Slugging-induced Mechanistic Coupling of Microcrystalline Cellulose-starch Disintegrants for Enhanced Tablet Disintegration

Abstract

Disintegrant performance in insoluble, poorly disintegrating matrices is strongly influenced by how the excipients are assembled at the granule level. This study investigated densified microcrystalline cellulose-starch (MCC-starch, 4:1) granular systems as direct compression disintegrants. In the screening stage, co-processed MCC-starch granules prepared by slugging at 10–190 MPa were incorporated into dibasic calcium phosphate (DCP) tablets at 10–15%, w/w. Disintegration behavior exhibited a strong dependence on slugging pressure, with low-pressure, less dense granules failing to disintegrate the tablets within the 15-min test window, while denser granules progressively shifted performance toward rapid disintegration. Based on these trends, granular densification (12.5%, w/w disintegrant; 190 MPa slugging) was examined with different starch types, maize and rice, and blends. Across both starch groups, tablets formulated with co-processed granules disintegrated significantly faster than tablets incorporating physical mixtures of separately densified components, while tablet tensile strength remained comparable between these formulations. Scanning electron microscopy images supported pressure-dependent changes in granule consolidation. Collectively, the results identify intragranular co-location of MCC and starch within a composite granule, rather than densification alone, as the critical determinant of disintegrant efficiency in DCP tablets, driven by the mechanistic coupling of MCC-mediated wicking and localized starch swelling when wetted.

Introduction

The oral tablet is the most popular dispensed dosage form due to its compactness, stability, good patient acceptability and cost-efficient manufacturing [1, 2]. The efficacy of immediate-release tablets is fundamentally governed by their ability to disintegrate promptly after ingestion into the stomach. This disintegration event marks the initial step in the bioavailability cascade, increasing the surface area for drug dissolution and absorption, thereby enhancing its bioavailability [3, 4]. Tablet disintegration is driven by disintegrants, a class of functional excipients that promote rapid tablet breakup on contact with the gastrointestinal fluid through mechanisms such as swelling, wicking, and strain recovery [4, 5]. Traditional disintegrants such as native starch have long been used; however, limitations in compressibility and the requirement for higher concentrations have spurred the development of superdisintegrants, including sodium starch glycolate, croscarmellose sodium, and crospovidone [2, 6].

More recently, the pharmaceutical industry has increasingly pivoted toward co-processing as a strategy to enhance excipient functionality [4]. By physically combining two or more excipients without chemical modification, these co-processed excipients typically outperform individual excipients and simple physical mixtures, while maintaining their regulatory status. Techniques such as spray drying, granulation and melt extrusion are commonly employed to produce co-processed excipients with tailored properties [7, 8].

Among potential disintegrants, microcrystalline cellulose (MCC) and starch offer a rational basis for performing as a co-processed system. MCC is a multifunctional excipient, serving as a dry binder, diluent, and flow aid, with some inherent disintegrant activity due to its wicking capabilities [6, 9, 10]. However, as a standalone disintegrant, it is often insufficient for rapid disintegration, especially in formulations containing hydrophobic active pharmaceutical ingredients [6, 10]. Conversely, native starch is a classic moderately swelling disintegrant which is naturally abundant and inexpensive [11, 12]. Native starches used as disintegrants are commonly derived from maize and potato; alternative botanical sources with local availability and differing physical characteristics are also gaining interest.

However, native starches typically require high concentrations of 10–15% to be effective as tablet disintegrants and present formulation challenges, especially in high-dose formulations [6, 12]. At such levels, starch impairs blend flowability, compressibility and content uniformity, rendering it less favored for direct compression. Moreover, excessive starch content may compromise tablet mechanical integrity due to its elastic deformative properties [13]. While this elastic recovery is typically viewed as a liability in terms of tablet mechanical properties, it also implies the presence of recoverable strain energy that could in principle be harnessed for disintegration if appropriately constrained within a composite structure [14].

