Difference in Tableting of Lubricated Spray-Dried Mannitol and Fluid-Bed Granulated Isomalt

Abstract

Background: Polyols are widely used as tablet diluents due to their high solubility, favourable taste, and ability to form robust tablets. Thus, commercially available polyols, such as mannitol and isomalt, can be considered for the preparation of low-drug-dose formulations with a high polyol load.

Methods/Results: This study investigated spray-dried mannitol (Mannogem^® XL Opal SD and Pearlitol^® 200 SD) and fluid-bed granulated isomalt (galenIQ™ 720 and galenIQ™ 721) at magnesium stearate levels of 0.5 and 3.0 wt.% and consolidation pressures of 100 and 300 MPa. During the tableting of 100 consecutive tablets, materials displayed different ejection force profiles: galenIQ™ 720 and galenIQ™ 721 demonstrated low and stable ejection pressures; Mannogem^® displayed a lubricant- and compaction pressure-dependent profile, whereas Pearlitol^® produced the highest ejection forces, particularly at 0.5 wt.% magnesium stearate. To elucidate these differences, the used materials were characterised in terms of SEM imaging, moisture content, surface area and porosity analysis, particle size distribution, pXRD, and densification kinetics. Using a compaction simulator, key parameters including pressure–displacement profiles, mean yield pressure, and strain rate sensitivity of the unlubricated materials were experimentally determined, while pressure transmission, residual die-wall pressure, and friction coefficient were computed.

Conclusions: The study concluded that variations in tableting properties were primarily governed by moisture content and, for mannitol grades, by manufacturing method-dependent differences in particle microstructure. These insights provide guidance for the rational selection of polyol excipients and appropriate lubrication levels in direct compression tablet formulations.

Introduction

Polyols, such as mannitol, sorbitol, and isomalt, are widely used as excipients in direct compression tablet formulations due to their superior compaction properties [1] and their high and pH-independent solubility [2]. Various grades are available on the market, including milled and classified crystalline, granular, and spray-dried forms. The particle size, shape, and morphology of polyols determine their flowability, which is crucial for direct compression formulations and high-speed tableting processes [1,3]. As bulk sweeteners, polyols are often used at high weight fractions in compressed, orally disintegrating [4], mouth-refreshing, and chewable tablets [5]. Unlike pharmaceutical monosaccharides, such as mannitol, sorbitol, and xylitol, isomalt is a disaccharide. Its commercial grades consist of a mixture of glucose-mannitol (α-d-gluco-pyranosyl-1-6-mannitol) and glucose-sorbitol (α-d-gluco-pyranosyl-1-6-sorbitol) [6,7]. In recent years, isomalt has gained popularity in solid dosage form formulations due to its physicochemical and technological properties comparable to sorbitol and its close-to-sugar sweetness profile [8].

Due to its different solid state and morphological characteristics, the tableting process and compaction behaviour of mannitol can change drastically [1,9,10,11] and can also vary depending on the amount of lubricant [12] and the duration of lubrication [13]. Suboptimal formulations, including high levels of mannitol and lubricant, can cause tablet defects [10,14]. Additionally, the increase in the hydrophobic lubricant content reduces tablet wettability, prolongs disintegration time, and decreases the dissolution rate, which can negatively influence consumer acceptance and/or biopharmaceutical performance of tablet products.

Commonly, tablet defects are associated with high adhesion between the tablet’s radial surface and the die wall [15,16]. Upon axial compression the material densifies and undergoes irreversible deformation at compression pressure around and above the mean yield pressure (Py) [17]. This deformation usually includes particle shape changes and fragmentation. It results in changes in the specific surface area and increases the particle-to-particle bonding surface area [18], as well as the contact area between the material and die wall. The die wall is an interface between the material on one side and the compression chamber on another. The redistribution of axial compaction pressure to the radial direction can be described by the ratio of the radial to axial stress during the compression stage—the Poisson’s ratio [19,20,21,22].

