LogP values

The flic presented contains 11 data items. The header lines arc property names as used by CACTVS [64, 65], and arc sufficiently self-descriptive. For example, E NHDONORS is the number of hydrogen bond donor.s, E SM1LES" is the SMILES string representing the structure of sulfamidc, and E LOGP is the logP value (octanol/water partition coefficient) for this substance. 

The chromatographic parameters were compared with calculated H2O-u-octanol logP value (2.23) (by CLOGP program) (96JC(A)135). 

Compared to Eq. (2), Eq. (3) shows a slight statistical improvement Also, is has a better predictability for ajb selective ligands, since a hypothetical molecule with very low range logP and sensitivity logP values would be predicted to have a ApJ[Pg.21]

Due to instrumental or laboratory variability, the information given by the experimental gradient retention times (tr) is not sufficient to obtain accurate and repeat-able logP values [38]. As described by Eqs. (4), (6) and (7) the lipophilicity measurement in gradient mode is therefore based on the determination of logfeo and S because both terms are necessary to obtain log few. 

The results obtained in gradient mode by Kaliszan et al. for logkw determination are based on a relatively complex mathematical treatment, using RPLC optimization software. As described, logP values were determined in the range -2correlation coefficient between log k and log P was satisfactory, and included in the range 0.94[Pg.343]

The final log P model was obtained by correlahng a total of 94 parameters with the logP values through MLR analysis. Correchon fragments idenhfied by the CASE program can be classified into four categories (i) tautomerization effects,... 

If during log P calculahon, fragmental or intramolecular interaction contribu-hons are not found in the internal databases, they are calculated by special secondary algorithms. In such cases the calculated logP values are provided with larger uncertainty limits ( 0.6 or greater). 

A. M. On the reliability of calculated logP-values Rekker-, Hansch/Leo- and Suzuki-approach. Quant. Struct.-Act. Relat. 1993, 12, 152-157. 

The 2D model was built from a wide array of descriptors, including also E-state indices, by Simulations Plus [89], The model is based on the associative neural network ensembles [86, 87] constructed from n=9658 compounds selected from the BioByte StarList [10] of ion-corrected experimental logP values. The model produced MAE = 0.24, r = 0.96 (R. Fraczkiewicz, personal communication). 

We also note that many ADME, QSAR or QSPR models, based on experimental or computed parameters, use a combination of log P and partial charges and/or fraction ionized at a given pH, as independent variables, rather than the potentially more physiological log or log values. This tendency may reflect a perceived superiority and accuracy of the logP values, whether computed or experimentally determined, and may also be reflected by the nature of the data stored observed among different industrial settings. 

Fig. 16.3 ionization scheme of niflumic acid (CAS-RN 4394-00-7). The macro- (pfCJ and microprotonation (p(t ) schemes of the compound are shown. The logP value is determined by partition of neutral species (dubbed as NO) only. The microconstants and partition coefficients of each microspecies as well as the nature and the concentration of... 

Comparison of logP values by HPLC with literature [63]... 

As mentioned before, the hydrophobicity and the partition coefficient can be related to the solubility of the solutes in water (also see Section 15.8.4). The partition coefficient (P) between octanol and water can be described as the 7r-constant of Hansch or the logP values of Rekker. The logP values calculated from the fragmental constant are then used for the optimization of RPLC. However, this method is not adequate to develop an optimization system for the mixtures of different types of compounds [71]. 

The function Data EqAH2, m simulates the pH-titration of a weak diprotic acid, AH2, in acid excess, with a strong base. The computation of the equilibria is similar to the examples Eql. m and Eq2. m given in the Chapters Example General 3-Component Titration (p.56) and Example pH Titration of Acetic Acid (p.58). From the present point of view, the important aspect is that all variables are collected in one structure s. The model is now stored in s.Model, the logP values in s. log beta, etc. Importantly, all the information contained in s is returned to the invoking programs. 

The general relationship between the type of solute and its retention can be seen by comparing the retention factors, k, of a set of standard compounds with their octanol-water partition coefficients, i.e. the logP value (listed in Table 4.1), as a measure of their relative solubility in water. The logarithm of the retention factor, log k, of these compounds measured in 50% aqueous acetonitrile on an octadecyl-bonded silica gel column shows a close linear relationship (Figure 4.1). 

Example 1 Separation of an alkylbenzene and an alkyl benzoate. The logP values of butyl benzoate and isopropylbenzene are 3.74 and 3.52, respectively, from Table 4.1. The separation of these compounds in 50% aqueous acetonitrile therefore requires a high plate number column as the log k values will be nearly identical. The most suitable eluent is 40% aqueous THF. See compounds 9 and 19 in Figure 4.3B. 

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 ... 

The difference between the log k values measured and those predicted by Equations 6.1 and 6.2 from log P values calculated by Rekker s hydrophobic fragmental constant was within 5%. An example of logk values obtained experimentally compared with those predicted from Rekker s logP values is shown in Figure 6.2, where the predicted and measured retention factors of aromatic acids are shown. The correlation coefficient was 0.993 (n = 32), and the slope was 1.014. The precision is very high. 

The physicochemical properties of a drag substance must be known and well characterized (e.g., solubility, acidic constant (pKa), distribution coefficient in octanol water (logP value), pH-dependent distribution coefficient (logD), and its physical state, e.g., morphology or salt stochiometry — if the drag forms a pharmaceutical salt). 

TABLE 5 LogP Values Measured by MEEKC vs. Literature Values... 

LogP values of the neutral form and logD values calculated by ACD/LogD Suite (LogD = LogP at physiological pH 7.4 with consideration of charged species). 

Zebrafish embryo assay results were compared to the ToxCast in vitro assay features from the predictive model of developmental toxicity (50). A majority of the features were significant between the zebrafish data and predictive models, despite the fact that the zebrafish assay did not correlate with global developmental toxicity defined by species-specific ToxRefDB data. The top 15 chemicals predicted to be developmental toxicants and bottom 15 chemicals predicted not to be developmental toxicants varied in their endpoint responses and logP values. Padilla et al. (35) noted that chemical-physical characteristics could limit the amount of chemical seen by the embryo due to poor solubility or poor uptake. This may be the reason that a majority of the bottom 15 chemicals with no zebrafish embryo activity had logP values less than 1.0. The bottom 15 chemicals with zebrafish embryo activity could almost exclusively be characterized by the negative predictors of the species-specific developmental toxicity models, which may be indicating that these predictors have differing roles between mammalian and zebrafish development. 

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