Amphiphilic disodium glycyrrhizin as a co-former for ketoconazole co-amorphous systems: Biopharmaceutical properties and underlying molecular mechanisms

[Display omitted] •Na2GA as a co-former was first applied to co-amorphous systems (CAMs).•KTZ-Na2GA CAMs exhibited good dissolution rate and stable supersaturation.•Such CAMs showed enhanced KTZ permeability when the concentration of Na2GA below CMC.•Molecular mechanisms involved hydrogen bond, solubilisation, crystal inhibition, etc..•Bioavailability of KTZ in CAMs has markedly increased compared to crystalline KTZ. Co-amorphous systems (CAMs) have been extensively investigated to improve the dissolution of hydrophobic drugs. However, drug precipitation during the storage or dissolution of CAMs has still been a major challenge. Here, disodium glycyrrhizin (Na2GA) was first used as a co-former in CAMs based on its multiple hydroxyl groups and amphiphilic structure. Ketoconazole (KTZ), a BCS class II drug, was selected as a model drug. KTZ-Na2GA CAMs at mass ratios of 1:1, 1:2.5, 1:5 and 1:10 were prepared by the spray drying method and further characterised by PXRD and DSC. The 1:2.5, 1:5 and 1:10 groups exhibited significantly enhanced Cmax (all approximately 26.67-fold) and stable maintenance of supersaturation compared to the crystalline KTZ and the corresponding physical mixtures in non-sink dissolution tests, while the 1:1 group exhibited an unstable medium Cmax (all approximately 14.67-fold). The permeability tests revealed that the permeation rate of KTZ in KTZ-Na2GA CAMs under the concentration of Na2GA in solution above the critical micelle concentration (CMC) showed a significant downwards trend compared to that below CMC. The underlying molecular mechanisms were involved in molecular miscibility, hydrogen bond interactions, solubilisation and crystallisation inhibition by Na2GA. Pharmacokinetic studies demonstrated that the AUC0-∞ of KTZ in 1:1, 1:2.5, 1:5 and 1:10 groups were significantly higher than those of the crystalline KTZ group with 2.13-, 2.30-, 2.16- and 1.86-fold, respectively (p