Ultrasound-assisted cocrystal of emodin and matrine: An opportunity to improve synergistic bioavailability

Drug-drug cocrystal technology especially for natural products, can optimize the physicochemical properties of drugs without altering their chemical structures, thereby enabling synergistic and dual-drug therapeutic effects. In this study, a novel drug-drug cocrystal composed of emodin (EM) and matrine (MA) was successfully prepared using ultrasound-assisted crystallization in a benchtop ultrasonic bath operating at a fixed frequency of 53  kHz. The optimal preparation conditions were a nominal ultrasonic power of 500  W, a crystallization temperature of 35°C, a sonication time of 3 h, and an EM:MA molar ratio of 1:1.5. The cavitation effects generated by ultrasound disrupted the pre-existing intermolecular hydrogen bonds (e.g., drug-solvent or drug self-association) and accelerated molecular diffusion, thereby facilitating the formation of desired drug-drug hydrogen bonds for rapid co-nucleation, shortened co-crystallization time, and high product uniformity. The process was systematically optimized using response surface methodology (RSM) and artificial neural networks (ANNs). The resulting EM-MA cocrystal was characterized by PXRD, DSC, FT-IR, SCXRD, and SEM, which confirmed the formation of O-H···O=C heterosynthons and the stabilizing role of hydrogen-bonding. Cellular assays showed that the cocrystal exhibited stronger inhibitory activity against 4 T1 breast cancer cells than the physical mixture of EM and MA. These results indicate that the novel cocrystal may have potential for further development as a combination drug product, which could improve the bioactivity of natural products.