A new insight into the mechanism of the tabletability flip phenomenon

Tabletability is an outcome of interparticulate bonding area (BA) – bonding strength (BS) interplay, influenced by the mechanical properties, size and shape, surface energetics of the constituent particles, and compaction pressure. Typically, a more plastic active pharmaceutical ingredient (API) exhibits a better tabletability than less plastic APIs due to the formation of a larger BA during tablet compression. Thus, solid forms of an API with greater plasticity are traditionally preferred if other critical pharmaceutical properties are comparable. However, the tabletability flip phenomenon (TFP) suggests that a solid form of an API with poorer tabletability may exhibit better tabletability when formulated with excipients. In this study, we propose another possible mechanism of TFP, wherein softer excipient particles conform to the shape of harder API particles during compaction, leading to a larger BA under certain pressures and, hence, better tabletability. In this scenario, the BA-BS interplay is dominated by BA. Accordingly, TFP should tend to occur when API solid forms are formulated with a soft excipient. We tested this hypothesis by visualizing the deformation of particles in a model compressed tablet by nondestructive micro-computed tomography and by optical microscopy when the particles were separated from the tablet. The results confirmed that soft particles wrapped around hard particles at their interfaces, while an approximately flat contact was formed between two adjacent soft particles. In addition to the direct visual evidence, the BA-dominating mechanism was also supported by the observation that TFP occurred in the p-aminobenzoic acid polymorph system only when mixed with a soft excipient.