Tabletability Flip of Drugs upon Formulation

Abstract

Tabletability is a key property that determines a powder’s ability to form tablets under applied stresses, typically represented by a plot of tablet tensile strength versus pressure. Tablet tensile strength reflects the contributions of interparticulate bonding area (BA) and bonding strength (BS) between adjacent particles in a tablet. BA is influenced by mechanical properties, particle characteristics, and tableting conditions, while BS is governed by molecular packing and intermolecular interactions. The tabletability flip phenomenon (TFP), wherein an active pharmaceutical ingredient (API) with worse tabletability exhibits superior tabletability upon formulation, has recently attracted increasing attention for its implications in API solid form selection and tablet product development. For example, poorly compressible solid forms should not be automatically excluded during early candidate screening, as their formulations may ultimately display enhanced tabletability. In this research, the generality and broad occurrence of this phenomenon was first demonstrated by showing that tabletability flip occurred across a diverse set of model systems. Then, two mechanisms of TFP: 1) the BA-dominating mechanism and 2) the BS-dominating mechanism were tested. The validity of the BA-dominating mechanism was substantiated by direct visual evidence of particle deformation in binary mixtures containing soft and hard particles. It is also confirmed by successful experimental confirmation of the predicted TFP with a soft excipient and its absence with a hard excipient for two APIs. The BS-dominating mechanism was confirmed through systems containing an excipient much softer than both API forms, demonstrating the dominating role of BS in TFP by minimizing contributions due to different BA. Subsequently, factors affecting TFP were systematically evaluated. Our results indicate that TFP is likely to occur when the plasticity of an excipient is comparable to the softer API, particularly at intermediate drug loadings and under high compaction pressures. Additionally, the particle size of the excipient significantly influences both the occurrence and extent of TFP, while API particle size and tableting speed have only a marginal impact. Further, we assessed the feasibility of predicting TFP using a recently developed mixture tabletability model across two different systems. The model accurately predicted the presence or absence of TFP, demonstrating its potential as a diagnostic tool during tablet formulation development. Finally, we investigated the occurrence and mechanisms of TFP in dry granulated formulations using acetaminophen (APAP) and ibuprofen (IBU) as model APIs, which exhibit TFP in non-granulated blends. For the more porous granules (19% porosity), extensive fragmentation of granules during compaction preserved TFP observed in the pre-blends. In contrast, the less porous granules (9% porosity) remained largely unfragmented, allowing the mechanical properties of granules to govern the BA–BS interplay. Although APAP granules showed smaller BA due to their lower deformability, their higher BS still led to TFP. However, TFP was eliminated by incorporating ≥1% MgSt to minimize BS difference between formulations because the softer IBU granules generated larger BA and, therefore, superior tabletability.