Stabilizing liquid-like drug-rich intermediates by bile salts to suppress phase transformation and promote rapid absorption of cocrystals.

Poorly soluble drugs pose significant clinical challenges, including low bioavailability, delayed therapeutic onset, and limited dose escalation in toxicity studies. Pharmaceutical cocrystals has emerged as a powerful strategy to overcome these limitations. However, unwanted phase transformations often compromise cocrystal performance, leading to inconsistent oral bioavailability and variable therapeutic efficacy. Herein, we report the use of sodium taurocholate (STC) to inhibit the phase transformation of indomethacin-nicotinamide cocrystals, resulting in a 5.4-fold increase in AUC and a 6.8-fold increase in Cmax in vivo. We demonstrate that the liquid-like drug-rich intermediates act as key transition states governing both the phase transformation kinetics and the oral absorption of cocrystals. Mechanistic studies using transmission electron microscopy, in situ inverted fluorescence microscopy, and molecular dynamics simulations further reveal that STC stabilizes these intermediates by adsorbing at the liquid-droplet interface. This creates a combined effect of electrostatic repulsion and enhanced hydration networks, which suppresses droplet aggregation and significantly elevates the nucleation barrier. Consequently, the stabilized drug-rich droplets facilitate rapid absorption onset and sustain an early absorption window, a pharmacokinetics profile particularly valuable for drugs requiring immediate therapeutic action. This work not only establishes the pivotal role of drug-rich intermediates in cocrystal dissolution but also highlights the stabilization of such transient phases as a fundamental strategy for maximizing the oral bioavailability of cocrystals.