Lipophilicity and pKa estimates from gradient high-performance liquid chromatography

Kaliszan, Roman; Haber, Piotr; Bączek, Tomasz; Siluk, Danuta; Valkó, Klára

doi:10.1016/s0021-9673(02)00114-0

Cited by 98 publications

(52 citation statements)

References 36 publications

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“…(3), a consistent value of 11.3 mM for the pH 7.4 aqueous solubility of glyburide is predicted. 13,14 Furthermore, a consistent value of 16.6 mM (8.22 mg mL À1 ) for the aqueous solubility of glyburide, measured at 25 C, has been reported by Seedher and Kanojia. 15 The spread in the 30 repeat measurements for glyburide can be seen in Figure 4, which also indicates the mean and 95% confidence intervals of the mean (8.52 and 9.98 mM).…”

Section: Validation Of the Automated Assaysupporting

confidence: 77%

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

Wenlock

Austin

Potter

et al. 2011

JALA: Journal of the Association for Laboratory Automation

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Aqueous solubility is an important physicochemical parameter for any potential drug candidate, and high-throughput kinetic assays are frequently used in drug discovery to give an estimate of a compound's aqueous solubility. However, the aqueous solubility data from an equilibrium (thermodynamic) shake-flask technique is considered more relevant, but is slower and more labor intensive to generate. A highly automated aqueous equilibrium solubility shake-flask technique is described and validated on a set of 15 marketed drugs, whose aqueous solubilities cover four orders of magnitude. The assay uses a Tecan Freedom Evo 200 liquid handling robot (Tecan Group Ltd., Männerdorf, Switzerland) with integrated appliances for the transportation, decapping and recapping, and centrifugation of sample tubes. These bespoke automation solutions help overcome the labor intensive steps associated with performing conventional, gold standard, aqueous equilibrium solubility shake-flask measurements, enabling the assay to be used as a primary-wave drug discovery screen.

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Section: Validation Of the Automated Assaysupporting

confidence: 77%

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

Wenlock

Austin

Potter

et al. 2011

JALA: Journal of the Association for Laboratory Automation

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“…That observation once more confirms the unique suitability of aluminabased column stationary phases for quantification of lipophilicity, as was noted many years ago [53]. On the other hand, for a structurally diversified series of drugs chromatographed on XTerra RP 18 column with methanol as organic modifier, the correlation between logk w assessed by gradient method and logP was relatively low (R=0.804) [54].…”

Section: Gradient Reversed-phase Hplc In Lipophilicity Determinationsupporting

confidence: 72%

New approaches to chromatographic determination of lipophilicity of xenobiotics

Kaliszan

Nasal

Markuszewski

2003

Analytical and Bioanalytical Chemistry

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Liquid chromatography and capillary electrophoresis are unique tools for fast and efficient modeling of pharmacokinetic properties of drug candidates. Therefore numerous new separation methods and procedures have very recently been introduced to facilitate the high-throughput screening of biopartitioning features of xenobiotics. This report is a concise, up-to-date review of progress in the chromatographic assessments of data of importance for medicinal chemistry and molecular pharmacology.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Andrés

Rosés

Ràfols

et al. 2015

European Journal of Pharmaceutical Sciences

163

102

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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.

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Lipophilicity and pKa estimates from gradient high-performance liquid chromatography

Cited by 98 publications

References 36 publications

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

A Highly Automated Assay for Determining the Aqueous Equilibrium Solubility of Drug Discovery Compounds

New approaches to chromatographic determination of lipophilicity of xenobiotics

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

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