Effect of mechanochemical grinding conditions on the formation of pharmaceutical cocrystals and co-amorphous solid forms of ketoconazole-Dicarboxylic acid

Mechanochemical grinding is one of the commonly used solvent-free methods for the successful preparation of pharmaceutical cocrystals, which is marked as green chemical processing. In this study neat grinding (NG) and liquid-assisted grinding (LAG) approaches were used to study the impact on the formation of new solid forms. Ketoconazole (KTZ) blends with different dicarboxylic acids namely fumaric acid (FA) and succinic acid (SA) were prepared by neat and liquid-assisted grinding. Immediately after preparation the solid state of the formulation was characterised by thermal analysis, spectroscopy along with PXRD (Powder X-ray diffraction), and their dissolution profile was assessed. Neat grinding of KTZ-FA and KTZ-SA resulted in co-amorphous and amorphous formulations while liquid-assisted grinding resulted in the formation of high quality cocrystals. The formed cocrystals presented enhanced dissolution rates in comparison to the bulk drug. However, this was not the case for the co-amorphous formulations which demonstrated poor dissolution rates. The time required for the cocrystal formation by liquid assisted grinding was determined by analysing the ground solids in a different time interval and it was found cocrystals formed very quickly in the case of liquid assisted grinding conditions.

Automated summary

Neat grinding and liquid-assisted grinding were used to prepare cocrystals and co-amorphous formulations of ketoconazole, with the latter resulting in high quality cocrystals and enhanced dissolution rates.