Log D values

For heat treatment, a D-value only refers to the resistance of a microorganism at a particular temperature. In order to assess the influence of temperature changes on thermal resistance a relationship between temperature and log D-value can be developed leading to the expression of a z-value, which represents the increase in temperature needed to reduce the D-value of an organism by 90% (i.e. 1 log cycle reduction Fig. 20.2B). For bacterial spores used as biological indicators for moist heat (B. stearothermophilus)... 

The measurement of extreme log P/log D values (generally accepted to be below -3 and above 4) requires a disproportionate volume ratio of the aqueous and solvent phases, making it difficult to sample a reasonable amount for the concentration determination and automated sampling almost impossible. 

Valko et al. [37] developed a fast-gradient RP-HPLC method for the determination of a chromatographic hydrophobicity index (CHI). An octadecylsilane (ODS) column and 50 mM aqueous ammonium acetate (pH 7.4) mobile phase with acetonitrile as an organic modifier (0-100%) were used. The system calibration and quality control were performed periodically by measuring retention for 10 standards unionized at pH 7.4. The CHI could then be used as an independent measure of hydrophobicity. In addition, its correlation with linear free-energy parameters explained some molecular descriptors, including H-bond basicity/ acidity and dipolarity/polarizability. It is noted [27] that there are significant differences between CHI values and octanol-water log D values. 

The log D value at a single pH is often influenced by ion partitioning, especially at neutral pH where log D may be used in quantitative structure-permeation relationships. Therefore, the lipophilicity profile may be essential to interpreting PK... 

The models developed for log D prediction usually aim at being global ones. This, however, does not work on practice. Sheridan et al. [109] noticed that the accuracy of log D prediction of molecules decreased approximately 2-3 times (RMSE = 0.75 versus 1.5-2) as the similarity of the test molecule to the molecules in the training set (using Dice definition with the atom pair descriptors) changed from 1 to 0 (most to least similar). Thus, if a test set molecule had a very similar molecule in the training set, it was possible to accurately predict its log D value. A detailed overview of state of the art methods to access the same problem was published elsewhere [117]. 

Centrifugal partition chromatography (CPC) has been used to characterize the partitioning behavior of hydrophilic molecules, where log D values as low as —3 can be obtained [371,377-379]. It is not as popular a method as it used to be, apparently due to instrumental challenges. Cyclic voltammetry (CV) has become the new method used to get access to very low log D values, with partition coefficients reported as low as —9.8 [261,269,362]. 

The shake-flask method has some drawbacks, however. One problem that occurs occasionally is the formation of micro-emulsions which remain stable for hours or days, and prevent the two solvent layers from separating. In this case it is not possible to measure the concentration of analyte in each phase. More generally, the upper and lower range of log D values is limited by problems of solution handling. For very high log D values the sample is much more soluble in octanol than in water. For example, if log D is 4 the sample is 10,000 times more soluble in octa-... 

Another source of high-quality measurement of log D values, though only for ion-izable drugs, is the pH-metric method. In this method, log P is calculated from the difference between the apparent pKa (p0Ka) measured in a dual-phase system, the volume ratio of the phases and the aqueous pKa. First described 50 years ago [8], this method was overlooked until the early 1990s, when it was developed at Sirius as the basis for log P measurement in the GLpKa instrument. The pH-metric method has been extensively described [9-13]. 

Approximately 300 drugs were tested in aqueous solubility, log D, and apparent permeability assays. Compounds having low values for solubility, or apparent permeability, or extreme log D values were flagged. The frequency of compounds with flags in each human absorption (%) bin is shown. 

In the design of new compounds as well as the design of experimental procedures an a priori calculation log P or log D values may be very useful. Methods may be based on the summation of fragmental [40-42], or atomic contributions [43-45], or a combination [46, 47]. Reviews on various methods can be found in references [40,48-51]. Further approaches based on the used of structural features have been suggested [48,... 

Another example of the relationship between log D values and intestinal absorption is taken from reference [1] (see Figure 3.4). Compounds with log D > 0 demonstrate a nearly complete absorption. Two exceptions are compounds with a MW above 500. Whether size as such, or the accompanying increase in the number of H-bonds, is responsible for poorer absorption is not fully understood. 

To use Fig. 21.7, one plots the values of log dm on the same scale, although not necessarily on the same range as the Hull-Davey chart using a sheet of tracing paper. Place this paper parallel to each axis until all the observed log d values fall on the chart [3]. The indices of the lines are the h, k, and / indices of the corresponding spots [3], The log d value corresponding to the 1,0 line is log a, whereas log b is 0,1[3]. 

FIGURE 5.14 Experimental versus predicted log D values for 21 designed monoamides.14... 

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