduce dose fluctuations and improve therapeutic efficacy and safety [4,5]. This approach is advantageous for drugs sensitive to acid conditions (pH 1.2–2.5). Given their stability profile in basic media, it is essential to ensure controlled drug delivery to a more suitable target site, optimising therapeutic efficacy under specific environmental conditions [6].

Controlled drug delivery aims to achieve appropriate temporal and spatial drug distribution while reducing the dose and dosing frequency [5,7]. In this context, polymer-based matrix systems represent a practical strategy, as drug release can be modulated through the physico-chemical properties of the polymer(s), including hydration, swelling, and erosion behaviour. Instead of previous strategies, the integration of both a time-controlled and pH-dependent responsive mechanism allows for greater versatility in formulation delivery systems, facilitating the achievement of specific therapeutic goals, as demonstrated in the literature [3,8,9]. Consequently, systematic characterisation and optimisation of polymer composition are essential to ensure manufacturing reproducibility and predictable dosage form performance.

Drug-release behaviour is largely governed by the physico-chemical properties of the polymeric matrix; therefore, systematic characterisation and optimisation of these properties are essential to ensure reproducible manufacturing and predictable dosage form performance. In general, modified-release oral systems aim to (i) sustain drug release over a prolonged period, and (ii) reduce fluctuations in drug exposure by controlling the timing and, when applicable, the gastrointestinal site of release [4,5,10].

Drug delivery systems are commonly classified as reservoir systems or matrix devices. In matrix devices, the drug is homogeneously dispersed within a continuous phase, which may be hydrophilic or hydrophobic [3]. Matrix systems are generally cost-effective, easy to scale up, and can attenuate the variability in plasma drug concentrations [6,11]. Depending on the materials used, matrix systems have been described as hydrophilic, hydrophobic, lipid-based, plastic, or biodegradable [9,12]. In aqueous media, modified-release matrices undergo an initial hydration step, leading to the formation of a superficial gel layer. As the medium penetrates the matrix, the gel layer expands, and drug release proceeds through diffusion across the gel barrier and/or erosion of the matrix surface [2,4]. The resulting kinetics are governed by medium penetration and polymer relaxation processes (hydration and swelling), and are influenced by drug properties (e.g., solubility and molecular weight), formulation variables (e.g., geometry and manufacturing method), and polymer-related factors such as type, viscosity, and blend proportions [1].

By optimising polymer composition and matrix content, a wide range of release rates can be achieved by modulating drug diffusivity through the gelled structure. Several studies have reported the use of hydroxypropyl methylcellulose (HPMC), time-dependent, in combination with other polymers, including sodium alginate [10,13] and Eudragit® S 100, pH-dependent ref. [7], to tailor release behaviour. Eudragit® S 100 is an anionic copolymer of methacrylic acid and methyl methacrylate, a pH-dependent polymer designed to remain intact under gastric conditions and to dissolve at higher pH values in the lower gastrointestinal tract, at pH 7.0, enabling targeted release and improved stability for acid-labile drugs [1,4,10,11,13,14]. In turn, HPMC is widely used as a hydrophilic matrix, since high viscosity can help maintain tablet integrity and provide mechanical strength through gastrointestinal (GI) transit; upon hydration and swelling, it forms a viscous gel layer around the tablet surface, acting as a barrier to control drug diffusion and modulating drug diffusion and erosion over extended periods [1,14]. This approach combines two or more excipients that synergically enhance the functional properties without altering their chemical structure, which has been represented in different studies [8]. Such strategies address the inherent limitations of single-mechanism delivery systems; for instance, pH-dependent systems are often restricted by significant inter- and intra-individual variability in gastrointestinal pH and gastric emptying rates. Similarly, time-dependent release can fluctuate based on intestinal transit times [15]. Consequently, integrating a pH-dependent polymer with a hydrophilic matrix offers a robust, rational design to protect pantoprazole from gastric acidity while ensuring a controlled and sustained release profile. This dual-mechanism strategy has been successfully exemplified in various studies combining enteric and swellable polymers [6,8,15]. In summary, the synergy between pH-dependent and matrix-controlled diffusion minimises physiological interference, ensuring reliable therapeutic performance for acid-labile drugs like pantoprazole [16,17].

While traditional pantoprazole stabilisation relies on complex, costly enteric coating processes, this study develops an efficient alternative: polymeric matrix mini-tablets. By combining Eudragit S®100 and HPMC, a robust gastro-resistant system was achieved through a single-step direct-compression approach. This approach simplifies manufacturing, eliminates organic solvents, and leverages the mini-tablet format for improved intestinal transit and patient compliance. Future research will focus on in vivo studies to establish an in vitro–in vivo correlation (IVIVC), alongside a deeper characterisation of the polymeric matrix properties, such as swelling dynamics and mechanical integrity during erosion.

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Materials

Pantoprazole powder was supplied by ROVI laboratories (ROVI, Madrid, Spain); Eudragit^® S 100 was obtained from Evonik (Evonik industries, Darmstadt, Germany). HPMC was purchased from Jescuder S.L (Terrassa, Barcelona, Spain), and Compritol^® 888 ATO was supplied by Gattefossé (Gattefossé, Saint-Pries, France). For analytical procedures and dissolution media, hydrochloric acid (HCl), potassium dihydrogen phosphate (KH₂PO₄), and Sodium hydroxide (NaOH), all of analytical grade, were purchased from Panreac Química S.L.U. (Castellar de Vallès, Barcelona, Spain). HPLC-grade solvents such as methanol and acetonitrile were purchased from Merck KGaA (Darmstadt, Germany). Water was ultra-pure Milli-Q Merck KGaA (Darmstadt,, Germany). All other reagents and chemicals used were of laboratory analytical grade.

Pardo, H.; Peña, M.Á.; Martínez-Alonso, B.; Torrado-Salmerón, C.; Guarnizo-Herrero, V. Polymeric Matrix Mini-Tablets Based on Eudragit^® S 100 and HPMC for Controlled Release of Pantoprazole. Pharmaceutics 2026, 18, 327. https://doi.org/10.3390/pharmaceutics18030327