In addition to the intrinsic mechanisms of disintegrants, recent evidence shows that how disintegrant particles are distributed or arranged within the tablet matrix can influence disintegration behavior. Raman chemical imaging has shown that complete homogeneity of disintegrant distribution is not strictly necessary for effective performance, provided that the disintegrant is sufficiently abundant and distributed throughout the tablet while avoiding large inactive zones [15]. This could be associated with the formation of percolating networks, whereby the connectivity of a hydrophilic or swellable phase within a tablet can influence the formation of water-conducting pathways and produce threshold-like changes in disintegration time [5, 16, 17]. This is also consistent with mechanistic studies suggesting that disintegration performance depends on how available water is distributed among tablet constituents and on the maintenance of effective hydrophilic pathways for liquid ingress [18]. Imaging- and MRI-based studies further demonstrate that formulation and disintegrant arrangement influence breakup pathways and fragment generation during disintegration [19, 20]. Furthermore, Zheng et al. [21] demonstrated that clustering of disintegrant particles facilitates faster tablet disintegration by promoting cumulative volumetric expansion of disintegrants during swelling or strain recovery; though excessive clustering may also retard disintegration when gel-plug formation impedes liquid penetration, particularly with strongly swelling disintegrants. This effect was particularly pronounced in formulations containing insoluble fillers such as dibasic calcium phosphate (DCP). Therefore, strategic clustering of disintegrants in such matrices may be more effective than having well-distributed discrete disintegrant particles.

Building on these insights, pre-compression by slugging or roller compaction emerges as a conceptually attractive proposal for developing co-processed disintegrants. Slugging is a process where powders are compressed into large, homogeneous tablets, also known as “slugs”, using punch-and-die systems [22,23,24]. This compression-based approach offers a means not only to harness the synergistic properties of MCC and starch but also to pre-densify them as composite disintegrant granules. Concentrating starch grains within a compacted granular domain with little interparticle voids enables their cumulative swelling action to exert a stronger and more effective response as a tablet disintegrant. However, densely packed starch grains alone may suffer from limited wetting or gel blocking, as water penetration into the interior of a compacted starch cluster can be restricted [3, 25]. MCC, in contrast, is recognized for its capillary wicking capacity and ability to promote liquid uptake but lacks the forceful swelling action required for rapid matrix fracture when wetted [4, 26]. Co-processing MCC and starch by slugging is therefore hypothesized to be a rational strategy to combine wicking action by MCC with cumulative swelling forces from tightly packed starch grains once hydrated.

In this study, the concept was explored using native starches from two botanical sources. Rice starch (Sr) was selected to examine its disintegrant potential, while maize starch (Sm) served as a well-established reference disintegrant. Preliminary screenings evaluating MCC and each starch as single components and as physical mixtures identified a 4:1 MCC-to-starch ratio as functionally synergistic, and this ratio was adopted for all co-processed and comparator systems. DCP was selected as the model filler to sensitively capture the effects of disintegrant clustering.

The overarching objective of this work is to provide a mechanistic proof-of-concept that MCC and starch, when engineered into densified composite granules, can enhance disintegrant performance in DCP tablets. To this end, the study was structured in two stages. In the first stage, MCC-starch blends at a fixed 4:1 ratio were slugged across a wide pressure range (10–190 MPa) and incorporated at 10, 12.5 and 15%, w/w into DCP tablets. This screening step was designed to establish how increasing slugging pressure enhances disintegrant performance relative to physical mixtures and to identify an intermediate disintegrant concentration that would yield disintegration times suitable for mechanistic evaluation.

In the second stage, tablets containing 12.5%, w/w disintegrant and granules slugged at 190 MPa were used as a mechanistic cross-section to compare different modes of incorporating MCC, including physical mixtures of raw components, combinations of raw MCC with densified starch, physical mixtures of separately densified components, and fully co-processed MCC-starch granules. Tablet disintegration time, tensile strength and granule-level characterization were evaluated to relate slugging-induced densification and composite architecture to the observed disintegration behavior.

Taken together, these two stages address two central questions: whether high-pressure densification by slugging can reliably enhance the disintegrant function of MCC-starch systems in DCP tablets, and whether the performance gain arises solely from densifying the individual components or specifically from engineering them into a composite intragranular architecture.

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Materials

Microcrystalline cellulose (MCC; Ceolus PH-101, Asahi Kasei, Japan), rice starch (Sr; Remy DR, BENEO-Remy, Belgium) and maize starch (Sm; Maize Starch-Native, Roquette Frères, France) were investigated as disintegrants. Dibasic calcium phosphate dihydrate (DCP; DI-CAFOS® D 160, Budenheim, Germany) was used as the filler, and magnesium stearate (MgSt; M-125, FACI Metalest S.L.U., Spain) was the lubricant in the tablet formulations.

Neo, M.S., Heng, P.W.S. & Liew, C.V. Slugging-induced Mechanistic Coupling of Microcrystalline Cellulose-starch Disintegrants for Enhanced Tablet Disintegration. AAPS PharmSciTech 27, 271 (2026). https://doi.org/10.1208/s12249-026-03518-z

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