title: Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts.
abstract: Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature ones.
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Axel
authors.initials: A
authors.lastname: Andrés
authors.affiliation: Departament de Química Analítica and Institut de Biomedicina (IBUB), Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
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, 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, 08028 Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bosch
authors.affiliation: Computational and Structural Drug Discovery Department, R&D Centre, Almirall S.A., Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Espinosa
authors.affiliation: Computational and Structural Drug Discovery Department, R&D Centre, Almirall S.A., Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Segarra
authors.affiliation: Computational and Structural Drug Discovery Department, R&D Centre, Almirall S.A., Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Huerta
mesh_terms: D020003:1-Octanol / Q000737:chemistry*; D002021:Buffers; D002853:Chromatography, Liquid; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D055808:Drug Discovery; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D004364:Pharmaceutical Preparations / Q000032:analysis*; D015203:Reproducibility of Results; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000737:chemistry*
chemical_list: D002021:Buffers; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; D020003:1-Octanol; D004121:Dimethyl Sulfoxide
keywords: Acetanilide (PubChem CID: 904); Atenolol (PubChem CID: 2249); Caffeine (PubChem CID: 2519); Haloperidol (PubChem CID: 3559); Hydrophobicity; Ketoconazole (PubChem CID: 456201); Lipophilicity; Metoprolol (PubChem CID: 4171); Octanol–water partition; Paracetamol (PubChem CID: 1983); Phenothiazine (PubChem CID: 7108); Salicylic acid (PubChem CID: 338); Shake-flask technique; Warfarin (PubChem CID: 54678486); logD; logP(o)(/w)