Partition coefficient measurement

Octanol" and "Membrane" pK in Partition Coefficients Measurement 67 Tab. 3.1 Octanol-water and liposome-water partition coefficients. ... 

However, as stated above, the partition coefficients measured by the shake-flask method or by potenhometric titration can be influenced by the potenhal difference between the two phases, and are therefore apparent values which depend on the experimental condihons (phase volume ratio, nature and concentrahons of all ions in the solutions). In particular, it has been shown that the difference between the apparent and the standard log Pi depends on the phase volume raho and that this relationship itself depends on the lipophilicity of the ion [80]. In theory, the most relevant case for in vivo extrapolation is when V /V 1 as it corresponds to the phase ratio encountered by a drug as it distributes within the body. The measurement of apparent log Pi values does not allow to differentiate between ion-pairing effect and partihoning of the ions due to the Galvani potential difference, and it has been shown that the apparent lipophilicity of a number of quaternary ion drugs is not due to ion-pair partitioning as inihally thought [80]. 

Geary RS, Wall CM, Miller MA, et al. 1994. Partition coefficient measurements of diisopropyl methylphosphonate (DIMP) and trichloroethylene in rats using microdialysis and incorporated in physiologically-based pharmacokinetic (PBPK) modelling [Abstract], Society of Toxicology 33rd Annual Meeting, Dallas, TX 13-17 March, 1994. Paper No. 82. 

A method where phospholipids are entrapped in the pores of resin beads, in the forms of multilamellar vesicles, has been described [313-319,376]. In some ways, the idea is similar to that of IAM chromatography, even though the resin is modified differently. The retention indices correlate very well with the partition coefficients measured in liposome-water systems (described below). 

Olive oil was the original model lipid for partition studies, and was used by Overton in his pioneering research [518,524], It fell out of favor since the 1960s, over concerns about standardizing olive oil from different sources. At that time, octanol replaced olive oil as the standard for partition coefficient measurements. However, from time to time, literature articles on the use of olive oil appear. For example, Poulin et al. [264] were able to demonstrate that partition coefficients based on olive oil-water better predict the in vivo adipose-tissue distribution of drugs, compared to those from octanol-water. The correlation between in vivo log Kp (adipose tissue-plasma) and log (olive oil-water) was 0.98 (r2), compared to 0.11 (r2) in the case of octanol. Adipose tissue is white fat, composed mostly of triglycerides. The improved predictive performance of olive oil may be due to its triglyceride content. 

The authors would like to acknowledge the contributions of the following researchers J.R. DeBaun and L.S. Mullen-Rokita, for helpful discussions E.B. Cramer, for assisting with the adsorption measurements L.-S. Yu-Farina, for the water solubility and partition coefficient measurements H. Myers, for the vapor pressure measurements and R.R. Winter, for running the MACCS molecular structure analyses. 

Garst, J.E. (1984) Accurate, wide-range, automated, high-performance chromatographic method for the estimation of octanol/water partition coefficients. II Equilibrium in partition coefficient measurements, additivity of substituent constants, and correlation of biological data. J. Pharm. Sci. 73, 1623-1629. 

Liang C, Pankow JF (1996) Gas/particle partitioning of organic compounds to enviromnental tobacco smoke partition coefficient measurements by desorption and comparison to urban particulate material. Environ Sci Technol 30 2800-2805... 

The approach of Hansch and Leo (1995) uses a small number of fragment values derived from very accurate partition coefficient measurements of a relatively small number of compounds, and requires a large number of correction factors. Some of the coefficient values are given in table 5.15. This approach has been designed for an automatic computer program that will do all the coefficients and corrections, called the CLOG. Hansch and Leo reported that for 7500 compounds tested, the correlation has a standard error of 0.336 and an = 0.978. 

Different balance between intermolecular forces can be accessible via partition coefficients measured in solvents systems other than the traditional 1-octanol/water. Therefore there was a growing interest in the partition processes in several solvent/ water systems [64, 65] and in particular the critical quartet of solvents which was designed to merge the main information about a solute concerning its partition and transport. Only a few studies have been performed to characterize the lipophilicity profile of new chemical entities in different solvent/water systems and consequently the number of methods attempting to model such partitioning systems is limited. 

Liang, C., and J. F. Pankow, Gas/Particle Partitioning of Organic Compounds to Environmental Tobacco Smoke Partition Coefficient Measurements by Desorption and Comparison to Urban Particulate Material, Environ. Sci, Technol., 30, 2800-2805 (1996). 

Table 7.5 Solute Partition Coefficients Measured by Countercurrent Chromatography in Two Ionic Liquid-Containing Diphasic Liquid Systems...

FIGURE 3.18 Water-octanol partition coefficients measured and calculated by CLOGP. [Graph reconstructed from data by Yang et al., J. Pharm. Sci., 91, 517 (2001).]... 

Table I shows that when the solvent systems are ordered in this way, the primary butanols are the least lipophilic and oleyl alcohol is the most lipophilic of the solvents in the left column. Up to this point, the partition coefficients of various solutes are accommodated by Equation 1. The separation of the solvents in the right-hand column as more lipophilic is somewhat arbitrary, of course, but the partition coefficients measured in these systems are poorly correlated with any of the systems in the left column and generally cannot be correlated well with each other.

Determination of Octanol/Water Partition Coefficients. Since oc-tanol/water partition coefficient data for trifluoromethanesulfonanilide (I) and its substituted derivatives have not been reported in the literature and since it was not apparent that any of the substituent tt values previously determined by Fujita et al. (11) would be directly applicable to the TFMS herbicidal system, all TFMS partition coefficients and tt values were determined experimentally. The fluoroalkanesulfonanilides are very acidic because of the electron-withdrawing power of the parent fluoro-alkanesulfonyl group (5). The parent TFMS compound (I), for example, has a pKa in water of 4.45 at 25 °C. This inherent acidity extends to all TFMS series members and requires that the usual partition coefficient measurement procedure described by Fujita et al. (11) be modified to obtain accurate values of log P and tt. 

The authors are indebted to J. Belisle for the partition coefficient measurements and to J. Waddington and D. Pauly for the pre-emergence herbicidal activity evaluations. 

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