Innovative aminoglutethimide co-crystals: synthesis, characterization, and insights into molecular interactions

Abstract

Aminoglutethimide (AG), a Biopharmaceutical Classification System II (BCSII) drug, is approved for treating certain patients with Cushing's syndrome and breast cancer. However, it is technically limited to clinical application due to poor aqueous solubility. The water solubility of AG can be enhanced through the utilization of the co-crystal method. To screen AG co-crystals, this work employed liquid-assisted grinding and slow solvent evaporation methods. Three novel co-crystals of AG were successfully synthesized based on NH₂–COOH supramolecular synthon theory. All co-crystals exhibited higher apparent solubility than pure AG in the dissolution experiments. The intermolecular interactions of the co-crystals were examined using single crystal X-ray diffraction along with other analytical methods to determine their crystal structures. The formation of co-crystals was dominated by N–H⋯O hydrogen bonds in molecular electrostatic potential (MEP) analysis. To further explore and visualize the intermolecular interactions that form co-crystals, Hirshfeld surface (HS) analyses and independent gradient model based on Hirshfeld partition (IGMH) analysis were applied. It was found that the van der Waals (vdW) force is another main driving force, working in conjunction with hydrogen bonds to form basic units of AG co-crystals. In addition, toxicity tests on liver and kidney organoids showed that three new co-crystals did not cause more serious toxicity than pure AG. Overall, this work has provided the structural analysis of three newly formed AG co-crystals, offering an insight into intermolecular interactions of co-crystals at the molecular level.