Preparation, Characterization, and Formulation Development of Drug-Drug Protic Ionic Liquids of Diphenhydramine with Ibuprofen and Naproxen

Chenguang Wang, Sujay A. Chopade, Yiwang Guo, Julia T. Early, Boxin Tang, En Wang, Marc A. Hillmyer, Timothy P. Lodge, Changquan Calvin Sun

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Diphenhydramine (DPH) has been used with ibuprofen (IBU) or naproxen (NAP) in combined therapies to provide better clinical efficacy as an analgesic and sleep aid. We discovered that DPH can form protic ionic liquids (PILs) with IBU and NAP, which opens the opportunity for a new delivery mode of these combination drugs. [DPH][IBU] and [DPH][NAP] PILs exhibit low ionicity, as confirmed by Fourier transform infrared and 1 H NMR spectroscopy, and accompanied by low diffusivity, high viscosity, and poor ionic conductivity. Evaluation of pharmaceutical properties of the two PILs showed that these PILs, despite high solubility and good wettability, exhibited low dissolution rates, owing to the poor dispersion of the PIL drops and the resultant small surface area during dissolution. However, when loaded into a mesoporous carrier, the PIL-carrier composites exhibited improved dissolution rates along with excellent flow properties and easy handling. Oral capsules of both PILs were developed using such composites. Such capsule products exhibited acceptable drug release and bioavailability as demonstrated by a predictive artificial stomach-duodenum dissolution test.

Original languageEnglish (US)
Pages (from-to)4190-4201
Number of pages12
JournalMolecular pharmaceutics
Issue number9
StatePublished - Sep 4 2018

Bibliographical note

Funding Information:
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 No. DMR-1420013. Partial funding for this work was provided by the National Science Foundation (DMR-1609459 and DMR-1707578). The authors thank Prof. Philippe Bühlmann for access to impedance spectroscopy equipment.

Publisher Copyright:
© 2018 American Chemical Society.

How much support was provided by MRSEC?

  • Shared

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.


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