Development octanol-water partition coefficient

The following physico-chemical properties of the analyte(s) are important in method development considerations vapor pressure, ultraviolet (UV) absorption spectrum, solubility in water and in solvents, dissociation constant(s), n-octanol/water partition coefficient, stability vs hydrolysis and possible thermal, photo- or chemical degradation. These valuable data enable the analytical chemist to develop the most promising analytical approach, drawing from the literature and from his or her experience with related analytical problems, as exemplified below. Gas chromatography (GC) methods, for example, require a measurable vapor pressure and a certain thermal stability as the analytes move as vaporized molecules within the mobile phase. On the other hand, compounds that have a high vapor pressure will require careful extract concentration by evaporation of volatile solvents. 

In a recent study of twenty disperse and solvent dyes, data for water solubility, octanol/ water partition coefficient, entropy of fusion and melting point were subjected to regression analysis. Complicating factors such as impurities, polymorphism, tautomerism, polarisation and hydrogen bonding precluded the development of reliable predictions of solubility and partition coefficient. Anthraquinone dyes exhibited much lower entropy of fusion than many of the azo dyes [64,65]. 

The dominant transport process from water is volatilization. Based on mathematical models developed by the EPA, the half-life for M-hexane in bodies of water with any degree of turbulent mixing (e.g., rivers) would be less than 3 hours. For standing bodies of water (e.g., small ponds), a half-life no longer than one week (6.8 days) is estimated (ASTER 1995 EPA 1987a). Based on the log octanol/water partition coefficient (i.e., log[Kow]) and the estimated log sorption coefficient (i.e., log[Koc]) (see Table 3-2), ii-hexane is not expected to become concentrated in biota (Swann et al. 1983). A calculated bioconcentration factor (BCF) of 453 for a fathead minnow (ASTER 1995) further suggests a low potential for -hcxanc to bioconcentrate or bioaccumulate in trophic food chains. 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

In formulation development, the octanol-water partition coefficient is commonly used it is defined as ... 

Ellington, J.J. and Stancil, F.E., Jr. Octanol/water partition coefficients for evalnation of hazardons waste land disposal selected chemicals. Office of Research and Development, U.S. EPA Report 600/M-88/010, 1988. 

This area is a development in the usage of NDDO models that emphasizes their utility for large-scale problems. Structure-activity relationships (SARs) are widely used in the pharmaceutical industry to understand how the various features of biologically active molecules contribute to their activity. SARs typically take the form of equations, often linear equations, that quantify activity as a function of variables associated with the molecules. The molecular variables could include, for instance, molecular weight, dipole moment, hydrophobic surface area, octanol-water partition coefficient, vapor pressure, various descriptors associated with molecular geometry, etc. For example, Cramer, Famini, and Lowrey (1993) found a strong correlation (r = 0.958) between various computed properties for 44 alkylammonium ions and their ability to act as acetylcholinesterase inhibitors according to the equation... 

The apparent first-order degradation rate constants of six dichlorophenols and three trichlorophenols were studied by D Oliviera et al. (1993). ft was determined that the first-order rate constant, k, correlated with the Hammett s constant o and the octanol/water partition coefficient. The Hammett correlation for the cholorophenols was developed as follows ... 

A correlation for less structurally related compounds was also developed by Amalric et al. (1996). To develop this correlation, meta- and para-substituted anisoles were studied. These aromatic compounds were substituted with F, Cl, N02, OH, and NH2 groups. The first-order degradation rate constant, kapf was predicted with the octanol/water partition coefficient (log Kow), Brown s constant (o+), and molar refractivity (MR) used as descriptors. The following correlation was developed ... 

The correlation was developed with a correlation coefficient of 0.903. The correlation was able to accurately predict the first-order degradation rate constants as a function of Brown s constant, the octanol/water partition coefficient, and molar refractivity. This correlation held for a broader class of aromatic compounds substituted at the meta and para positions, as compared to a simple substitution at one position on the aromatic ring. Table 9.6 lists the experimental and predicted values for the first-order degradation rate constants of substituted anisoles. 

Three general classes of estimation method are in frequent use. The first exploits the considerable data on octanol water partition coefficient Kow and the well developed estimation methods for that quantity by seeking a relationship between solubility and KqW. The second attempts to relate molecular structure to solubility by a variety of techniques involving counting bonds or groups or calculating molecular volumes, areas, or other topological indices such as connectivity. 

The pH dependence of the octanol / water partition coefficient was calculated using the ACD PhysChem computational program (version 6.0, Advanced Chemistry Development, Toronto, Canada), and these results are plotted in Figure 2. The plot demonstrates that the neutral compound is mildly hydrophobic, but that the ionized form is strongly hydrophilic. This finding is in accord with the solubility data. 

A variety of approaches have been developed to describe and predict the delivery of drugs into the brain. The early examples were restricted to small series of small and mostly homogeneous non-electrolytes and showed acceptable correlations with their octanol-water partition coefficients [59]. 

---