Boosting oral bioavailability of icaritin and piperine: A co-amorphous approach with molecular insights and performance validation

PURPOSE: To overcome the poor aqueous solubility limitations of Icaritin (ICT) and Piperine (PIP), which restrict their therapeutic potential, by developing a co-amorphous drug delivery system. SIGNIFICANCE: The co-amorphous strategy presents a promising solution to enhance solubility, dissolution rate, and oral bioavailability of poorly water-soluble drug combinations, thereby improving their pharmaceutical applicability. METHODS: The optimal 1:1 molar ratio of ICT-PIP was determined through in vitro anti-inflammatory evaluation and combination modeling. Molecular dynamics simulations were employed to investigate intermolecular interactions, while Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), and Differential Scanning Calorimetry (DSC) analyses were used to confirm co-amorphous formation and characterize solid-state properties. RESULTS: The ICT-PIP co-amorphous system demonstrated significantly improved solubility (3.5-fold for ICT, 3.7-fold for PIP) and intrinsic dissolution rate (2.0-fold for ICT and 1.8-fold for PIP) compared to crystalline forms. PXRD confirmed complete amorphization with no detectable crystalline peaks, FT-IR revealed intermolecular hydrogen bonding interactions between ICT and PIP, and DSC showed a single glass transition temperature (Tg) at 164.6 °C, confirming single-phase amorphous system formation. Pharmacokinetic studies revealed 1.6-fold and 1.4-fold enhancements in oral bioavailability for ICT and PIP, respectively. The system maintained excellent physical stability for six months under storage conditions. CONCLUSION: This study successfully developed a stable ICT-PIP co-amorphous system with superior solubility and bioavailability characteristics, demonstrating the effectiveness of co-amorphization as a viable strategy for optimizing the delivery of poorly soluble drug combinations.