Distribution coefficient log

Tetko, I. V., Bruneau, P. Application of ALOGPS to predict 1-octanol/water distribution coefficients, log P, and log D, of AstraZeneca in-house database. 

The un-ionized form is assumed to be sufficiently lipophilic to traverse membranes in the pH-partition hypothesis. If it were not, no transfer could be predicted, irrespective of pH. The lipophilicity of compounds is experimentally determined as the partition coefficient (log P) or distribution coefficient (log D) [16]. The partition coefficient is the ratio of concentrations of the neutral species between aqueous and nonpolar phases, while the distribution coefficient is the ratio of all species between aqueous and nonpolar phases [17,18],... 

APEO concentrations in suspended matter samples were similar to the sediment concentrations. From these values, in situ organic carbon corrected suspended matter/water distribution coefficients (log Koc) were calculated. For the separate ethoxymers NP, A9PE0i, A9PE02,... 

As indicated earlier (Section 3.1.1) the sorption of organic compounds onto dissolved matter can significantly increase the solubility of the compound. This can in turn affect the fate of these chemicals in the environment. We can use physicochemical parameters such as distribution coefficients (log D), aqueous acid dissociation constants (pAia), and octanol-water partition coefficients (p/to )-These attributes are also linked to the acidity and alkalinity of the environment as well as lipohilicity of the compound. The mathematical relationships between these attributes are outlined below to explore how each of these impacts the fate of PPCPs in the environment. 

Figure 5 Illustration of the lock-in mechanism for estradiol-CDS. Octanol-water log partition (log P) and distribution coefficients (log D) are shown to illustrate the significant changes in partition properties. The lipophilic CDS (5) (log P > 4) can easily cross the blood-brain barrier (BBB), but the hydrophilic intermediate (6) (log D < 0) is no longer able to come out providing a sustained release of the active estradiol (7). 

The partition coefScient is defined as the ratio of the concentration of a solute in the organic phase to its concentration in the water phase. This definition applies to the same neutral microspecies. However, many small molecules of pharmaceutical, agricultural and environmental interest may assume different protomeric and tautomeric forms, which increases the complexity of the above (simple) definition. Indeed, many small molecules contain moieties that ionize in water, thus contributing to a decrease in lipophilicity. The distribution coefficient, log D y, measures the pH-dependent distribution of drug in octa-nol-water phases at pH xy. 

The previous considered methods usually depend on linear methods (MLR, PLS) to establish structure-solubility correlations for prediction of solubility of molecules. The work of Goller et al. [51] used a neural network ensemble to predict the apparent solubility of Bayer in-house organic compounds. The solubility was measured in buffer at pH 6.5, which mimics the medium in the human gastrointestinal tract. The authors used the calculated distribution coefficient log/1 (at several pH values), a number of 3D COSMO-derived parameters and some 2D descriptors. The final model was developed using 4806 compounds (RMSE = 0.72) and provided a similar accuracy (RMSE = 0.73) for the prediction of 7222 compounds that were not used to develop the model. The method, however, is quite slow, and it takes about 15 seconds to screen one molecule on an Intel Xeon 2.8 GHz CPU. 

Fundamental physicochemical properties (see Chapter 5) such as partition coefficient (log P) and distribution coefficient (log D) and pfCa are well predicted directly from chemical structure [42, 43]. Aqueous solubility may also be predicted reasonably well [44—46] (see Chapter 4), though there are warnings on the accuracy of solubility predictions for in-house pharmaceutical company compounds since these tend to be quite different chemical structures from those used to develop the commercial models [47]. 

QSAR) studies often involve octanol-water distribution coefficients (Log D). 

The partition coefficient refers to the intrinsic lipophilicity of the drug, in the context of the equilibrium of unionized drug between the aqueous and organic phases. If the drug has more than one ionization center, the distribution of species present will depend on the pH. The concentration of the ionized drug in the aqueous phase will therefore have an effect on the overall observed partition coefficient. This leads to the definition of the distribution coefficient (log D) of a compound, which takes into account the dissociation of weak acids and bases. 

Equilibrium distribution coefficient (log P or log D) is an important parameter to assess the solvent effect. Asymmetric reduction of 4-chloroacetophenone to (R)-l-(4-chlorophenyl)ethanol by Lactobacillus kefir showed an increase in product yield with increase in log D value of the ILs [104]. However, auother study [117], which used ILs as coating of lipase (Novozyme 435) for esterification of methyl a-o-glucopyranoside with fatty acids, showed a remarkable increase in the product yield with increase in the polarity of the IL used for coating which is opposite in trend to that observed when ILs were used as solvent as discussed above. This altered effect of more polar IL coating on product yield was attributed to their better absorption ability on the polyacrylate beads used for immobilization of enzymes in this case [117]. 

Li (1981) has proposed that the distribution coefficients reflect adsorption-desorption reactions at the surface of mineral grains. To emphasize this point, Li plotted a slightly different distribution coefficient (log Cop/Q , where Qp and Cs are the concentrations in oceanic pelagic clay sediments and seawater respectively vs the first hydrolysis constants of the metals or the dissociation constant of the oxyanion acids. The argument is that those elements that hydrolyze the strongest will adsorb the... 

Since the cornea is a membrane barrier containing both lipophilic and hydrophilic layers, drugs possessing both lipophilic and hydrophilic properties permeate it most effectively. The optimal range for the octanol/buffer pH 7.4 distribution coefficient (log P) for corneal permeation is 2 to 3 (Schoenwald and Ward 1978), observed for a wide variety of drugs. 

The lipophilicity of a compound is often considered as an important design factor since it is related to processes such as absorption, brain uptake, volume of distribution and protein binding. This property is often expressed as the partition coefficient (log P) or distribution coefficient (log D, typically measured at pH 7.4). By several lines of evidence it was shown that log P values should be... 

The influence of these structural changes on the UpophiUcity/hydrophobicity properties of the resulting analogs was investigated. The distribution coefficients (log D) were determined at cytosolic pH (7.4) and vacuolar pH (5.2) by HPLC [60]. In addition, the ionization proportion of neutral, monoprotonated, and diprotonated forms was determined by the Henderson-Hasselbach equation from experimental p/Q values [60]. It has been shown that all compounds are highly hydrophilic at vacuolar pH (5.2) and are mostly in their diprotonated form. At this pH, the lipophilicity of these analogs can be ranked as follows MeRQ > MeFQ > RQ > FQ > CQ. At vacuolar pH, the differences between the coefficients of distribution are small. In addition, replacing the iron atom of FQ by ruthenium in RQ has no influence on the lipophilicity of the molecules. 

For active substances that can be ionised the distribution coefficient (log D) has been defined. The oD-water distribution coefficient (log Do/w value) for a substance is presented in (16.2) ... 

As discussed later, the values and physicochemical meaning of this parameter change from one organic solvent to another. By definition, partition coefficients apply to solutes in a single, well-defined electrical state. Most published partition coefficients are those of neutral species, whereas the accurate measurement of the log F values of ions and zwitterions remains a current challenge. As such, partition coefficients must be carefully discriminated from distribution coefficients (log D), which apply to ionizable solutes at a given pH and are thus the combined expression of the lipophilicity of at least two ionic species in a pH-dependent proportion. ... 

The polarity parameter A is a different approach based on Eq. [5] using another structural parameter of amino acid side chains. For the side chain of each amino acid in the free zwitterionic form and in protected form ° (amide plus ester), Eq. [5] permitted calculation of the polarity parameter A from the computed molecular volume V and the experimental distribution coefficient log D. 

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