Transformation of biopharmaceutical classification system class I and III drugs into ionic liquids and lipophilic salts for enhanced developability using lipid formulations

Hywel D. Williams, Leigh Ford, Shea Lim, Sifei Han, John Baumann, Hannah Sullivan, David Vodak, Annabel Igonin, Hassan Benameur, Colin W. Pouton, Peter J. Scammells, Christopher J.H. Porter

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Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by 1H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.

Original languageEnglish
Pages (from-to)203–216
Number of pages14
JournalJournal of Pharmaceutical Sciences
Issue number1
Publication statusPublished - 2018


  • Biopharmaceutics classification system
  • Developability
  • Formulation vehicle
  • Lipids
  • Oral drug delivery
  • Salts/salt selection
  • Self-emulsifying
  • Solubility
  • Zwitterion

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