Investigating the Mechanical Behaviour of Viscoelastic and Brittle Pharmaceutical Excipients During Tabletting: Revealing the Unobvious Potential of Advanced Compaction Simulation

Abstract

Background: The compaction of formulation blends is a critical stage in pharmaceutical tablet manufacturing, particularly when drug substances or functional excipients exhibit limited flowability and tabletability.

Objectives: This study systematically examined the mechanical behaviour of viscoelastic microcrystalline cellulose (MCC) and brittle anhydrous dibasic calcium phosphate (DCPA), as well as their mixtures, to check how deformation mechanisms influence powder handling and tablet performance.

Methods: A compaction simulator, mimicking a small rotary tablet press, was used to evaluate tablet weight variability, densification profiles, die-filling height, force–displacement behaviour, and in-die Heckel analysis. Additional assessments included compression times, breaking force, tensile strength, elastic recovery, as well as in-die and out-of-die tablet thickness across various compositions and compaction pressures.

Results/Conclusions: Bulk density values from the simulator showed strong correlation with pharmacopeial measurements (R² ≥ 0.997). Measurable differences in true density and cohesiveness led to poor flowability for MCC and good flow for DCPA, with mixtures containing higher DCPA concentration displaying markedly improved flow characteristic. Compaction analyses confirmed extensive plastic deformation for MCC and fragmentation for DCPA. Increasing MCC content elevated die-fill height, compaction energy, and tablet weight variability, whereas higher DCPA fractions decreased apparent density of tablets and reduced energy demand. Tabletability and compressibility profiles reflected that MCC generated hard tablets but exhibited higher elastic recovery, while DCPA formed softer tablets with closer to linear strength–pressure relationships. Energy profiling demonstrated that MCC stored more elastic energy and required higher overall compression work, whereas DCPA reduced elastic accumulation. Overall, blending viscoelastic and brittle excipients offers a robust strategy for optimizing manufacturability, mechanical strength, and energy efficiency in tablet production.

Introduction

For many years, compressed tablets have been the most widely used dosage form, offering high patient acceptability, a well-understood manufacturing process, and cost-effectiveness [1,2]. Recently, drug manufacturers have increasingly adopted direct compression (DC) to reduce production costs because it eliminates granulation, which is a time- and energy intensive process. DC is also well suited for heat- or moisture sensitive active pharmaceutical ingredients (APIs). Although it involves the fewest processing steps, DC is very sensitive to variations in API properties and performs suboptimal with poorly flowing materials [3,4].

The vast majority of drug substances, as well as functional excipients, have limited flowability and compactibility. Ensuring suitable powder flowability is particularly important, as in production lines they pass through numerous pipes and pieces of equipment. Mixtures of powders with differing flow properties can segregate, while insufficient flow may cause blockages that stop the process. In the tablet press, poorly flowing mixtures fill matrices unevenly, leading to high variability in tablet weight and non-uniform dosage. Poor tabletting properties can also reduce mechanical strength of the tablets, so they may be damaged or even break during subsequent process steps, including coating or packaging [5,6,7,8,9,10]. Overcoming these issues is crucial for efficient tabletting, particularly with DC technology. Proper selection of specialized DC-grade excipients helps counteract the adverse properties of drug substances and ensures tablets with the required mechanical strength [11].

Excipients used in large quantities to enhance production and performance are known as fillers-diluents (or fillers-binders) [12,13,14]. They can be further divided into three types based on their compression behaviour: brittle, viscoelastic (ductile), and elastic. During tableting, brittle substances such as lactose, dibasic calcium phosphate, or mannitol fracture first, and, if further fragmentation is impossible, may then deform by yielding. Ductile materials like microcrystalline cellulose show significant plastic (irreversible) and elastic (reversible) deformation, whereas elastic materials such as starches deform predominantly reversibly [14,15]. Thorough knowledge of the deformation behaviour of individual substances and their blends is essential for designing an efficient tablet manufacturing with high-speed rotary presses that produce tablets of the desired quality [16].