The compression of the tablet is followed by decompression and relaxation, which can be characterised by the residual radial die-wall pressure [23,24]. This stage is followed by ejection. The ejection stress depends on the radial contact area, density (porosity) of the compressed material, the interaction between the material and die wall, and the residual radial die-wall pressure upon ejection [25,26].

The efficiency of the lubricant can be expected to depend on brittle fracture (opening of new unlubricated surfaces) and material behaviour upon decompression and relaxation. In turn, radial tablet pressure on the die wall should be a function of material plasticity (ability to undergo plastic deformation), applied compression pressure, punch speed, and compression pressure transmission in the radial direction.

The ejection force is recommended as an effective metric to identify and mitigate the risks of tablet defects [26], while an ejection pressure of less than 3 MPa is recommended for a successful tableting process [27]. Nowadays, the use of an instrumented die allows the measurement of the die-wall pressure, providing valuable information since high wall pressure can increase the risk of tablet radial side scratching as well as provoke tablet defects, such as capping, lamination, or chipping.

Taking into account good palatability and sweetness profiles, the high-mannitol or isomalt-loaded tablets can be considered for the preparation of low-drug-dose formulations. Thus, the investigation of the applicability of different grades of isomalt and mannitol represented by placebo tablet formulations is a meaningful task. This study aimed to investigate the effect of lubricant amount on the tableting of two grades of spray-dried mannitol (Mannogem® XL Opal SD and Pearlitol® 200 SD) and two grades of fluid-bed granulated isomalt (galenIQ™ 720 and galenIQ™ 721) at two levels of magnesium stearate concentrations (0.5 and 3.0 wt.%) and two levels of compaction pressures (100 and 300 MPa). Experiments were conducted using a compaction simulator and an instrumented die, considering ejection force, residual radial die-wall pressure, and other parameters.

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Materials and Methods

Spray dried grades of mannitol Pearlitol^® 200 SD (#EQ98Q; Roquette, Lestrem, France) and Mannogem^® XL Opal SD (#122403728; SPI Pharma, Wilmington, NC, USA), isomalt galenIQ™ 721 (#L121390741) and galenIQ™ 720 (#L1212919U1; BENEO Palatinit GmbH, Obrigheim/Pfalz, Germany), and magnesium stearate (MgSt; #299546; Magnesia 4264; Magnesia GmbH, Lüneburg, Germany) were used in this study.

2.11. Tableting

Tableting cycles simulated the movement of small rotary press punches. According to STYL’One Nano presets, the simulated small rotary press had a turret diameter of 180 mm, precompression roll diameter of 44 mm, angle between rollers of 65 degrees, compression roll diameter of 160 mm, angle between main compression and the beginning of the compression ramp of 60 degrees, and an angle of ejection ramp of 20 degrees. A simulated tableting speed of 70 rpm (maximum for STYL’One Nano) was used. That corresponds to a loading, unloading, and ejection punch speed of 90 mm/s, geometric dwell time of 24 s, and relaxation time (based on the experimental data) of 170–200 ms. A pre-compression force of 5 kN (50 MPa) and compression forces of 10 and 30 kN (100 and 300 MPa) were applied (Figure 1B). Powder mixtures were tableted with round flat tooling (diameter of 11.28 mm) to obtain a target mass of 500 mg using a STYL’One Nano (MEDELPHARM , Beynost, France) compaction simulator. Powder feeding into the die was performed automatically via the feed shoe [38].

Mohylyuk, V.; Kukuls, K.; Frolova, A.J.; Horváth, Z.M.; Kolisnyk, T.; Buczkowska, E.M.; Pētersone, L.; Pelloux, A. Difference in Tableting of Lubricated Spray-Dried Mannitol and Fluid-Bed Granulated Isomalt. Pharmaceutics 2025, 17, 1566. https://doi.org/10.3390/pharmaceutics17121566