title: Transformation of acidic poorly water soluble drugs into ionic liquids.
abstract: Poor water solubility of active pharmaceutical ingredients (API) is a major challenge in drug development impairing bioavailability and therapeutic benefit. This study is addressing the possibility to tailor pharmaceutical and physical properties of APIs by transforming these into tetrabutylphosphonium (TBP) salts, including the generation of ionic liquids (IL). Therefore, poorly water soluble acidic APIs (Diclofenac, Ibuprofen, Ketoprofen, Naproxen, Sulfadiazine, Sulfamethoxazole, and Tolbutamide) were converted into TBP ILs or low melting salts and compared to the corresponding sodium salts. Free acids and TBP salts were characterized by NMR and IR spectroscopy, DSC and XRPD, DVS and dissolution rate measurements, release profiles, and saturation concentration measurements. TBP salts had lower melting points and glass transition temperatures and dissolution rates were improved up to a factor of 1000 as compared to the corresponding free acid. An increase in dissolution rates was at the expense of increased hygroscopicity. In conclusion, the creation of TBP ionic liquids or solid salts from APIs is a valuable concept addressing dissolution and solubility challenges of poorly water soluble acidic compounds. The data suggested that tailor-made counterions may substantially expand the formulation scientist's armamentarium to meet challenges of poorly water soluble drugs.
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074 Würzburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Balk
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074 Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiest
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074 Würzburg, Germany; Novartis Pharma AG, Lichtstraße 35, CH-4002 Basel, Switzerland.
authors.forename: Toni
authors.initials: T
authors.lastname: Widmer
authors.affiliation: Novartis Pharma AG, Lichtstraße 35, CH-4002 Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Galli
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074 Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, DE-97074 Würzburg, Germany. Electronic address: l.meinel@pharmazie.uni-wuerzburg.de.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D006863:Hydrogen-Ion Concentration; D052578:Ionic Liquids; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D012997:Solvents; D013055:Spectrophotometry, Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D044366:Transition Temperature; D014867:Water / Q000737:chemistry*; D017155:Wettability
chemical_list: D052578:Ionic Liquids; D009943:Organophosphorus Compounds; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; C050172:tetrabutylphosphonium
keywords: Dissolution rate; Hygroscopic; Ionic liquid; Pharmaceutical salts; Poorly water soluble drugs