title: Ionic liquid versus prodrug strategy to address formulation challenges.
abstract: OBJECTIVE
  A poorly water soluble acidic active pharmaceutical ingredient (API) was transformed into an ionic liquid (IL) aiming at faster and higher oral availability in comparison to a prodrug.
  
  
  METHODS
  API preparations were characterized in solid state by single crystal and powder diffraction, NMR, DSC, IR and in solution by NMR and ESI-MS. Dissolution and precipitation kinetics were detailed as was the role of the counterion on API supersaturation. Transepithelial API transport through Caco-2 monolayers and counterion cytotoxicity were assessed.
  
  
  RESULTS
  The mechanism leading to a 700 fold faster dissolution rate and longer duration of API supersaturation of the ionic liquid in comparison to the free acid was deciphered. Transepithelial transport was about three times higher for the IL in comparison to the prodrug when substances were applied as suspensions with the higher solubility of the IL outpacing the higher permeability of the prodrug. The counterion was nontoxic with IC50 values in the upper μM / lower mM range in cell lines of hepatic and renal origin as well as in macrophages.
  
  
  CONCLUSIONS
  The IL approach was instrumental for tuning physico-chemical API properties, while avoiding the inherent need for structural changes as required for prodrugs.
authors.affiliation: Institute for Pharmacy, Am Hubland, University of Würzburg, 97074, Würzburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Balk
authors.forename: Toni
authors.initials: T
authors.lastname: Widmer
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiest
authors.forename: Heike
authors.initials: H
authors.lastname: Bruhn
authors.forename: Jens-Christoph
authors.initials: JC
authors.lastname: Rybak
authors.forename: Philipp
authors.initials: P
authors.lastname: Matthes
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller-Buschbaum
authors.forename: Anastasios
authors.initials: A
authors.lastname: Sakalis
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Berghausen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Bruno
authors.initials: B
authors.lastname: Galli
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D018938:Caco-2 Cells; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007408:Intestinal Absorption; D052578:Ionic Liquids / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D010539:Permeability; D033362:Powder Diffraction; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D052578:Ionic Liquids; D011355:Prodrugs; D018091:Receptors, AMPA