High-throughput excipient discovery enables oral delivery of poorly soluble pharmaceuticals

Jeffrey M. Ting, Swapnil Tale, Anatolii A. Purchel, Seamus D. Jones, Lakmini Widanapathirana, Zachary P. Tolstyka, Li Guo, Steven J. Guillaudeu, Frank S. Bates, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean areaunder- the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Original languageEnglish (US)
Pages (from-to)748-755
Number of pages8
JournalACS Central Science
Issue number10
StatePublished - Oct 26 2016

Bibliographical note

Funding Information:
The authors gratefully thank Prof. Timothy P. Lodge, Prof. Marc A. Hillmyer, and Dr. Robert L. Schmitt for helpful discussions. We thank Sara M. Ouellette and Linda K. Stoneburner for operating the high-throughput experiments. This work was financially supported by The Dow Chemical Company. J.M.T. acknowledges support from the National Science Foundation (NSF) Graduate Research Fellowship under Grant 00006595 and the University of Minnesota Doctoral Dissertation Fellowship. Part of this work was carried out in the College of Science and Engineering Characterization Facility, University of Minnesota, which has received capital equipment funding from the NSF through the UMN MRSEC program under Award Number DMR-1420013. The University of Minnesota and The Dow Chemical Company have submitted a patent application covering aspects of the work described in this report to the U.S. Patent Office.

How much support was provided by MRSEC?

  • Shared

Reporting period for MRSEC

  • Period 3

PubMed: MeSH publication types

  • Journal Article

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