A New Screening Strategy for Flavonoid Components to Obtain a Satisfactory Co-Amorphous System with Piperine

Abstract

Flavonoids are a large class of compounds with a variety of biological activities. Nevertheless, their therapeutic application remains limited due to the generally low water solubility. In the present study, an integrated approach was provided to guide the design of flavonoid co-amorphous systems co-formed with piperine (PIP). Firstly, 7 flavonoid compounds showed good miscibility with PIP from 13 flavonoid candidates. Then, molecular dynamics simulation confirmed hydrogen bond formation between 5 flavonoid compounds (i.e., BAI, HES, ISO, NAR and KAE) and PIP. Herein, 5 flavonoid compounds were successfully co-amorphized with PIP by the melting and quench cooling method, which were proved via PLM, PXRD and DSC measurements. FTIR results showed the potential hydrogen bond interactions between -OH of flavonoid molecules and C = O of PIP molecule in the formed co-amorphous systems, which were consistent with RDF analyses in molecular models. For dissolution tests, 4 co-amorphous systems (i.e., BAI-PIP CM, HES-PIP CM, ISO-PIP CM and NAR-PIP CM) appeared abnormally reduced dissolution compared to their original crystalline counterparts arising from the formation of gels during dissolution, while only KAE-PIP CM displayed significantly enhanced dissolution (5.83-fold of crystalline KAE at 12 h) with long-time supersaturated concentration. Meanwhile, KAE-PIP CM kept physically stable at least 3 months under 25°C and 40°C conditions, and possessed excellent physical stability over individual amorphous components, which was attributed to the stronger intermolecular interaction by higher binding energy analysis. Therefore, this study provides a design strategy to guide the screening of flavonoid co-amorphous systems through combining theory-model-experiment techniques.

Graphical Abstract