Enhanced Performance of Blended Polymer Excipients in Delivering a Hydrophobic Drug through the Synergistic Action of Micelles and HPMCAS

Ziang Li, Lindsay M. Johnson, Ralm G. Ricarte, Letitia J. Yao, Marc A. Hillmyer, Frank S. Bates, Timothy P. Lodge

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39 Scopus citations


Blends of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and dodecyl (C12)-tailed poly(N-isopropylacrylamide) (PNIPAm) were systematically explored as a model system to dispense the active ingredient phenytoin by rapid dissolution, followed by the suppression of drug crystallization for an extended period. Dynamic and static light scattering revealed that C12-PNIPAm polymers, synthesized by reversible addition-fragmentation chain-transfer polymerization, self-assembled into micelles with dodecyl cores in phosphate-buffered saline (PBS, pH 6.5). A synergistic effect on drug supersaturation was documented during in vitro dissolution tests by varying the blending ratio, with HPMACS primarily aiding in rapid dissolution and PNIPAm maintaining supersaturation. Polarized light and cryogenic transmission electron microscopy experiments revealed that C12-PNIPAm micelles maintain drug supersaturation by inhibiting both crystal nucleation and growth. Cross-peaks between the phenyl group of phenytoin and the isopropyl group of C12-PNIPAm in 2D 1H nuclear Overhauser effect (NOESY) spectra confirmed the existence of drug-polymer intermolecular interactions in solution. Phenytoin and polymer diffusion coefficients, measured by diffusion-ordered NMR spectroscopy (DOSY), demonstrated that the drug-polymer association constant increased with increasing local density of the corona chains, coincident with a reduction in C12-PNIPAm molecular weight. These findings demonstrate a new strategy for exploiting the versatility of polymer blends through the use of self-assembled micelles in the design of advanced excipients.

Original languageEnglish (US)
Pages (from-to)2837-2848
Number of pages12
Issue number11
StatePublished - Mar 21 2017

Bibliographical note

Funding Information:
The authors gratefully thank Prof. Theresa M. Reineke, Dr. Jeffrey M. Ting, and Anatolii A. Purchel for helpful discussions. This study was funded by The Dow Chemical Company through agreement 224249AT with the University of Minnesota. Parts of this work were carried out in the College of Science and Engineering Characterization Facility, University of Minnesota, which has received capital equipment funding from the NSF through theUMNMRSEC program under award number DMR- 1420013. NMR instrumentation was supported by the Office of the Vice President of Research, College of Science and Engineering, and the Department of Chemistry at the University of Minnesota. The Bruker Avance III HD NMR was supported by the Office of the Director, National Institutes of Health under award number S10OD011952. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2017 American Chemical Society.

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PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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