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.; Berzinš, 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 supersaturation, 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 in α-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.
Bibliographical noteFunding Information:
M.H.F. was partially supported by the PhRMA Pre-Doctoral Fellowship in Pharmaceutics and the Rowell Graduate Fellowship from the University of Minnesota. This project was partially funded by the William and Mildred Peters Endowment Fund. Powder XRD work was carried out at the Characterization Facility at the University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). We thank Upsher-Smith Laboratories (Drs. Limin Shi and Howard Chen) for providing access to spray drying equipment. We thank Karlis Berziņs,̌ Jiangnan Dun, Janice Laramy, Michaela Roslawski, and Wei-Jhe Sun for their help.
Copyright © 2018 American Chemical Society.
- amorphous solid dispersions
- molecular mobility
- physical stability
- Succinic Acid/chemistry
- Microscopy, Electron, Scanning
- Drug Stability
- Organic Chemicals/chemistry
- X-Ray Diffraction
- Molecular Structure
- Oxalic Acid/chemistry
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Journal Article