Title : Lipid media with supercritical CO2 for promoted formation of itraconazole cocrystals
Abstract:
Pharmaceutical cocrystal is one of the crystal engineering techniques to improve the solubility and bioavailability of active pharmaceutical ingredients (APIs). Cocrystal is a crystal composed of API and other molecules called as coformer. There are many fabrication techniques for cocrystal formations. In particularly, some methods using supercritical CO2 have been focused on to reduce the use of organic solvents and the safety risk. However, supercritical CO2 techniques reported so far have an issue that the limited API species are targeted.
To expand the supercritical CO2 techniques to more API species, this work aims to develop a new method using the combination of supercritical CO2 and fatty acid (as safe media) and analyze the cocrystallization mechanism by a thermodynamics model with molecular informatics approach. We applied itraconazole (ITZ), succinic acid (SUC) and linoleic acid (LA) as model API, coformer and fatty acid, respectively. Itraconazole cocrystal was fabricated successfully by many conventional methods but it was fabricated with using toxic organic solvents. Moreover, we used the conductor-like screening model (COSMO) as molecular informatics approach for understanding the mechanism of the cocrystal formations.
As a result of experimental approach, fatty acid under high-pressure CO2 (5 and 10 MPa) significantly promoted the itraconazole cocrystallization compared to those in only fatty acid media or in only high- pressure CO2 (5 and 10 MPa). The comparative experiment of cocrystallization in the two phase and the homogeneous phase system suggested that fatty acid rich phase including high-pressure CO2 mainly contributed to the ITZ cocrystallization. Additionally, the calculation based on the thermodynamics model with molecular informatics suggests that fatty acid rich phase with CO2 could has the higher Gibbs free energy than pure fatty acid phase, which means that fatty acid with CO2 is more unstable than pure fatty acid. Conclusively, the experimental result supports that the combined system of high-pressure CO2 and fatty acid is a suitable and safe media to fabricate ITZ cocrystal and the calculation approach is expected to be useful for the design of the media to promote cocrystallization.
Audience Take Away Notes:
- How to design the fabrication process of cocrystal using supercritical CO2
- Suggest the new cocrystallization in lipid media with supercritical CO2
- Use of molecular information for design the suitable media for cocrystal formation
