Twin-screw melt granulation of Eudragit® FS100: optimization of coating-free delayed-release matrix tablets with HPMC K4M modulation

Abstract

This study aimed to develop a scalable, coating-free delayed-release matrix tablet via twin-screw melt granulation (TSMG) using Eudragit® FS100 and extra-granular hydroxypropyl methylcellulose K4M (HPMC). A Central Composite Design was employed to optimize three critical variables (drug load (10–30 %), screw speed (20–50 rpm), and HPMC concentration (5.6–13.1 % w/w)) to achieve <10 % drug release at 2 h in gastric conditions (pH 1.2) and >85 % in intestinal conditions (pH 7.4). The optimized formulation (30 % drug load, 20 rpm, 12.2 % HPMC) achieved 7.78 ± 0.15 % drug release at 2 h in acidic pH and complete release within 10 h in alkaline pH. Drug release kinetics showed excellent agreement with the Korsmeyer–Peppas model (R² = 0.9826; n = 1.132), indicating a Super Case II transport mechanism driven by polymer relaxation and erosion, approaching zero-order release. Gel thickness analysis confirmed formation and subsequent disintegration of a cohesive hydrogel barrier; while swelling and erosion studies supported the observed biphasic profile. Structural transitions generated by hydration were captured using microscopy. PXRD and DSC analyses indicated partial amorphization post-extrusion, with FTIR showing no chemical interaction between components. Accelerated stability testing confirmed formulation integrity. This work demonstrates a novel formulation strategy in which the interplay of pH-responsive and pH-independent polymers, along with controlled swelling–erosion behavior, achieves robust delayed-release profiles without the need for additive manufacturing or multi-step coating processes.

Introduction

Despite the emergence of complex manufacturing techniques and personalized dosage forms, these technologies often fall short in practical implementation due to high infrastructural demands, regulatory ambiguity, and limited scalability. Regardless of the innovative appeal of intricate dosage form development techniques, few of these systems have translated into widely accessible, non-invasive drug delivery platforms. In contrast, conventional oral solid dosage forms retain their primacy in global healthcare due to factors such as low manufacturing cost, dose accuracy, stability, and patient adherence. Tablets account for the majority of all drug products on the market, serving as the industrial backbone of pharmaceutical manufacturing (Pradhan et al., 2025, Zema et al., 2017). However, a significant proportion of orally administered active pharmaceutical ingredients (APIs) exhibit chemical instability, pH dependent solubility, or gastric mucosal irritancy, making them vulnerable in the harsh acidic environment of the stomach (Bhugra and Pikal, 2008, Gue et al., 2013, Syed et al., 2024). This underscores the need for advanced formulation strategies capable of shielding the drug during gastric transit while ensuring precise and controlled release at downstream sites within the gastrointestinal tract (Subedi et al., 2022).

Numerous formulation strategies have been explored to prevent premature drug release in the stomach. Enteric coating remains the most widely used strategy for delayed release, but it suffers from several drawbacks. Coating processes are time- and energy-intensive, often requiring organic solvents that raise environmental and safety concerns. Defects in the coating or variability in thickness can lead to dose dumping, compromising drug safety (Knop and Kleinebudde, 2013, Pathak et al., 2025, Zhang, 2016). Similarly, 3D printing and pelletization offer design flexibility but involve complex workflows, expensive equipment, and limited scalability, making them impractical for routine large-scale manufacturing (Zema et al., 2017).

Matrix-based systems have emerged as a viable alternative to traditional film-coated formulations for achieving delayed release (Siepmann et al., 2008, Vo et al., 2020). In these systems, the drug is uniformly dispersed or molecularly distributed within a pH-responsive polymer network, enabling controlled release triggered by gastrointestinal pH changes. Such systems based on methacrylic acid and methyl methacrylate derivatives have proven to be effective. Unlike coated dosage forms, matrix-based granules offer greater robustness against mechanical stress and reduce the risk of dose dumping. Salofalk®, Asacol® (Mesalamine/5-aminosalicylic acid); Entocort®, Budenofalk® (Budesonide); Aciphex® (Rabeprazole); Prevacid® (Lansaprazole) are some pH-sensitive oral products utilizing these polymers that are already available on the market (Gvozdeva and Staynova, 2025).

The successful development of matrix-based systems for delayed release relies not only on polymer selection but also on the choice of manufacturing technique. Melt granulation was first introduced by Royce et al. as an alternative to wet granulation for moisture-sensitive drugs, using thermal binders that solidify upon cooling to form granules (Royce et al., 1996). This approach evolved with the application of twin-screw extrusion and was later advanced by van Melkebeke and others to establish twin-screw melt granulation (TSMG) as a robust method for pharmaceutical processing (Van Melkebeke et al., 2006). As a continuous granulation platform, TSMG offers solvent-free operation, precise control over thermal and mechanical input, and compatibility with modern regulatory expectations for scalability and process analytical technology (PAT) tools for continuous manufacturing technologies. The resulting granules can be directly compressed with external excipients, simplifying downstream processing and enhancing overall manufacturability (Gupta et al., 2025; Kittikunakorn et al., 2020, Liu et al., 2021, Patil et al., 2024, Steffens and Wagner, 2019).

