The impact of compaction by pellet type, spatial arrangement and drug release on MUPS tablets

Abstract

Introduction

Sustained-release dosage forms can be administered orally as single or multiple-unit dosage forms. Multiple-unit dosage forms have several advantages over single-unit systems, although the drug release from both dosage forms can be similar [1]. The major advantages of multiple-unit dosage forms are reduced susceptibility to dose dumping and better distribution in the gastrointestinal tract as subunits [2, 3]. Thus, the failure of a few units may not be as consequential as the failure of a single-unit system. Overall, multiple-unit systems will result in fewer side effects, better bioavailability, and less variability in drug release [4]. Examples of multiple-unit dosage forms include multi-particulates, usually pellets, filled into a capsule or compressed into a multiple-unit pellet system (MUPS) tablet. The reduced risk of product tampering, lower manufacturing costs, and higher production rates [5], as well as health and cultural concerns related to the use of gelatin in capsules, have promoted the growing interest in MUPS tablets.

Compaction of MUPS tablets is challenging as the integrity of the functional coat on the pellets may be compromised by the compaction force [6], leading to subsequent loss in functionality such as sustained-release, taste-masking, or drug stabilization. The polymeric coating must be able to withstand the compaction forces to maintain the functionality of the coated pellets in the MUPS tablets. It may deform but must avoid rupture during tableting because cracks in the coat will alter the drug release characteristics [7, 8]. Thus, the type and size of the pellets, coating formulation, properties of tableting excipients, and compaction parameters must be optimized to produce an integral dosage form with the desired drug release properties [9].

The intrinsic properties of the pellet core, such as crushing strength, deformability, porosity, and osmotic potential, can play a pivotal role in the ability of coated pellets to withstand the compaction force during tableting and coat rupture during dissolution. Increasing pellet core porosity may enhance drug release by facilitating fluid penetration and reducing diffusional resistance within the compacted core matrix [10, 11]. Soluble sugar-based pellet cores may contribute to coat rupture from internal osmotic pressure. Crospovidone-based pellet cores of lower crushing strengths are more prone to coat damage during compaction [12]. Microcrystalline cellulose (MCC)-based pellet cores, with a dominant plastic deformation mechanism, have been widely used in MUPS tablets since the 1990s [13–15]. Sugar-based pellet cores have also been used in MUPS tablets [16]. Yet, few studies have systematically examined how differences in pellet composition and structure translate into differences in coat integrity performance during dissolution testing after compaction.

Release barrier polymers used for film coating are usually either cellulosic or acrylic polymers [17]. These polymers can be prepared in organic solutions or formulated as aqueous colloidal dispersions with polymeric particles that are mechanically deformable and fuse as films under specified conditions. The residual internal stresses within the polymeric film caused by film shrinkage, as well as differences in thermal expansion between the coat and the substrate during solvent evaporation, can induce cracks [18]. Acute changes in shape and density, impact and friction from the die and punch surfaces during tableting of the coated pellets could also give rise to cracks in the polymeric film, compromising the coating film integrity and further influencing the sustained-release property. Therefore, the mechanical properties of the polymeric film have been studied to determine its durability and suitability for coating pellets to be tableted. Films prepared from acrylic polymers are more flexible, while ethyl cellulose films are more brittle, exhibiting weaker mechanical properties [19].

In addition to the choice of coating polymer used, cushioning filler and pellet-to-filler ratio are also very important considerations in MUPS tableting and have been studied extensively [20–22]. Pellet-to-filler ratio is an important parameter during compaction. It directly affects almost all the characteristics of MUPS tablets, such as fragility, disintegration time, drug content uniformity, functional coating film integrity, and drug release [23]. It was found that when the pellets exceeded one-third of their volumetric pellet-to-filler ratio, the extent of pellet coat damage increased [24]. In order to form a permeable network of deformable materials, a sufficient proportion of cushioning filler must be present to prevent excessive direct contact between the pellets and the surfaces of the punch/die wall and pellet-pellet contacts [25, 26].

