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Abstract PurposesThe tabletability flip phenomenon (TFP), where an active pharmaceutical ingredient (API) with poorer tabletability exhibits better tabletability when formulated with excipients, has been well documented in direct compression systems. However, the impact of granulation on TFP remains unexplored. Hence, the purpose of this work was to investigate the occurrence and underlying mechanisms of TFP in dry-granulated formulations. MethodsAcetaminophen (APAP) and ibuprofen (IBU) were used as model APIs since they exhibit TFP in non-granulated blends. Granules of each API were prepared at two porosity levels (9% and 19%) by controlling compaction pressure. Granules with and without varying levels of extragranular magnesium stearate (MgSt) were evaluated for tabletability, bonding area (BA), and bonding strength (BS). ResultsFor the more porous granules (19% porosity), extensive fragmentation during compaction preserved TFP through the same mechanism observed in the pre-blends. In contrast, the less porous granules (9% porosity) remained largely unfragmented during compaction, allowing their intrinsic mechanical properties to govern the BA–BS interplay. Although APAP granules showed smaller BA due to lower deformability, the higher BS led to superior tabletability, thus maintaining TFP. The incorporation of ≥ 1% MgSt minimized BS difference between formulations, effectively eliminating TFP, since the softer IBU granules exhibited higher tabletability due to larger BA. ConclusionThese results demonstrated the applicability of the BA–BS framework in explaining TFP in granulated systems and highlight the importance of controlling granule porosity and MgSt levels to optimize tabletability in dry granulation processes. 

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