Although pH-responsive polymers and melt granulation are well established individually, their combined application in delayed-release formulations remains underexplored in matrix based delayed release systems. Most existing studies focus on coated systems or single-polymer matrices, with limited attention to how formulation and process variables influence lag time and release profiles. However, a small pore opening in coating shell may result in leaching out of the drug if the drug has high solubility. Thus, a systematic formulation strategy to optimize the performance of melt granulated systems for delayed drug release is needed.

Previous work has demonstrated the utility of Eudragit® FS100 as a pH-dependent carrier for delayed-release formulations. Zhang successfully employed a single-screw melt extrusion process to prepare FS100-based granules containing 5-ASA and other model drugs, establishing foundational insights into the role of granule size, drug loading, and drug-induced microenvironmental pH on release behavior. The work highlighted the polymer’s potential for acid resistance and pH-triggered release; however, complete suppression of drug release in acidic media was not consistently achieved, particularly with highly soluble compounds, limiting its utility for drugs requiring strict gastric protection (Zhang, 2016). Balogh et al. explored FS100 in electrospun and extruded solid dispersions, showcasing its processability and suitability for poorly soluble drugs. Nevertheless, the dissolution testing in that study bypassed intermediate pH conditions (e.g., pH 6.8), and stability considerations were not reported (Balogh et al., 2017).

This study aims to fabricate and optimize a delayed-release oral formulation by employing twin-screw melt granulation to prepare matrix granules using a novel combination of pH-dependent and swelling polymers. The innovative aspect of this work lies in integrating both pH sensitivity and polymeric swelling as release-controlling mechanisms within a coating-free melt granulated system, offering a solvent-free and scalable approach for achieving delayed drug release. Acetaminophen (APAP) was chosen as the model drug owing to its high aqueous solubility and pH-independent dissolution profile, presenting a stringent challenge for delayed-release formulations and thereby serving as a robust indicator of the strategy’s potential applicability to other highly soluble or pH-independent drugs. A central composite design (CCD) was employed to evaluate the impact of drug loading, screw speed, and extra-granular HPMC K4M concentration on drug release behavior. The goal was to achieve minimal release under acidic conditions, followed by complete release at higher pH. By systematically studying the formulation and processing parameters, this work seeks to provide understanding into the design of scalable, coating-free delayed-release systems for a highly soluble drug using a continuous manufacturing platform.

Beyond optimization, this study also explores the underlying release mechanism to evaluate whether swelling and erosion can be leveraged to achieve a zero-order release profile following an initial lag phase. Gel layer thickness, matrix erosion, and liquid uptake studies were conducted to assess gel formation, structural integrity, and fluid interaction over time. Microscopy was used to visualize dissolution medium penetration into granules. These mechanistic insights aim to determine whether matrix-based transformations alone can enable reproducible, coating-free delayed release with minimal drug release in the initial 2 h followed by sustained, near zero-order kinetics.

This study explores a novel implementation of continuous twin-screw melt granulation to design and optimize delayed-release oral matrix tablets. The strategy leverages the complementary mechanisms of pH-dependent and swelling polymers within melt-granulated matrices to achieve precise control of drug release. Importantly, this approach not only enables reproducible delayed-release profiles but also provides a robust, solvent-free, and scalable manufacturing pathway that aligns with commercial production requirements and regulatory expectations.

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Materials

Acetaminophen (APAP) was purchased from SpecGx LLC (Raleigh, NC, USA). Eudragit® FS100 and Eudragit® S100 were obtained from Evonik Industries (Darmstadt, Germany). Hydroxypropyl methylcellulose (HPMC K4M) was kindly provided by Ashland (Wilmington, DE, USA), and ethyl cellulose N10 (EC N10) was sourced from Dow Chemicals (Midland, MI, USA). Sodium phosphate tribasic and sodium hydroxide were purchased from Fischer Chemical (Ottawa, ON, Canada), while hydrochloric acid (HCl) was obtained from RICCA Chemical Company (Arlington, TX, USA). All reagents and solvents used were of analytical grade and were procured from Fischer Scientific (Fair Lawn, NJ, USA). Scintillation vials and centrifuge tubes were purchased from Fisher Scientific (Hampton, NH, USA).

Indrajeet Karnik, Prateek Uttreja, Nagarjuna Narala, Srikanth Baisa, Rasha M. Elkanayati, Esraa Al Shawakri, Sateesh Kumar Vemula, Michael A. Repka, Twin-screw melt granulation of Eudragit® FS100: optimization of coating-free delayed-release matrix tablets with HPMC K4M modulation, International Journal of Pharmaceutics, Volume 686, 2025, 126325, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126325.

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