Studies on the effect of pellet spatial position in MUPS tablets on coat damage have been reported [27]. Coated pellets located at the periphery were more susceptible to damage by compaction, with pellets located at the top-radial position showing the greatest extent of coat damage. Besides determining whether the coated pellets are apart (separated) or in direct contact with one another (conjoint), pellet spatial arrangements would be employed to indirectly reflect the extent to which the pellets were embedded within the cushioning filler. Specifically, the separated pellets configuration could contribute to forming a permeable network of deformable materials with a low pellet-to-filler ratio, where individual pellets are isolated and surrounded by excipients acting as the cushioning filler. In contrast, the conjoint pellets configuration can simulate a microenvironment with a high pellet-to-filler ratio and facilitate greater mechanical stress transmission owing to direct inter-pellet contact and reduced cushioning effect due to incomplete surrounding filler material. Coated pellets in a conjoint spatial arrangement would be more prone to coat damage induced by the compaction pressure and inter-pellet mechanical interactions, leading to accelerated drug release rate, particularly under high compaction pressures.

The interrelationship between compaction pressure, coating polymer type, pellet core properties, and pellet spatial arrangement forms a complex and multifactorial system that collectively determines the drug release behaviour from MUPS tablets. In this study, a controlled MUPS compaction model was established to systematically integrate four critical variables. By utilizing a pre-determined separated pellet arrangement to avoid pellet–pellet contacts and their confounding stress-transmission effects, this deconstructive approach provides an alternative analytical perspective that magnifies the role of intrinsic pellet attributes and facilitates the mechanistic deconvolution of compaction-induced release behaviour. This design allows for a mechanistically driven dissection of how external compaction forces, membrane mechanical integrity, and localized stress environments synergistically dictate post-compaction drug release. Ultimately, this work helps progress MUPS research from empirical observation towards a more mechanistic understanding, which can provide a robust, data-driven framework for the rational design and optimization of sustained-release MUPS tablets.

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Materials

Metformin hydrochloride (MET; USP grade, Granules India Limited, India) was the model drug used to prepare MET-containing pellets by extrusion-spheronization and drug layering. Three grades of MCC were used; MCC PH-101 (Ceolus PH-101, Asahi Kasei, Japan) was used as the pelletization aid in extrusion-spheronization, MCC CP-507 cores of size fraction 500–710 μm (Celphere CP-507, Asahi Kasei, Japan) were one of the starter seed core types used for drug layering and MCC PH-102 (Avicel PH-102, Asahi Kasei, Japan) was the cushioning filler in the MUPS tablet formulation. The other type of starter seed cores for drug layering was sugar (SGR) cores of size fraction 500–600 μm (Suglets, Colorcon, USA). Hydroxypropyl methylcellulose (HPMC; Methocel VLV, Dow Chemical, USA) was used as the film-forming polymer, and polyvinylpyrrolidone (PVP; Plasdone C-15, Ashland, USA) as the co-film-forming agent in the drug layering formulation. Acrylic (AC) and ethyl cellulose (EC) coats were the two types of sustained-release coating polymer employed. For the AC coat, an aqueous methacrylic acid copolymer dispersion (Eudragit RS30D, Evonik, Germany) was employed with triethyl citrate (Merck, Germany) as a plasticizer and talc (Chemipure, Singapore) as an anti-tack agent. For the EC coat, an aqueous EC dispersion (Surelease, Colorcon, USA) was used. Sodium starch glycolate (SSG; Primojel, DFE Pharma, Germany) was used as the disintegrant in the MUPS tablet formulation. Deionized water was the moistening liquid during extrusion-spheronization, for diluting the AC or EC dispersion, and degassed for use as the dissolution medium.

Liew, C. V., Liu, W., Veronica, N., Wang, G., & Heng, P. W. S. (2026). The impact of compaction by pellet type, spatial arrangement and drug release on MUPS tabletsJournal of Pharmacy and Pharmacology, 78(4). https://doi.org/10.1093/jpp/rgag041

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