Extension of the liquid chromatography/quantitative structure–property relationship method to assess the lipophilicity of neutral, acidic, basic and amphotheric drugs

The influence of lipophilicity in drug discovery and design

“…The chromatographic hydrophobicity index (CHI) developed by Valko et al can be used as an independent measure of hydrophobicity [44] and offers a simple way to evaluate the log P of a drug [45]. In fact, the need to correct chromatographic measurements with the hydrogen bond acidity to get reliable log P values has been demonstrated recently [42,46]. This is a remarkable feature since pure chromatographic methods only offer good estimations of log P for compounds without significant hydrogen bond acidity.…”

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts

“…The guidelines about log D 7.4 values and their implication for drug development are illustrated in Table 1 (Comer, 2003;Taylor and Triggle, 2007). There are many different approaches which can be used to determine a partition coefficient experimentally (Avdeef, 1993;Donovan and Pescatore, 2002;Gulyaeva et al, 2008;Hitzel et al, n.d.;Kaliszan et al, 2002;Pallicer et al, 2012Pallicer et al, , 2010Ràfols et al, 2012;Stopher and Mcclean, 1990;Takács-Novák and Avdeef, 1996;Valko et al, 2001;Wiczling et al, 2008), but the most direct one is the shake-flask method. In this method, an aqueous solution of a compound is mixed in a flask with an organic solvent (usually water saturated n-octanol).…”

“…The partition coefficient (P) refers to the ratio of compound concentration in each phase and can be determined experimentally by a variety of methods including the well-known shake-flask method (EPA, 1996;OECD 107 Method, 1995), potentiometric methods (Avdeef, 1993(Avdeef, , 1992Ràfols et al, 2012;Takács-Novák and Avdeef, 1996), chromatographic methods (Donovan and Pescatore, 2002;Kaliszan et al, 2002;Liang and Lian, 2015;OECD 117 Method, 2004;Pallicer et al, 2012Pallicer et al, , 2010Wiczling et al, 2008) and others. Besides, lipophilicity can also be estimated using computer software and extensive studies about the accuracy of calculated log P values by different computer software has already been carried out (Chou and Jurs, 1979;Leo, 1987;Mannhold et al, 2009;Pallicer et al, 2014;Tetko et al, 2009).…”

Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs

“…The used simplified approach involves only one descriptor, the Abraham's A parameter, which can be easily estimated from the compound structure using either a commercial software package (ACD/Labs) or the open access UFZ-LSER Database (Ulrich et al, 2017). It was proved that this method is able to properly estimate log Po/w values from -1 to 7 (Pallicer et al, 2012), broadening in two orders of magnitude the lipophilicity range proposed in previous guidelines (OECD, 2004). d) Two potentiometric titrations of the drug, with and without n-octanol, allow the log Po/w determination of compounds with acid-base properties.…”