Physical Stability and Dissolution Behavior of Ketoconazole–Organic Acid Coamorphous Systems
Michelle Fung, Ka̅rlis Be̅rziņš, Raj Suryanarayanan
文献索引：10.1021/acs.molpharmaceut.8b00035
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摘要
In an earlier investigation, coamorphous systems of ketoconazole (KTZ) prepared with each oxalic (OXA), tartaric (TAR), citric (CIT), and succinic (SUC) acid, revealed drug–acid ionic or hydrogen bonding interactions in the solid-state (Fung et al, Mol. Pharmaceutics, 2018, 15 (3), 1052–1061). We showed that the drug–acid interactions in KTZ–TAR were the strongest, followed by KTZ–OXA, KTZ–CIT, and KTZ–SUC. In this study, we investigated the crystallization propensity and dissolution behavior of the KTZ–acid coamorphous systems. When in contact with water (either as water vapor or as aqueous phosphate buffer), while KTZ–CIT and KTZ–TAR were physically stable and resisted crystallization, KTZ–SUC and KTZ–OXA crystallized more readily than KTZ alone. The dissolution performances of the coamorphous systems were compared using the area under the curve (AUC) obtained from the concentration–time profiles. KTZ–OXA exhibited the highest AUC, while it was about the same for KTZ–TAR and KTZ–CIT and the lowest for KTZ–SUC. The enhancement in dissolution appeared to become more pronounced as the strength of the acid (OXA > TAR > CIT > SUC) increased. Coamorphization with acid caused at least a two-fold increase in AUC when compared with amorphous KTZ. The decrease in pH of the diffusion layer of the dissolving solid, brought about by the acid, is at least partially responsible for the dissolution enhancement. In addition, the particles of KTZ–OXA, KTZ–TAR, and KTZ–CIT were much smaller than those of KTZ–SUC. The consequent effect on surface area could be another contributing factor to the initial dissolution behavior.