A tablet is the most common pharmaceutical dosage form for small molecule drugs. Tablets are typically made by compressing precisely metered powder or granulated formulation, normally a well-blended mixture of active and inactive ingredients, using a set of tools comprising of a die and a matching set of lower and upper punches. When producing a large quantity of tablets, this process is often carried out via the use of a rotary press, whereby a number of the toolings are assembled in a rotating turret with cam tracks that control the linear motion of the upper and lower punches along the die axis. After the filling of the die-cavity, and thanks to the rollers, the powder is compressed (loading) by the vertical movement of the punches and the applied force is then removed (unloading) when the punches move backwards. The tablet is ejected afterwards using the upward movement of the lower punch as guided by the ejection cam.

As with any pharmaceutical dosage form, a tablet must meet a set of predefined specifications such as its dose strength (‘label claim’) and how much of the active ingredient therein is dissolved (‘released’) after a period of time; it also must be free of defects upon ejection and subsequent processing (e.g. dedusting, spray film coating, packaging, transportation, etc.).

The success of producing defect-free tablets that meet the specified qualities depends on the interplay between the properties of the formulation and the manufacturing process. This interaction can be complex because the material volume reduction that occurs during tableting and the inter-particle bonding that makes it possible for a solid tablet to be formed at the end of the process may be the result of elastic and plastic deformations, fragmentation, breakage, and bonding–all of which may take place simultaneously–of the individual particles that make up the formulation. In addition, the nature of the material deformation may also be dependent upon the rate at which it occurs (i.e. viscoelasticity and viscoplasticity), therefore the outcome of the tableting process may change depending on its scale and throughput. Owing to such complexities, some aspects of tablet development remain largely reliant on empirical knowledge which are not easily linked to mechanistic or scientific explanations.

The current work concerns one aspect of the last stages of the tableting process, specifically, the decompression (‘unloading’) and ejection steps, and how they can impact the properties of a tablet. Decompression refers to the process that occurs during the retraction of the punches (i.e. until the punches are no longer in contact with the material). At such a state, the only pressure still present in the system is that exerted between the tablet and the die-wall. The pressure remaining at the end of the decompression stage is often referred to as the residual die-wall pressure (RDP). Following decompression, the tablet is ejected out of the die by the lower punch (see above). It is worth noting that the force required to eject the tablet is non-zero, and can in fact be significant, as a consequence of the RDP and the tablet/die-wall friction (Sun, 2015).

Tablet elastic recovery is known to occur during the decompression stage, which manifests as an increase in the in-die tablet thickness and a reduction in the die-wall pressure magnitude from the maximum value to the RDP. Moreover, a number of studies have also shown that plastic deformation also occurs during this stage. Hiestand (Hiestand et al., 1977), for example, subjected materials to multiple cycles of compression and decompression and showed that plastic deformation occurred early during the decompression stage. On the other hand, other researchers (Doelker and Massuelle, 2004, Long, 1960) argued that plastic deformation only occurred late during the decompression stage as a result of material yielding when the die-wall pressure exceeds the axial pressure. Regardless of these two opposing hypotheses, the effect of such plastic deformation on the final tablet properties is currently unclear.

Another phenomenon that may occur during the decompression stage is the formation of microcracks, i.e. the rupture of the bonding between particles or the fracturing of particles themselves, within the tablet. These microcracks weaken the tablet and can potentially lead to tablet failures. For example, lamination, which is characterized by the separation of a tablet into two or more layers along its band, can occur when the aforementioned microcracks propagate to the surface as a result of localized stresses formed along the tablet band as it emerges from the die (Garner et al., 2014, Long, 1960, Mazel and Tchoreloff, 2022). Lamination has been shown to be (partially) a consequence of the residual die-wall pressure (Hiestand, 1991).

On a broader note, the presence of microcracks can also compromise the characterization of the compaction behavior of active pharmaceutical ingredients (API) that is often performed by formulation scientists in the early stages of drug development, for example, in the case of a comparison of tensile strengths of compacts made under varying compression pressures for a new active. Here, microcracks may lead to some bias in the experimental result because they prevent the true bonding strength of the particles–and how it varies with compression pressure–to be properly quantified. In extreme cases microcracks can merge and lead to macroscopics cracks and to phenomena like lamination or capping. In those cases, an intact tablet cannot be produced and therefore characterized.

To address the issue of not being able to form intact tablets, Hiestand et al. (Hiestand and Smith, 1984) introduced the concept of triaxial decompression. Under such a process, decompression is achieved not only by unloading in the compression (axial) direction, but also in the sagittal and coronal directions [terms borrowed from anatomical planes] using a custom-built die with a square cross-section. These decompression mechanics serve two functions: (1) lowering the die-wall pressure during decompression so it never exceeds the axial pressure, and (2) completely eliminating the RDP. Both conditions were hypothesized to lead to defect-free tablets for any material (Hiestand and Smith, 1984).

Presuming that a tablet free of microcracks can be produced via a triaxial decompression process, and further presuming that the same tablet is subject to microcrack formation therein when produced with a rigid die, then the strength of the former tablet should be quantifiably greater than that of the latter one. The question remains, however, as to whether the same conclusion can be drawn for tablets that are free of defects even when made with a rigid die.

Recent work (Radojevic et al., 2021) indeed suggests that triaxial decompression makes it possible to produce stronger tablets for ‘ideal’ excipients under certain conditions. Specifically, significant differences were observed when comparing the tensile strength of internally lubricated microcrystalline cellulose (MCC) compacts made under triaxial decompression and those made using a rigid die. The effect of triaxial decompression on tensile strength, however, was found to be negligible for externally lubricated lactose and MCC compacts. This finding is surprising because MCC, even when internally lubricated, still possesses a high tensile strength and a low RDP, whereas the opposite is true for lactose. As such, the effect of die-wall constraints during decompression can be expected to be more significant for lactose.

One possible explanation for this unexpected result is related to the differing tablet shapes used for the comparison in the study. Compacts made under a triaxial decompression process had a square cross-section, whereas those made with a rigid die were round. As demonstrated in previous studies, tensile strength calculations can be dependent upon the shape of the compact used in the failure tests, i.e. transversal loading for square tablets and diametral loading for round tablets may not always give comparable results (Hiestand and Peot, 1974).

To address the ambiguities cited in the preceding paragraphs, the present work revisits the lactose, MCC, and mannitol experiments performed by Radojevic et al. (Radojevic et al., 2021) – all of which are commonly used pharmaceutical excipients and the first two materials were shown to be, respectively, the least and the most influenced by triaxial decompression in that study. However, in the current study, triaxial decompression experiments are performed using both cylindrical and cuboid custom-built dies whose walls comprised multiple sections that can move outwards as a function of the axial pressure. In addition, the cylindrical die system is also instrumented with piezoelectric sensors for measuring the die-wall pressures throughout the decompression process. Using these experimental setups allows studying the influence of the decompression and ejection processes on the final properties of tablets in ways that previous studies could not accomplish and enables new insights into factors affecting the elastic and plastic deformation that occurs during unloading on the tableting process and their impact on the tableting outcome.