Direct Observation of Nanostructures during Aqueous Dissolution of Polymer/Drug Particles

Ralm G. Ricarte, Ziang Li, Lindsay M. Johnson, Jeffrey M. Ting, Theresa M. Reineke, Frank S. Bates, Marc A. Hillmyer, Timothy P. Lodge

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Abstract

To elucidate the aqueous solubility enhancement mechanism of solid dispersions (SDs), metastable blends of an active pharmaceutical ingredient (API) and a polymer excipient, we investigated the dissolution of hydroxypropyl methylcellulose acetate succinate (HPMCAS) SDs in phosphate buffered saline (PBS). Two hydrophobic active pharmaceutical agents, phenytoin and probucol, were employed at loadings of 10, 25, and 50 wt % relative to polymer. Light scattering measurements of HPMCAS solutions showed that the polymer itself formed a mixture of ∼10 and ∼100 nm sized structures (attributed to linear and covalently coupled polymer chains, respectively) in both tetrahydrofuran and PBS. The measurements also revealed that PBS is a poor solvent for HPMCAS at and below 37 °C, potentially inducing the polymer to associate with itself or other hydrophobic species in solution. During in vitro dissolution of HPMCAS SDs-containing either phenytoin or probucol as the API-the polymer and hydrophobic drug formed <100 nm amorphous nanoparticles. Using a combination of cryogenic transmission electron microscopy (both imaging and electron diffraction) and small-angle X-ray scattering, a direct correlation between SD dissolution profiles and nanostructure evolution was discovered for both drugs. In other words, the drug that is measured in the dissolution assay is retained in the supernatant in the form of nanoparticles. The size, shape, and lifespan of the nanoparticles were a function of drug identity, loading, and targeted concentration. These findings confirm the importance of persistent nanostructures to SD dissolution and particularly to maintenance of supersaturation.

Original languageEnglish (US)
Pages (from-to)3143-3152
Number of pages10
JournalMacromolecules
Volume50
Issue number8
DOIs
StatePublished - Apr 25 2017

Bibliographical note

Funding Information:
This study was supported by the National Science Foundation Graduate Research Fellowship under Grant No. 00039202. This work was funded by The Dow Chemical Company (Dow) through Agreement 224249AT with the University of Minnesota. We thank Dr. Jodi Mecca, Dr. Timothy Young, Dr. Steven J. Guillaudeu, Dr. Robert L. Schmitt, Dr. William Porter, Dr. Wei Zhang, Dr. Robert Hafner, Dr. Tim Gillard, Ingrid Haugan, and Peter Schmidt for helpful discussions. Parts of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC program. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract DE-AC02-06CH11357.

Publisher Copyright:
© 2017 American Chemical Society.

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  • Shared

Reporting period for MRSEC

  • Period 4

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