(M1330-11-74) Mechanism and Generality of the Tabletability Flip Phenomenon

Purpose: Sufficient mechanical strength is required for tablets to withstand stresses during transport and handling. Thus, the tabletability of active pharmaceutical ingredients (APIs) is an important property for developing a quality tablet product.¹ Typically, plastic APIs exhibit good tabletability because they can deform permanently during compaction, leading to a larger bonding area between particles.² It has been commonly assumed that a solid form of an API with better tabletability also exhibits better tabletability when formulated with excipients. However, it was recently shown API solid forms with poorer tabletability could exhibit better tabletability in formulations, i.e., tabletability flip.³ Consequently, solid forms could have been erroneously eliminated during the preformulation stage on the ground of expected poor tabletability. To avoid such errors, it is important to understand the mechanism of the tabletability flip phenomenon and its universality. We hypothesize that tabletability flip results from the better conformation of plastic excipient particles to the shape of harder API particles during compaction, leading to a larger bonding area and higher tensile strength (Figure 1a). This work is aimed at: 1) testing the hypothesized mechanism by visualizing the deformation of particles and their bonding areas in a tablet; and 2) investigating the generality of the tabletability flip phenomenon using six different systems.

Methods: Soft PlayDoh and hard glass beads (3 mm) were selected as a model system due to their profoundly different mechanical properties. All PlayDoh particles, with a diameter of approximately 2 mm, were hand-rolled, and subsequently coated by magnesium stearate (MgSt). The mixture of glass beads and PlayDoh particles was compressed at a compaction pressure of 100 MPa by a compaction simulator. Micro-computed X-ray tomography (micro-CT) was used to obtain images of the particles in the tablet. Two polymorphic pairs, theophylline (THEO) forms II and IV and p</em>-aminobenzoic acid (ABA) forms α and β; a salt/acid pair, potassium acesulfame (Acs-K) and acesulfame free acid (Acs-H); a crystalline/amorphous pair, acetaminophen (APAP) and 15% acetaminophen amorphous solid dispersion with copovidone (ASD); and L-alanine (ALA)/ibuprofen (IBU) were selected as model systems. The plasticity of these materials was quantified using the mean yield pressure (P_y) values obtained from in-die Heckel analyses (Table 1).⁴ These powders were used to prepare binary mixtures with microcrystalline cellulose (MCC, Avicel PH102), a plastic excipient, in API:MCC = 1:4 (w/w) ratio. Additionally, tablet formulations consisting of 20% API, 49.67% MCC, 24.83% lactose monohydrate, 5% crospovidone, and 0.5% MgSt were prepared and tested for THEO IV and IBU. For each powder, a series of compacts were obtained over the compaction pressure range of 20- 350 MPa using a compaction simulator. Diametrical breaking force was determined using a texture analyzer. Tablet tensile strength was calculated from the maximum breaking force and tablet dimensions.

Results: The different radiopacities of PlayDoh and glass and the presence of MgSt on the surface of the PlayDoh particles allowed us to distinguish them and visualize the bonding area between them (Figure 1b). The plastically-deformed PlayDoh particles wrapped around the hard glass beads, whereas contacts between adjacent PlayDoh particles were approximately flat and those between neighboring glass beads were point-like. Thus, bonding area followed the descending order of PlayDoh-glass > PlayDoh-PlayDoh > > glass-glass. This finding supports the hypothesis that significantly larger bonding areas are developed between hard API and soft excipient particles than those between soft API and soft excipient particles during compaction (Figure 1a). This insight not only explains the tabletability flip phenomenon, but also suggests an effective formulation approach for preparing tablets with sufficient mechanical strength for poorly compressible APIs, i.e., selecting excipients with sufficiently high plasticity as quantified by sufficiently low P_y values. Results from the investigation of six drastically different model systems invariably showed that the more plastic API exhibited better tabletability than the less plastic one in the absence of an excipient (Table 1, Figure 2, odd columns). However, the tabletability of plastic APIs was lower when formulated with MCC or a realistic placebo formulation (Table 1, Figure 2, even columns). Thus, the tabletability flip phenomenon broadly occurs. Additionally, tabletability flip was more evident at a higher compaction pressure (Figure 2, even columns), because higher pressure magnifies the difference in bonding area between different pairs of particles.

Conclusion: By visually showing the plastic deformation of particles in a mixture consisting of soft and hard particles, we have demonstrated a possible mechanism of the tabletability flip phenomenon. The mechanism entails that softer excipient particles conform to the shape of harder API particles during compaction, resulting in a larger bonding area and higher tensile strength. We have also demonstrated the generality of the tabletability flip phenomenon, which occurred in all six systems tested in this work. Therefore, solid forms of an API with poor tabletability should not be automatically excluded from the list of candidates for tablet development, as they may actually exhibit better tabletability upon formulation.

References: (1) Sun, C. C. Microstructure of Tablet-Pharmaceutical Significance, Assessment, and Engineering. Pharm. Res. 2017, 34 (5), 918–928. https://doi.org/10.1007/s11095-016-1989-y.
(2) Sun, C. C. Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity. J. Adhes. Sci. Technol. 2011, 25 (4–5), 483–499. https://doi.org/10.1163/016942410X525678.
(3) Paul, S.; Wang, C.; Sun, C. C. Tabletability Flip – Role of Bonding Area and Bonding Strength Interplay. J. Pharm. Sci. 2020, 109 (12), 3569–3573. https://doi.org/10.1016/j.xphs.2020.09.005.
(4) Vreeman, G.; Sun, C. C. Mean Yield Pressure from the In-Die Heckel Analysis Is a Reliable Plasticity Parameter. Int. J. Pharm. X 2021, 3, 100094. https://doi.org/10.1016/j.ijpx.2021.100094.

Acknowledgements: This work was supported by a grant from BMS.

Figure 1. a) The hypothesized mechanism of tabletability flip, where a soft API develops a larger bonding area (BA) between particles when a pure API powder was compressed but smaller BA when the API is formulated with a soft excipient. b) The micro-CT images (2D slices) of a PlayDoh-glass bead tablet.

Table 1. Py values of materials used in this work (n = 3). A lower Py value signifies higher plasticity.

Figure 2. The tabletability plots of pure materials (odd columns) and mixtures (even columns) for different systems. Binary mixtures: (a) THEO polymorphs; (b) ABA polymorphs; (c) Acs-K and Acs-H; (d) APAP and ASD; (e) IBU and ALA; generic formulation: (f) THEO IV and IBU.