Predicting tabletability flip in pharmaceutical powders via a mixture tabletability model

Abstract

The tabletability flip phenomenon (TFP), in which a solid form of an active pharmaceutical ingredient (API) with lower inherent tabletability exhibits better tabletability when mixing with the same excipients, underscores the importance of solid-form selection and formulation design. Although previous studies have provided insights into the mechanisms and factors influencing TFP, a reliable method for predicting its occurrence early in tablet formulation development remains essential to fully implement a quality-by-design approach. In this study, 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 in both cases, demonstrating its potential as a diagnostic tool during tablet formulation development. Moreover, the observed deviations between model predictions and experimental data highlight the need for further investigation into the impact of particle size on the predictive performance of mixture tabletability model.

Introduction

Adequate mechanical strength is essential to ensure that tablets remain intact from manufacturing through administration (Augsburger and Hoag, 2016). Tabletability is assessed by plotting tablet tensile strength (σ) as a function of compaction pressure (P) (Joiris et al., 1998, Sun and Grant, 2001, Tye et al., 2005). Recently, the tabletability flip phenomenon (TFP) has been widely reported, where a solid form of an active pharmaceutical ingredient (API) with inherently lower tabletability exhibits superior tabletability when formulated (Paul et al., 2020, Wang et al., 2023). This observation highlights the need to reconsider traditional solid-form selection criteria, as solid forms that exhibit poor tabletability in their pure state may deliver enhanced performance once formulated.

Tabletability arises from the interplay between the interparticulate bonding area (BA) and bonding strength (BS) (Shi and Sun, 2024, Sun, 2011). Two mechanisms have been proposed to explain the TFP based on the BA-BS interplay framework. For pure materials, higher plasticity typically enhances tabletability because larger BA can form during compaction (Benabbas et al., 2020, Chen et al., 2022, Kale et al., 2020, Wang et al., 2025a, Wu et al., 2025, Yadav et al., 2017). When two API solid forms are blended with an excipient whose plasticity is comparable to that of the softer API, the excipient can deform and wrap around the harder API particles, forming a larger BA than the nearly flat contact formed between the softer API and soft excipient particles (Capece and Czyzewski, 2024). This is referred to as the BA-dominant mechanism (Wang et al., 2024). In contrast, when the excipient is much softer than both API forms, the BA remains similar for both mixtures because the excipient envelops both API particles to a comparable extent. Under these conditions, TFP arises when the harder API exhibits higher BS, representing the BS-dominant mechanism (Paul et al., 2020). Both mechanisms suggest that incorporating a plastic excipient can promote the occurrence of TFP.

Additionally, TFP is more likely to occur at intermediate drug loads and under high compaction pressures (Wang et al., 2025b). Among formulation and process variables, excipient particle size has a pronounced influence on the extent of the TFP, whereas API particle size and tableting speed exert only marginal effects (Wang et al., 2025b). Despite these advances, a reliable approach for predicting TFP during the early stage of tablet formulation development remains lacking, which hinders the attainment of a true quality-by-design framework for tablet formulation.

The Vreeman-Sun (V-S) equation effectively describes powder tabletability using three parameters:
, the theoretical maximum tensile strength at infinite compaction pressure; α, which characterizes the onset pressure required to form tablets with measurable mechanical strength; and β, which reflects powder plasticity (Vreeman and Sun, 2022). Recently, a predictive model combining the V-S equation with a power-law mixing rule was developed to estimate the tabletability of mixtures based on that of their individual components (Bhagali et al., 2025). If valid, this model could also predict TFP, which arises from the tabletability of mixtures. The present study is aimed at evaluating the feasibility of using this model to predict TFP across two different model systems.

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Materials

Hypromellose (HPMC; Benecel™ K4M PHARM CR, Ashland, Wilmington, DE), dibasic calcium phosphate dihydrate (DCPD; Emcompress®, JRS Pharma, Patterson, NY), urea (Fisher Scientific, Hampton, NH), and ferulic acid (FA; Sigma Aldrich, St. Louis, MO), along with microcrystalline cellulose (MCC; Avicel PH105, FMC Biopolymers; Philadelphia, PA) were used as received.

Zijian Wang, Changquan Calvin Sun, Predicting tabletability flip in pharmaceutical powders via a mixture tabletability model, International Journal of Pharmaceutics, Volume 686, 2025, 126340, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126340.

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