The aim of the present study was to evaluate the potential offered by a compaction simulator for examining the deformation behaviour of selected excipients commonly used in tablet formulations. Employment of compression simulation during formulation and process development helps reduce scale-up failures by identifying defects such as capping and lamination at an early stage. Because only limited quantities of drug substances are typically available during development, and their cost is often high, the use of compaction simulators can facilitate rapid formulation development while minimizing material consumption.

Viscoelastically deforming microcrystalline cellulose (MCC), brittle anhydrous dibasic calcium phosphate (DCPA), and their mixtures were investigated in this study. The true densities of these two materials are 1.512–1.668 g/cm3 [17] and 2.89 g/cm3 [18], respectively. From the many commercially available grades, two types with comparable average particle sizes but significant differences in bulk density, porosity, and particle shape were selected for the study. MCC, Ceolus™ UF-711 (Asahi Kasei, Tokyo, Japan), has irregularly shaped fibrous particles with an average particle size of approximately 50 μm (the particle morphology is shown in Figure 1A). It is characterized by high porosity and a low bulk density of about 0.22 g/cm3, as stated by the manufacturer [19]. In contrast, particles of DCPA PharSQ® Coarse A 60 (Chemische Fabrik Budenheim KG, Budenheim, Germany) are densely packed agglomerates with fairly spherical shapes, averaging around 60 μm in size (the particle morphology is shown in Figure 1B). The powder exhibits a relatively high bulk density of approximately 1.3 g/cm3 and very low porosity [20].

The study analysed changes in the compaction behaviour of powders during tabletting as their nature shifted from viscoelastic to brittle. A compaction simulator was used to precisely assess deformation and densification, based on force–displacement and tabletability profiles. The research presented here continued earlier work. In these works, using the same formulations, in-die/out-of-die Heckel plots and brittle deformation of DCPA, as well as dwell time according to force as a function of powder composition and compression force, were investigated [21,22].

Figure 2 shows an example of a force–displacement plot illustrating the stages of powder densification during tabletting and energy distribution.

 

E1 represents rearrangement energy. The sum of E2 and E4 is the plastic energy, the total energy provided to the tablet during compaction. E3 is the elastic energy (or energy lost), as the product returns energy by pushing the punches back. E4 represents plastic flow energy, which occurs when the force decreases while the material continues to deform. This phenomenon is characteristic of ductile materials. E4 arises because the compression pressure remains higher than the mean yield pressure (Py). The sum of E1, E2, and E3 constitutes the compaction energy. Py is a measure of plasticity, indicating the point beyond which deformations become irreversible. It should be noted that, although yield typically occurs over a range, the Py value derived from a Heckel plot is treated as a single point representing the average yield pressure.

In the study, a STYL’One Nano compaction simulator (MEDELPHARM, Beynost, France) was used to mimic the compression dynamics of small industrial rotary tablet presses at 70 rpm and compaction forces of 10–50 kN (equivalent to 100–500 MPa). With high-accuracy sensors, it enabled detailed monitoring of tabletting process, providing insights into elastic recovery, elasticity, compression energy, plastic energy, elastic energy, rearrangement energy, specific work of compression, and cohesion index [7,24,25]. Comprehensive analysis of compaction behaviour with a compression simulator can help anticipate production issues and prevent defects associated with over-compression.

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Materials

Microcrystalline cellulose (MCC), CEOLUS ™ UF-711 (Asahi Kasei, Tokyo, Japan), shown in Figure 1A. Anhydrous dibasic calcium phosphate (DCPA, CaHPO4), PharSQ®Coarse A 60 (Chemische Fabrik Budenheim KG, Budenheim, Germany), shown in Figure1B. Precipitated amorphous silica SYLOID® 244 FP (Grace GmbH, Worms, Germany). Sodium stearyl fumarate (SSF) PRUV® (JRS Pharma, Rosenberg, Germany).

Zakowiecki, D.; Kukuls, K.; Cal, K.; Pelloux, A.; Mohylyuk, V. Investigating the Mechanical Behaviour of Viscoelastic and Brittle Pharmaceutical Excipients During Tabletting: Revealing the Unobvious Potential of Advanced Compaction Simulation. Pharmaceutics 2025, 17, 1606. https://doi.org/10.3390/pharmaceutics17121606

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Read also our introduction article on Microcrystalline Cellulose here: