Abstract
In an earlier report, ionic interactions between ketoconazole (KTZ), a weakly basic drug, and poly(acrylic acid) (PAA), an anionic polymer, resulted in a dramatic decrease in molecular mobility as well as reduced crystallization propensity of amorphous solid dispersion (ASD) in the solid state. On the other hand, weaker dipole-dipole interactions between KTZ and polyvinylpyrrolidone (PVP) resulted in ASDs with higher crystallization propensity (Mistry Mol Pharm., 2015, 12 (9), 3339-3350). In this work, we investigated the behavior of the ketoconazole (KTZ) solid dispersions in aqueous media. In vitro dissolution tests showed that the PAA ASD maintained the level of supersaturation for a longer duration than the PVP ASD at low polymer contents (4-20% w/w polymer). Additionally, the PAA ASDs were more resistant to drug crystallization in aqueous medium when measured with synchrotron X-ray diffractometry. Two-dimensional 1H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug-polymer interactions in D 2O. The interaction was accompanied by a reduced drug diffusivity as monitored by 2D diffusion ordered spectroscopy (DOSY) NMR and enthalpy-driven when characterized by isothermal titration calorimetry (ITC). On the other hand, drug-polymer interactions were not detected between ketoconazole and PVP in aqueous solution, with NOESY, DOSY, or ITC. The results suggest that interactions that stabilize ASDs in the solid state can also be relevant and important in sustaining supersaturation in solution.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 174-186 |
| Number of pages | 13 |
| Journal | Molecular pharmaceutics |
| Volume | 18 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 4 2021 |
Bibliographical note
Funding Information:This project was funded by the National Science Foundation (grant number NSF-CMMI-1662046) and partially supported by the William and Mildred Peters endowment fund. K.K.A.E. acknowledges the Bighley Graduate Student Fellowship. The research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory, under contract number DE-AC02-06CH11357. Dr. Wenquian Hu and Dr. Andrey Yakovenko (beamline 17-BM-B) are acknowledged for their help. The authors are grateful to Dr. Courtney Aldrich, University of Minnesota, for granting access to an ITC-200 microcalorimeter (NIH shared instrumentation grant S10-OD017982) and Dr. Anant Paradkar, University of Bradford, for granting access to a USP dissolution apparatus IV. We also thank Dr. Letitia Yao (NMR), Dr. Michelle Miller (NMR), Evan Alexander (ITC), and Dr. Shivprasad Deshmukh (dissolution tests) for their help with experiments and Dr. Eva Munoz and Dr. Juan Sabin for their help with fitting of the ITC data.
Publisher Copyright:
© 2020 American Chemical Society.
Keywords
- DOSY
- ITC
- NMR
- NOESY
- amorphous solid dispersion
- crystallization
- dissolution apparatus IV
- drug-polymer interactions
- ketoconazole
- synchrotron X-ray diffractometry
- X-Ray Diffraction/methods
- Water/chemistry
- Polymers/chemistry
- Spectroscopy, Fourier Transform Infrared/methods
- Calorimetry, Differential Scanning/methods
- Pharmaceutical Preparations/chemistry
- Crystallization/methods
- Povidone/chemistry
- Hydrogen Bonding
- Solubility/drug effects
- Ketoconazole/chemistry
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Journal Article
- Research Support, N.I.H., Extramural