Evaluation of In-Die Compression Data for a Deeper Understanding of Altered Excipient Properties upon Temperature Rise
The thermodynamic analysis of tablet formation includes the thermal and mechanical analysis during compression. The aim of this study was to evaluate alterations of force–displacement data upon temperature rise as an indicator for changed excipient properties. The tablet press was equipped with a thermally controlled die to imitate the heat evolution from tableting on an industrial scale. Six predominantly ductile polymers with a comparably low glass transition temperature were tableted at temperatures ranging from 22-70°C. Lactose served as a brittle reference with a high melting point. The energy analysis included the net and recovery work during compression, from which the plasticity factor was calculated. The respective results were compared to the changes in compressibility obtained via Heckel analysis. Elevated temperatures reduced the necessary work for plastic deformation for the ductile polymers, which was reflected in decreasing values for the net work of compaction and the plasticity factor. The recovery work slightly increased for the maximum tableting temperature. Lactose showed no response to temperature variations. Changes in the net work of compaction showed a linear correlation to the changes in yield pressure, which could be correlated to the glass transition temperature of a material. It is therefore possible to detect material alterations directly from the compression data, if the glass transition temperature of a material is sufficiently low.
Introduction
Direct compression is a commonly known technique for the manufacture of tablets. The mechanical strength of a compact is dependent on the bonding strength from molecular interactions and the established bonding area [1, 2]. During a compression cycle, powder consolidation includes rearrangement, slippage, and elastic and plastic deformation as well as fragmentation [1]. Sufficient tablet integrity therefore requires energy input, which is partially lost to heat generation [3,4,5]. A significant temperature rise during tableting has been proven in several studies [5,6,7,8,9]. Local temperatures > 100°C have been discussed [10]. This might affect the resulting tablet characteristics if the physicochemical properties of a material are thereby altered [11].
For the thermodynamic analysis of tablet formation, the consumed work and generated heat during compression have been subject to numerous studies. The thermal analysis includes infrared thermography [6,7,8], calorimetry [9, 12,13,14,15], and finite element analysis [5, 16]. Changes in temperature arise from the conversion of mechanical to thermal energy. The mechanical energy input can be derived from force–displacement profiles, which provide detailed information about a powder’s compression behavior [17,18,19]. Their shape is influenced by the material properties, the tableting equipment, and the applied settings [20]. From the calculated distance between the punches, the compact height and porosity during compression can be evaluated simultaneously [21]. Several widely used compression equations relate the porosity, or the respective relative density, to the applied pressure [22, 23]. These methods, including Heckel analysis, can be utilized to characterize the mechanistic deformation behavior of materials. Although the temperature might rise drastically during prolonged compression periods, the influence of the generated heat on energy parameters has rarely been studied.
To serve this purpose, either the production process needs to be run for a significant time or the powder has to be heated before compression to mimic the temperature rise on an industrial scale. Ketolainen et al. [6] correlated the mechanical and thermal energy when a tableting process was run for a maximum of 65 min. The investigation included microcrystalline cellulose (MCC) and dicalcium phosphate dihydrate (DCPDH), which were tableted with and without lubrication. While a drastic temperature change could be observed for some formulations, the energy parameters remained unchanged after an initial stabilization period. It is unlikely, however, that MCC and DCPDH were thermally affected by the evolving heat. For MCC, three step transitions upon heating have been identified at 132, 159, and 184°C via differential scanning calorimetry [24], while DCPDH also shows no event until it dehydrates above 100°C [25].
Those temperatures were clearly not reached during the tableting procedure. Cespi et al. [26] analyzed the temperature-dependent mechanical properties of four common pharmaceutical excipients using a fan heater within a modified tablet press. Heckel and energy analysis revealed a notable influence on the ductility of materials that undergo a thermally induced transition, while there was no considerable effect on the calculated energy values. It was concluded that either the effect was too weak or the investigation of energetic indexes is not sufficiently sensitive. The results were confirmed in a subsequent study investigating blends of acetylsalicylic acid and polyethylene oxides with different molecular weights [27]. In both studies, however, there was either no thermal transition in the investigated temperature range or it was only faint when the glass transition temperature (Tg) of a material was approached. In another study of Partheniadis et al. [11], the elevated temperatures were generated by a heating element, which was fitted to the die. A decrease in the work of compaction for a polymer with a Tg close to the tableting temperature was noted, which was explained with a decrease in friction as the material transforms to the viscous state.
Hence, it appears reasonable to consider a polymer’s thermal sensitivity when evaluating energy parameters. In ductile materials, the Tg can be identified as a crucial parameter for compression experiments. Upon temperature rise, polymers leave the rigid state and become more deformable, as their molecular mobility increases [28]. This affects their compressibility, which is the capacity of a powder to reduce its volume upon pressure [29]. When the compressibility is evaluated using Heckel analysis, a temperature-dependent decrease in yield pressure (Py) has frequently been observed, which is influenced by the Tg of a material [11, 26, 30, 31]. The reduced resistance against deformation promotes a higher strength of compacts after tableting [10]. As in-die Heckel analysis is derived from parts of the force–displacement data, changes in Py should also be reflected in the energy calculation.
The aim of this study was to evaluate in-die compression data as a tool for changed excipient properties upon temperature rise and their correlation to the Tg of a material. In contrast to a previous study, the equilibration time of the powder within the die was kept short to mimic the temperature increase on an industrial scale [32]. The applicability of the plasticity factor, as introduced by Stamm and Mathis [33], was critically assessed for elevated temperatures. The Tg of all investigated polymers was within or closely above the investigated temperature range.
Table I List of the Investigated Excipients
| Trade name | Abbreviation | Chemical composition | Supplier | T/°C |
|---|---|---|---|---|
| Flowlac® 100 | FL | α-Lactose monohydrate | Meggle (Germany) | 216 m* |
| Kollidon® SR | KSR | Polyvinyl acetate, polyvinylpyrrolidone, sodium lauryl sulfate, and silica (ratio 8:1.9:0.08:0.02) | BASF (Germany) | 42 g* |
| Eudragit® E PO | EPO | Copolymer of N,N-dimethylaminoethyl methacrylate, methyl methacrylate, and butyl methacrylate | Evonik Industries (Germany) | 49 g* |
| Eudragit® RS PO | RS | Copolymer of ethyl acrylate, methyl methacrylate, and methacrylic acid ester | Evonik Industries (Germany) | 58 g* |
| Eudragit® RL PO | RL | Copolymer of ethyl acrylate, methyl methacrylate, and methacrylic acid ester | Evonik Industries (Germany) | 70 g* |
| Soluplus® | SP | Copolymer of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol | BASF (Germany) | 75 g* |
| Nisso HPC SSL | SSL | Hydroxypropyl cellulose | Nippon Soda (Japan) | 82 g** |
| Parteck® LUB MST | - | Magnesium stearate | Merck (Germany) | 140 g*** |
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Grumann, H.D., Klinken, S. & Kleinebudde, P. Evaluation of In-Die Compression Data for a Deeper Understanding of Altered Excipient Properties upon Temperature Rise. AAPS PharmSciTech 24, 89 (2023).
https://doi.org/10.1208/s12249-023-02554-3