(T1130-04-24) A Potential Mechanism of Tabletability Flip Phenomenon

Purpose: Mechanical properties of crystal forms are being increasingly characterized, by computer prediction from crystal structure, nanoindentation, and powder compaction simulation, to aid the selection of an optimal API solid form with tablet manufacturability in mind.¹ In this effort, an underlying assumption is that a pure crystal form exhibiting better tabletability also exhibits better tabletability when formulated in the same excipient matrix. However, we recently observed a “tabletability flip” phenomenon, where a pure crystal form having higher tabletability exhibits a lower tabletability when mixed with a  plastic excipient.² Here, we describe a mechanism for the tabletability flip phenomenon, where a harder (less plastic) crystal form can develop a larger bonding area under compaction when mixed with softer excipients than a more plastic crystal form, leading to higher tabletability (Figure 1). The purpose of this work is to test this mechanism, by studying the compaction properties of two pairs of systems with quite different mechanical properties. A clear elucidation of the mechanism of this phenomenon is the first step toward identifying a set of rules for accurate predictions of tabletability of blends from the mechanical properties of drugs.

Methods: A salt-acid pair, potassium acesulfame (Acs-K) and acesulfame (Acs-H), and a crystalline-amorphous solid dispersion pair, acetaminophen (APAP) and 15% APAP in Copovidone (w/w) (ASD), were selected as model systems. The pharmaceutical excipient used in this work was Avicel PH102 (MCC). Powder X-ray Diffractometry was used to verify the phase purity of the model crystals. The true densities of all samples were determined by a helium pycnometer (n = 5). The in-die Heckel analysis was used to characterize the plasticity of materials (n = 3).³ Different binary mixtures of model compounds with excipients (20%, 40%, 60%, 80%, w/w) were mixed using a Turbula mixer for 15 min at 49 rpm. Before compaction, 1% MgSt was added to the mixture and mixed for 1.5 min at 49 rpm using the Turbula mixer. For each powder, a series of compacts were obtained over the compaction pressures up to 350 MPa using a compaction simulator. The diameters and thicknesses of tablets were measured by a digital caliper. Diametrical breaking force was determined using a texture analyzer. Tablet tensile strength was calculated from the maximum breaking force and tablet dimensions.

Results: This possible mechanism originated from interparticulate bonding area-bonding strength (BA-BS) interplay^4,5 during compaction. If both components of a binary mixture are soft, all particles tend to have comparable plastic deformation under compaction (Figure 1a). However, if a binary mixture consists of one soft material and one hard material, particles of hard materials do not undergo extensive plastic deformation, and the soft particles can cover undeformed hard particles and develop much more plastic deformation than that of soft particles in the soft-soft system when compaction pressure is high enough (Figure 1b), which leads to larger bonding area and better tabletability. Results from studying the two model systems with MCC are summarized below. Acs-K vs. Acs-H: The tabletability of Acs-H is significantly better than the Acs-K (Figure 2), which is attributed to its higher plasticity, as suggested by its significantly lower mean yield stress, P_y (40 ± 1.5 MPa) than that of Acs-K (92.6 ± 2.3 MPa). Tabletability flip occurred in mixtures with 80% MCC. Moreover, the extent of tabletability flipping is more prominent when higher compaction pressures are used (Figure 2). APAP vs. ASD: APAP (P_y = 89.5 ± 2.7 MPa) is less plastic than ASD (P_y = 70.8 ± 2.4 MPa) based on their in-die P</em>_y values. Accordingly, while no intact tablets of APAP could be made, intact tablets of ASD were obtained under the same compression conditions (Figure 3). When mixed with MCC, tabletability flip occurred at 20% and 40% drug loading levels, and 40% loading has a more prominent tabletability flip phenomenon than 20% drug loading (Figure 3).

Conclusion: Results from this work confirm that the “tabletability flip” phenomenon broadly occurs, and they support the hypothesized mechanism that binary mixtures between soft excipient and hard drug develop larger bonding areas than soft-soft binary mixtures, leading to better tabletability. On the other hand, the tendency of tabletability flipping when mixing with a plastic excipient at low drug loadings under high compaction pressures can be explained by this mechanism since the extent of forming an extensive bonding area in the soft-hard system is highly dependent on the percolation threshold, which is governed by both the composition of individual components and compaction pressures. The positive results from this work lay a ground work for further investigating this mechanism by statistical design of experiments.

References: (1) Krishna, G. R.; Shi, L.; Bag, P. P.; Sun, C. C.; Reddy, C. M. Correlation Among Crystal Structure, Mechanical Behavior, and Tabletability in the Co-Crystals of Vanillin Isomers. Cryst. Growth Des. 2015, 15 (4), 1827–1832. https://doi.org/10.1021/cg5018642.
(2) 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.
(3) 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.
(4) 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.
(5) Osei-Yeboah, F.; Chang, S.-Y.; Sun, C. C. A Critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting. Pharm. Res. 2016, 33 (5), 1126–1132. https://doi.org/10.1007/s11095-016-1858-8.

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

Figure 1. Illustration of the potential mechanism of “tabletability flip”, (a) soft-soft system; (b) soft-hard system.



Figure 2. The compaction properties of mixtures of Acs-K/ACs-H with MCC under different compaction pressures.



Figure 3. The compaction properties of mixtures of APAP/ASD with MCC under different compaction pressures.