title: Lipophilicity of amphoteric and zwitterionic compounds: A comparative study of determination methods.
abstract: Common drugs intended for action in plasma (antibacterials, antiallergics, diuretics...) often display both acidic and basic behavior, and some of these amphoteric compounds can appear as zwitterions. In such cases, accurate profiling of lipophilicity vs. pH, which plays a fundamental role in drug pharmacokinetics, might be complex. In the present work two common lipophilicity determination methods based on the drug distribution between 1-octanol and aqueous buffer i.e. phase equilibration (shake-flask) and two-phase titration (potentiometry), were compared with a high-throughput lipophilicity index, the Chromatographic Hydrophobicity Index (CHI). The results were also compared with log Do/wpH-profiles calculated by different algorithms from ACD/Labs. Accurate and similar results were obtained for both octanol-water approaches but, due to the lower determination times and the absence of different ion-pairing buffers, potentiometry was shown to be the most convenient method. CHI vs. pH profiles provide rapid and efficient information, which is very convenient for lipophilicity screening purposes, but may differ slightly from shake-flask and potentiometric results.
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain. Electronic address: crafols@ub.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Ràfols
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain. Electronic address: xavier.subirats@ub.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Subirats
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain. Electronic address: jr@masso.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Rubio
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain. Electronic address: marti.roses@ub.edu.
authors.forename: Martí
authors.initials: M
authors.lastname: Rosés
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain. Electronic address: e.bosch@ub.edu.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bosch
mesh_terms: D020003:1-Octanol / Q000737:chemistry*; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002021:Buffers; D004364:Pharmaceutical Preparations; D014867:Water; D002939:Ciprofloxacin; D020003:1-Octanol
keywords: Ampholyte; Chromatographic Hydrophobicity Index (CHI); Lipophilicity; Potentiometry; Shake-flask; Zwitterion