Enhancing water solubility of phytosterols through Co-amorphization with food-grade coformers

Phytosterols (PS) offer significant health benefits in human diet, but its poor solubility limits its effectiveness and application. This study explored enhancing PS solubility by testing thirteen food-grade coformers, three preparation methods and proportions screening to obtain the optimal formulation. Nicotinamide (Nic) was identified as the most effective coformer. A 20:1 (w/w) PS-Nic co-amorphous (CM) mixture, prepared via freeze-drying, achieved a solubility of 1536.4 μg/mL, significantly higher than pure PS. X-ray diffraction and differential scanning calorimetry confirmed the amorphous state of the mixture. Fourier-transform infrared, Raman, and ¹H NMR spectroscopies, along with molecular dynamics simulations, revealed strong intermolecular interactions between PS and Nic. The PS-Nic CM demonstrated up to 60% in vitro dissolution and release within 2 h and maintained stable after storage at 4 °C for 6 months and under accelerated conditions equivalent to 10 months at room temperature. In sum, the crystal structure of PS was altered, and formed a co-amorphous system by using Nic as the optimal ligand via lyophilization to increase solubility. These findings suggest that the PS-Nic CM system has potential applications in functional foods, offering a feasible strategy to enhance the bioavailability of PS.