Co-amorphization of posaconazole using citric acid as an acidifier and a co-former for solubility improvement

The co-amorphous system is an efficacious approach in enhancing the solubility and dissolution of insoluble drugs. Several small molecules, such as organic acids, amino acids, and organic amines, are commonly used ligands to prepare co-amorphous systems. In this study, a co-amorphous system of posaconazole (POS), a weakly alkaline insoluble drug, with citric acid (CA) was prepared by the solvent evaporation method. An amorphous solid dispersion (ASD) of POS-VA64 was also prepared for comparison. Powder X-ray diffraction pattern and scanning electron microscopy indicated that POS exists in an amorphous form in the POS-CA and POS-VA64 groups. Fourier-transform infrared spectroscopy showed that an intermolecular hydrogen bonding was formed between POS and CA in the co-amorphous system. The amorphous state of POS exhibited increased solubility and dissolution, and the POS-CA form showed the best solubility and dissolution, which may be attributed to the amorphization and acidic environment provided by CA. In addition, the pharmacokinetic study and stability test of the POS-CA form showed superior performance. Therefore, the rational use of small-molecule ligands to prepare co-amorphous compounds can significantly improve the properties of drugs.