Influences of variations of the amount of compressed material on compressibility, tabletability and compactability

Abstract

Compression analysis is essential for the investigation of materials and processes in the manufacturing of pharmaceutical tablets. In the past, the influence of various process parameters on compression analysis has been investigated. The strength of these influences can significantly depend on the properties of the compressed material. One example is the effect of tablet compression speed on tabletability. The impact of tablet geometry has also been studied. However, what is still missing in the literature is the investigation of the influence of the quantity of the compressed material. This publication provides a starting point for understanding the effect of material quantity in compression analysis. In addition to the material quantity, two different tablet diameters were also investigated. The study demonstrates that the extent to which material quantity has an influence on compression analysis highly depends on the material properties. It clearly shows that the tabletability and even the compactability of materials can vary significantly depending on the amount of material compressed.

Highlights

Investigated how variations in mass influence tablet parameters

Leveraged large databases to enhance data robustness and improve reliability

Details on regression analysis

Introduction

In tablet manufacturing, the critical quality attributes of tablets are influenced by both the properties of the compressed materials and the process conditions, as well as the interactions between these factors. Material properties can be broadly categorized into chemical properties, which stem from the molecular composition of the materials, and physical particle properties. Together, these properties govern the deformation behavior of the bulk solid during compression. Process conditions, on the other hand, can be classified into controllable factors, such as punch geometry, punch velocity profile, room temperature, and air humidity at the manufacturing site, and uncontrollable factors, such as the die temperature increases during operation, which is influenced by material properties and the speed of the tableting press 1,2. Understanding the interplay between material properties and process parameters is essential for compression analysis, as it directly impacts tablet quality.

Among the physical properties of tablets, mechanical resistance and solid fraction are particularly critical. Mechanical resistance affects the durability of tablets during post-processing and patient handling. This property is commonly evaluated using diametrical compression tests, where a crushing force is applied to the tablet until fracture occurs. The resulting force is used to calculate the tensile strength, which accounts for the tablet’s geometry. The tensile strength equation for flat-faced tablets is derived from the stress distribution within cylindrical bodies 3 and was refined by Fell and Newton 4. Despite its widespread use in research, the validity of the test conditions has been a subject of debate since its inception. Solid fraction, which determines tablet porosity, plays a pivotal role in the disintegration and dissolution of active pharmaceutical ingredients 5, 6, 7, 8. It is often used as a surrogate parameter for predicting these properties due to its ease of measurement. Both tensile strength and solid fraction are influenced by the maximum compression pressure during the tableting process, with these relationships referred to as compressibility, tabletability, and compactability 9. Each material can be represented by a curve within this three-dimensional space. The trajectory of this curve, however, can be influenced and altered by additional process parameters.

The influence of process parameters on compressibility, tabletability, and compactability has been extensively studied. For instance, tableting speed significantly affects tablet properties due to its impact on material deformation during compression 10,11. At higher speeds, the shorter duration of pressure application can reduce tabletability, depending on material properties, while compactability remains relatively unchanged. Additionally, the tableting speed also influences the filling behavior of the dies 12. Variations between different tableting machines 13 and the inclusion of a precompression step have been shown to enhance tabletability and mitigate defects caused by trapped air expansion 14, 15, 16. Feed frame design and settings also affect die-filling homogeneity and the risk of overlubrication 17. The geometry of punches influences tablet strength 18, material deformation behavior 19, and the stress distribution 20 as well as the density distribution within tablets 21, 22, 23. Furthermore, punch displacement profiles, determined by roller geometry and punch head design, play a key role in the duration of the compaction process on rotary presses 24.

Lastly, changes in temperature during the tableting process can impact the deformation behavior of certain materials, altering tablet properties 25,26. This enumeration of the influences of process parameters is certainly not exhaustive but demonstrates that a wide range of different parameters has already been investigated in published literature.
While the literature has extensively explored these named variables, limited attention has been given to the effect of tablet weight and thickness on tablet properties like tensile strength. Mazel et al. investigated the lamination of tablet of varying thicknesses under increasing pressures 27. Newton et al. investigated elongated beam-like tablets with varying thicknesses but did not observe significant differences in tensile strength or solid fraction 28. Diarra et al. concluded a Drucker Drucker–Prager Cap simulation study on the effect of tablet thickness on the density distribution within the tablet by the estimation that found variations may have an impact in the tensile strength of tablets 21. A study on the multivariate decomposition of tableting data did not identify a significant effect of tablet mass 29. However, the publication did not analyze raw data directly but rather assessed the clustering of more than 60 parameters. Within this clustering, tablet mass appeared to have a minimal influence. These findings are counterintuitive, given the known non-uniform distribution of solid fraction within tablets 30, 31, 32. Variations in thickness could reasonably be expected to influence the distribution patterns of solid fraction and, consequently, the mechanical properties of tablets.

