A new insight into the mechanism of the tabletability flip phenomenon

March 4, 2024, midnight - by Zijian Wang , Chenguang Wang , Yiwang Guo , Deepak Bahl , Alex Fok , Changquan Calvin Sun

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Tabletability arises from the dynamic interplay between interparticulate bonding area (BA) and bonding strength (BS), which is influenced by various factors such as the mechanical properties, size, shape, and surface energetics of the constituent particles, as well as the compaction pressure. Generally, a more pliable active pharmaceutical ingredient (API) tends to exhibit superior tabletability compared to less pliable APIs, primarily due to the formation of a larger BA during tablet compression. Consequently, solid forms of an API with higher plasticity are conventionally favored, provided other critical pharmaceutical properties remain consistent. However, the tabletability flip phenomenon (TFP) introduces the notion that a solid form of an API with initially poorer tabletability might actually demonstrate improved tabletability when combined with excipients. This study proposes an alternative explanation for TFP, suggesting that during compaction, softer excipient particles conform to the contours of harder API particles, thereby increasing the BA under specific pressures and consequently enhancing tabletability. In this scenario, the BA-BS interplay is predominantly governed by BA. Consequently, TFP is more likely to occur when API solid forms are paired with a soft excipient. This hypothesis was tested by observing particle deformation in a model compressed tablet using nondestructive micro-computed tomography and optical microscopy when the particles were removed from the tablet. The findings validated the phenomenon, demonstrating that soft particles enveloped hard particles at their interfaces, while nearly flat contacts were formed between adjacent soft particles. In addition to the visual evidence, the BA-dominant mechanism was further supported by the observation that TFP occurred solely in the p-aminobenzoic acid polymorph system when mixed with a soft excipient.

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