Chemistry and Geometry of Counterions Used in Hydrophobic Ion Pairing Control Internal Liquid Crystal Phase Behavior and Thereby Drug Release

Kurt Ristroph, Malinda Salim, Andrew J. Clulow, Ben J. Boyd, Robert K. Prud'Homme

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


The combination of Flash NanoPrecipitation and hydrophobic ion pairing (HIP) is a valuable approach for generating nanocarrier formulations of ionic water-soluble drugs with controllable release properties dictated by liquid crystalline structuring of the ion pairs. However, there are few examples of this in practice in the literature. This work aims to decipher the influence of the nature of the hydrophobic counterion used in HIP and its consequent impact on liquid crystalline structuring and drug release. The hypothesis of this study was that hydrophobic counterions with different head and tail groups used for FNP with HIP would give rise to different liquid crystalline structures, which in turn would result in different drug release behavior. A cationic, water-soluble antibiotic, polymixin B, was complexed with eight different hydrophobic counterions with varying head and tail groups and encapsulated into nanocarriers 100-400 nm in size prepared using FNP. Sixteen formulations were assessed for internal structure by synchrotron small-angle X-ray scattering, and drug release was measured in vitro in physiological conditions. The liquid crystalline phases formed depended on the counterion head group and tail geometry, drug:counterion charge ratio, and the ionic strength and pH of the release medium. Drug release occurred more rapidly when no liquid crystalline phases were present and more slowly when higher-ordered phases existed. Specific findings include that phosphonic acid counterions lead to the formation of lamellar structures that persisted at pH 2.0 but were not present at pH 7.3. In contrast, sulfonic acids lead to lamellar or hexagonal phases that persisted at both pH 7.3 and 2.0, while hydrophobic counterions without alkyl tails did not form internal structures. It was also clear that the lipophilicity of the counterion does not dictate drug release. These findings confirm that the liquid crystalline phase behavior of the drug:counterion complex dictates drug release and significantly improves our understanding of the types of controlled release formulations that are possible using FNP with HIP.

Original languageEnglish (US)
Pages (from-to)1666-1676
Number of pages11
JournalMolecular Pharmaceutics
Issue number4
StatePublished - Apr 5 2021

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine
  • Pharmaceutical Science


  • controlled release
  • drug delivery
  • flash nanoprecipitation
  • hydrophobic ion pairing
  • nanocarrier
  • small-angle X-ray scattering


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