The present study aims to systematically address this gap. The focus lies on investigating whether a correlation exists between the tablet mass and the measured tensile strength. Initially, parts of the database from Berkenkemper et al. were re-evaluated 29. These results were then reproduced to enhance the reliability of the findings. Furthermore, a new database was created, focusing on single-component systems to keep the complexity of the investigation appropriately aligned with the research question. In addition to varying tablet mass, tablets were produced using punches with two different diameters and at two distinct tableting speeds. The objective was not to explain the observed effects mechanistically but to provide an exploratory analysis of influences on tablet properties, such as tensile strength, which have been largely overlooked in existing literature.

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Materials and Methods

Reevaluation of database of Berkenkemper et al.

The database compiled by Berkenkemper et al. comprises tablet manufacturing data for 12 pharmaceutically utilized excipients. The materials were compressed under varying compression pressures, punch velocities, and punch geometries. Tablet mass was adjusted to 150 mg, 200 mg, and 250 mg. For each parameter setting, at least three tablets were compressed. A detailed description of the dataset can be found in the original publication ²⁹.

In the present study, the data of 8 mm tablets from the database were re-evaluated. The analysis of the tabletability of these tablets is detailed in Section ‎2.2.

Tableting

The compression experiments were performed using a compaction simulator (STYL’One Evo, MEDELPHARM, France). The machine was equipped with EU-B 8 mm and 11.28 mm round, flat-faced punches. Prior every tableting process, the punches and the die were externally lubricated with magnesium stearate (Ligamed MF-2-V, Peter Greven Nederland CV, Netherlands) using a brush. Subsequently, the die was filled manually. The weight of the tablets was adjusted by the change of the position of the lower punch during the filling phase of the die. For every material at least 6 different tablets weights were investigated. During the compression phase, the punches were driven at a constant speed of 3 mm s^-1 or 15 mm s^-1 in thickness mode of the machine. The minimum of the in-die thickness was adjusted to cover the range from approximative 50 to 1000 MPa for the compression pressure in 10 factor levels. At every setting 10 tablets were produced. Limitations of the machine, such as excessively high ejection forces or a too low minimum thickness, occurred at the edges of the experimental range. Consequently, variations between the minimum and maximum values of individual settings were occasionally encountered. In total 9241 individual tablets were produced and tested. The data of the compaction simulator, including the position of the punches, the compaction pressure and the process time was gathered in a frequency of 10 kHz. The data of the punch positions was corrected for the deformation of the punches and machine parts using the Analis Software of Medelpharm. The whole database will be made available on request.

An overview over the materials and settings included in the investigations is provided in Table 1. Fujicalin® and DiCaFos® A60 were selected to enable the comparison of the effects of significant differences in particle shape. The particle size of both grades is quite similar, with the dx₅₀ in a range of 60 – 80 µm ²⁹. For similar reasons, the spherical spray-agglomerated grade Tablettose® 70 and the coarse milled GranuLac® 200 were included in the study. HPC SL FP serves as an example of a mostly elastically and plastically deformable material. Vivapur® 102 is included to cover a typical grade of microcrystalline cellulose for compression while PROSOLV® HD 90 and PROSOLV® ODT serves as examples for co-processed excipients. Polyglycol 20000 P was investigated to include a material of an exotic deformation behavior.

Table 1. Materials and settings and helium pycnometry density.

Trade name	Material	Supplier	Tablet weight / mg	Punch speed / mm s^-1	Punch diameter / mm	He density / mg mm^-3
DiCaFos® A60	anhydrous dibasic calcium phosphate	Budenheim (Germany)	140 – 300 mg	3	8	$2.828 \pm 0.002$
Fujicalin®	anhydrous dibasic calcium phosphate	Fuji Chemical Industries Co., LTD. (Japan)	110 – 470 mg	3 & 15	8 & 11.28	$2.780 \pm 0.003$
HPC SL FP	hydroxypropyl cellulose	Nippon Soda (Japan)	120 – 270 mg	3	8	$1.200 \pm 0.001$
Vivapur® 102	microcrystalline cellulose	JRS Pharma (Germany)	110 – 470 mg	3 & 15	8 & 11.28	$1.535 \pm 0.001$
PROSOLV® HD 90	microcrystalline cellulose, colloidal anhydrous silica	JRS Pharma (Germany)	110 – 300 mg	3	8	$1.550 \pm 0.002$
PROSOLV® ODT	microcrystalline cellulose, colloidal anhydrous silica, mannitol, fructose, crospovidone	JRS Pharma (Germany)	120 – 300 mg	3	8	$1.483 \pm 0.002$
Polyglycol 20000 P	polyethylene glycol	Clariant (Switzerland)	100 – 260 mg	3	8	$1.213 \pm 0.00$ 2
Tablettose® 70	α-lactose monohydrate	Meggle (Deutschland)	100 – 470 mg	3 & 15	8 & 11.28	$1.524 \pm 0.001$
GranuLac® 200	α-lactose monohydrate	Meggle (Deutschland)	110 – 310 mg	3	8	$1.523 \pm 0.006$

Anh Tuan Tran, Stefan Klinken-Uth, Influences of variations of the amount of compressed material on compressibility, tabletability and compactability, Journal of Pharmaceutical Sciences, 2025, 103831, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2025.103831