(M1330-07-47) Tabletability Flip in Dry Granulated Systems

Purpose: Tabletability is a key property that determines a powder’s ability to form tablets under applied stresses. It reflects the contributions of interparticulate bonding area (BA) and bonding strength (BS) between adjacent particles in a tablet.¹ Tabletability flip phenomenon (TFP) entails that a solid form of an active pharmaceutical ingredient (API) with lower tabletability exhibits better tabletability when mixed with the same excipients.² The TFP underscores the importance of proper use of tabletability of pure compounds in solid-form selection and formulation design.³ Two mechanisms of TFP were proposed previously, e.g., BA-dominating mechanism⁴ and BS-dominating mechanism² (Figure 1a-b). To date, all investigations of the TFP have focused only on direct compression systems. It is useful to investigate the impact of granulation on the TFP. Granulation transforms a “heterogeneous” powder mixture into “homogeneous” granules (Figure 1c). Consequently, the tabletability of granules is a result of the BA-BS interplay among granules. We hypothesized that granules containing softer APIs exhibit higher plasticity, when compared to those containing harder APIs, leading to larger BA. When the BS is similar, the TFP is unlikely to occur in granule systems. In this work, we aimed to test this hypothesis using generic formulation systems.

Methods: Ibuprofen (IBU) and acetaminophen (APAP) were selected as model APIs. Each formulation comprised of 20% API, 50% microcrystalline cellulose (Avicel PH102, MCC) as soft excipient, 24.5% lactose monohydrate (LM), 5% crospovidone, and 0.5% magnesium stearate (MgSt). Ribbons with two target porosities (19% and 9%) were produced for each formulation using a roller compactor. The ribbons were subsequently milled, and granules within the 500–710 µm sieve cut were collected. Granule size and morphology were characterized by image analysis and scanning electron microscopy (SEM), respectively. For each sample, a series of cylindrical compacts were prepared by compression at pressures ranging from 15 to 350 MPa using a compaction simulator. Tablet tensile strength was calculated from the maximum breaking force and tablet dimensions, following a standard procedure.⁵ Tabletability profile was obtained by plotting tablet tensile strength against compaction pressure. Plasticity was assessed based on the mean yield pressure (P_y) determined from in-die Heckel analysis.^6,7 The BS of the formulations was quantified by the σ_max value obtained from fitting the Vreeman-Sun equation.⁸ Granule fragmentation during compaction was assessed using SEM.

Results: IBU exhibited significantly better tabletability than APAP, which can be attributed to its higher plasticity, as indicated by a significantly lower P_y value than that of APAP (Table 1). However, owing to TFP, the APAP formulation exhibited better tabletability than the IBU formulation (Figure 2a), as expected from the BA-dominating mechanism of TFP where the larger BA by the “wrapping” contact between hard API particles and soft excipient particles leads to stronger tablets (Figure 1a). For granules with 19% porosity, the IBU formulation showed higher plasticity than the APAP formulation, as expected (Table 1). However, TFP still occurred at high compaction pressures (Figure 2b), which is attributed to the higher BS of APAP formulation than that of IBU formulation (Table 1). Although it was demonstrated that the addition of 1% MgSt with 30 min blending time effectively eliminated the difference in BS of the IBU and the APAP granules (Figure 2f), TFP persisted despite the addition of 1% MgSt (Figure 2c). This observation suggests the occurrence of extensive granule fragmentation during compression, which was confirmed by SEM analysis of tablet fracture surfaces. The extensive fragmentation of granules transforms the granules back to a “heterogeneous” system of fine particles of formulation components, leading to the TFP. For granules with 9% porosity, SEM analysis showed that granules largely remained intact in tablet, effectively maintaining a “homogeneous” granular system. Therefore, the tabletability of the granules is determined by the BA-BS interplay among granules. Without MgSt, TFP was still observed although IBU formulation are more plastic than APAP formulation, due to the significantly lower BS of IBU formulation than that of APAP formulation (Figure 2d, Table 1). Upon attaining comparable BS by mixing with 1% MgSt, TFP was eliminated because of the larger BA of the IBU formulation relative to the APAP formulation (Figure 2e, Table 1).

Conclusion: We observed that granules containing softer APIs can still demonstrate lower tabletability despite their higher plasticity, if extensive granule fragmentation takes place. The TFP was eliminated when extensive granule fragmentation is avoided and when mixed with 1% MgSt to minimize any differences in BS across formulations. The insights gained from this investigation can be used to guide the optimization of dry granulation process to enable improved tabletability. For example, granules of an API with poor tabletability should be prepared to have more extensive fragmentation propensity, e.g., by maintaining a higher porosity, so that higher tabletability could be attained.

References: 1. Sun, C. C. Decoding Powder Tabletability: Roles of Particle Adhesion and Plasticity. J. Adhes. Sci. Technol. 25, 483–499 (2011).
2. Paul, S., Wang, C. & Sun, C. C. Tabletability Flip – Role of Bonding Area and Bonding Strength Interplay. J. Pharm. Sci. 109, 3569–3573 (2020).
3. Wang, Z., Wang, C., Bahl, D. & Sun, C. C. The ubiquity of the tabletability flip phenomenon. Int. J. Pharm. 643, 123262 (2023).
4. Wang, Z. et al. A new insight into the mechanism of the tabletability flip phenomenon. Int. J. Pharm. 654, 123956 (2024).
5. Fell, J. T. & Newton, J. M. Determination of Tablet Strength by the Diametral-Compression Test. J. Pharm. Sci. 59, 688–691 (1970).
6. Heckel, R. W. Density–Pressure Relationships in Powder Compaction. Trans Met. Soc AIME 221, 671–675 (1961b).
7. Vreeman, G. & Sun, C. C. Mean yield pressure from the in-die Heckel analysis is a reliable plasticity parameter. Int. J. Pharm. X 3, 100094 (2021).
8. Vreeman, G. & Sun, C. C. A powder tabletability equation. Powder Technol. 408, 117709 (2022).

Acknowledgements: We thank the National Science Foundation for support through the Industry University Collaborative Research Center (IUCRC) grant IIP-2137264, Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP).


Figure 1. a) The BA-dominating mechanism, b) BS-dominating mechanism for the TFP, and c) a hypothesized mechanism of TFP elimination by granulation.


Figure 2. Tabletability profiles of a) APAP/IBU powder formulations, b) granules of APAP/IBU formulations with 19% porosity, c) granules of APAP/IBU formulations with 19% porosity + 1% MgSt, d) granules of APAP/IBU formulations with 9% porosity, and e) granules of APAP/IBU formulations with 9% porosity + 1% MgSt. f) σ_max values of granules of APAP/IBU formulations with 9% porosity at various levels of MgSt.


Table 1. The Py and σ_max of samples of interests in this work.