Effect of organic acids on molecular mobility, physical stability and dissolution of ternary ketoconazole spray dried dispersions.

In an earlier investigation, ketoconazole (KTZ)-organic acid coamorphous systems were prepared, wherein, in the solid-state, there was ionic and/or hydrogen bonding interactions between the drug and the acid (Fung, M.; Berzins, K.; Suryanarayanan, R Mol. Pharmaceutics, 2018, 15 (5), 1862-1869). While the coamorphous systems accelerated KTZ dissolution, the organic acids were not effective in maintaining super saturation, and drug precipitation was observed. Ternary drug-polymer-acid amorphous solid dispersions (ASDs) were prepared with KTZ, polyvinylpyrrolidone (PVP), and each oxalic (OXA), tartaric (TAR), citric (CIT), or succinic (SUC) acid. When compared with amorphous KTZ, solid dispersions of KTZ-PVP exhibited a moderate reduction in molecular mobility and small improvement in dissolution performance. The incorporation of acid (OXA, TAR, or CIT) in PVP-KTZ solid dispersion led to orders of magnitude increase alpha-relaxation times and decrease in the crystallization propensity. These ternary ASDs were stable while crystallization of the cocrystal was observed in the SUC system. Moreover, the addition of acids also dramatically improved the dissolution performance of KTZ, a result attributed to KTZ-acid interactions.