Logarithm partition coefficients

Almost all widely used, reliable prediction models for logarithmic partition coefficients, and especially for the octanol-water partition coefficient log P w, are linear regression models with respect to fragment counts, atom types, bond types or... 

The nonlinear character of log has not often been discussed previously. Nevertheless, Jorgensen and Duffy [26] argued the need for a nonlinear contribution to their log S regression, which is a product of H-bond donor capacity and the square root of H-bond acceptor capacity divided by the surface area. Indeed, for the example above their QikProp method partially reflects for this nonlinearity by predichng a much smaller solubility increase for the indole to benzimidazole mutation (0.45 versus 1.82 [39, 40]). Abraham and Le [41] introduced a similar nonlinearity in the form of a product of H -bond donor and H -bond acceptor capacity while all logarithmic partition coefficients are linear regressions with respect to their solvation parameters. Nevertheless, Abraham s model fails to reflect the test case described above. It yields changes of 1.8(1.5) and 1.7(1.7) [42] for the mutations described above. 

A problem of all such linear QSPR models is the fact that, by definition, they cannot account for the nonlinear behavior of a property. Therefore, they are much less successful for log S as they are for all kinds of logarithmic partition coefficients. 

JT Smith, DV Vinjamoori. Rapid determination of logarithmic partition coefficients between IV-octanol and water using micellar electrokinetic capillary chromatography. J. Chromatogr. B 669 59-66 (1995). 

It should be noted that Eq. (6.9) gives the partition coefficient in terms of mole fractions, as is common in the chemical engineering literature. We therefore denoted it as if. In chemistry it is usual to report partition coefficients in mol/l units, and to denote them by K. Although the partition coefficient is dimensionless in both conventions, it differs by the ratio of the molar volumes of the two solvents. As we will see in more detail in the next chapter, logarithmic partition coefficient data have been used heavily for the parameterization of COSMO-RS. The octanol-water partition... 

During the last 15 years, Abraham and his co-workers have established a set of five descriptors for the general description of logarithmic partition coefficients by linear regression. Their so-called linear free energy relationship (LFER) descriptors E, S, A, B, and V are effective parameters for the polarizability, polarity, hydrogen-bond acidity and basicity, and volume of the solute molecules, respectively [113-116]. They are mainly derived from experimental refraction and partition coefficients of the solutes. 

Finally, unlike most other QSAR approaches, the cr-moment approach allows for the graphical visualization of the logarithmic partition coefficients as local surface properties of the solutes,... 

The accurate prediction of the aqueous solubility of drugs and drug-like compounds is much further away from a satisfactory solution because the existing QSAR- or group-contribution-based solubility prediction models exhibit quite limited predictive power for new drug classes. Why is it that the extremely important problem of the prediction of aqueous solubility much less solved than the prediction of less important partition coefficients The answer is that the development of prediction models for logarithmic partition coefficients is much simpler, because the molecule X under consideration only acts as a solute at infinite dilution in the two phases. Hence the task is only to calculate the free energy of... 

Therefore, logarithmic partition coefficients exhibit a rather linear behavior with respect to surface-composition or group-contribution variables, and many approaches of this kind have proved to be quite successful. 

Table 4. Calculated Logarithmic Partition Coefficients (Log P) for 10-Deoxoartemisinin Analogues...

As can be seen in Figure 5-17, some search fields (e.g., POW [= Power]) do not need any input in the search mask this means that all entries with any content of those Helds are retrieved. However, other fields always demand an input. In case the input is omitted (for example for the decadic logarithm of the partition coefficient), a corresponding error message results. Since the PCB are more soluble in the organic phase, the input of that Field is restricted to positive values. 

A series of studies has been made by Yalkowsky and co-workers. The so-called general solubility equation was used for estimating the solubility of solid nonelectrolytes [17, 18]. The solubility log S (logarithm of solubility expressed as mol/L) was formulated with log P logarithm of octanol/water partition coefficient), and the melting point (MP) as shown in Eq. (11). This equation generally... 

The ending caine stems from cocaine, the first clinically employed local anaesthetic. Procaine and tetracaine are ester-linked substances, the others are amides. Amide bonded local anaesthetics usually contain two i s in their name, ester-bonded only one. In the structure drawings, the lipophilic portion of the molecule is depicted at the left, the amine at the right. The asterisk marks the chiral centre of the stereoisomeric drugs. Lipid solubility is given as the logarithm of the water octanol partition coefficient, log(P). 

Molecular weight Density Melting point Bolling point Logarithm of partition coefficient ... 

Gel Filtration. The lyophilized protein was redissolved in 50 mM phosphate buffer, pH 7.4 0.15 m NaCl 0.013 % sodium azide and loaded on a Superdex 75HR1030 column equilibrated with the same buffer. Elution was downward flow (0.15 ml/min) and 0.25 ml fi actions were collected. Fractions with pectin lyase activity were combined, dialyzed against distilled water and used in the next step. To estimate the molecular mass of PNL, the column was calibrated with standard proteins (Sigma MW-GF-70 Albumin, 66,000 Da Carbonic Anhidrase, 29,00 Cytochrome, 12,400 and Aprotinin, 6,500). The proteins were eluted in the conditions described above and their volumes (F ) were calculated fi om the peak maximum of the absorbance at 280 nm. The partition coefficient was obtained fi om the relationship where F, represents the bed volmne of column and F the void volume (which was calculated using blue dextran. Sigma). The molecular mass was determined using a standard curve of vs the logarithm of the molecular masses of the standards [28, 29]... 

Clog P Calculated hydrophobicity of the whole molecule (calculated logarithm of partition coefficient (P) in M-octanol/water) ji Calculated hydrophobicity of the substituent... 

The quantitative descriptor of lipophilicity, the partition coefficient P, is defined as the ratio of the concentrations of a neutral compound in organic and aqueous phases of a two-compartment system under equilibrium conditions. It is commonly used in its logarithmic form, logP. Whereas 1-octanol serves as the standard organic phase for experimental determination, other solvents are applied to better mimic special permeation conditions such as the cyclohexane-water system for BBB permeation. Measurement of log P is described in Chapters 12 and 13 as well as in Ref [22]. 

A general definition of log P and log D, in its simplest form, can be given as the logarithm of the ratio (P or D) of the concentration of species of interest (the drug in a pharmaceutical context) in each phase, assuming the phases are immiscible and well separated prior to analysis. P is defined as the partition coefficient, whereas D is the distribution coefficient. However, the simplest form does not reveal some of the intricacies of the determination and use of these parameters, and further explanation is necessary. 

In general, there is a positive correlation between hydrophobicity of solvents and nontoxicity for biocatalysts. The log P value was demonstrated to be a suitable parameter for characterization of solvent hydrophobicity (Table 1). Log P is the logarithm of the partition coefficient of a solvent in a water-l-octanol two-phase system [11,12,41,77]. Solvents with log P > A are very hydrophobic and generally nontoxic for biocatalysts. 

Another kind of descriptors is the so-called physicochemical ones. They include log P, lipophylicity, etc. Log P is the logarithm of the partition coefficient between octanol water. This descriptor has been used since the first QSAR models, and originally it was measured. Nowadays it is much more common to calculate it. 

---