Lipophilicity Systems

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic (= fat-loving) environment and is commonly measured by the partition coefficient, (where aaa represent a generic biphasic system, e.g. oct indicates the standard octanol-water). P is valid for a single electrical species, to be specified (P for neutral forms and P for ionized species). The distribution coefficient, expressed as is a pH-dependent descriptor (Eq. 3) for ionizable solutes and results from the weighted contributions of all electrical forms present at this pH  

Energy decomposition based on BLW-ED theory [5]. Average number of molecules able to form H-bonds with the ion considered. 

Contribution of solvent and solute polarization to overall polarization effects showing that polarization of the solvent is the main effect but the solute itself is polarized by the aqueous environment. 

Electron flow across the solute-solvent surface. 

lipophilicity can be determined in many systems that are classified by the characteristics of the nonaqueous phase. When the second phase is an organic solvent (e.g. n-octanol), the system is isotropic, when the second phase is a suspension (e.g. liposomes), it is anisotropic, and when the second phase is a stationary phase in liquid chromatography, it is an anisotropic chromatographic system [6]. Here, we discuss the main aspects of isotropic and anisotropic lipophilicity and their biological relevance the chromatographic approaches are investigated in the following chapter by Martel et al. 

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The formation of nitrosamines in aprotic solvents has applicability to many practical lipophilic systems including foods (particularly bacon), cigarette smoke, cosmetics, and some drugs. The very rapid kinetics of nitrosation reactions in lipid solution indicates that the lipid phase of emulsions or analogous multiphase systems can act as "catalyst" to facilitate nitrosation reactions that may be far slower in purely aqueous media (41, 53, 54). This is apparently true in some cosmetic emulsion systems and may have important applicability to nitrosation reactions in vivo, particularly in the GI tract. In these multiphase systems, the pH of the aqueous phase may be poor for nitrosation in aqueous media (e.g., neutral or alkaline pH) because of the very small concentration of HONO or that can exist at these pH ranges. 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

The CLIP approach was developed by the group of Testa [55]. It is based on the atomic lipophilic system of Broto and Moreau [56] and uses a modified exponential distance function of which differs from the e function of Fauchere et al. [45]. In addition the authors restricted the distance function at 4A to avoid influence of too distant elements. The most recent version of CLIP uses a Fermi-like distance function, which does not need any cutoff values [57]. Another implementation of the approach is available in the VEGA software provided by Pedretti et al. [58]. 

The second condition which can permit a linear relationship between log P values is illustrated in the equations in Table III which relate the more lipophilic systems to octanol/water. For the isopentyl acetate and the nitrobenzene systems, the correlation with the octanol system is quite good with a single equation, but the only solute values available were those from a single homologous series (the carboxylic acids), and we predict that a wider selection of solutes would result in a poor correlation. 

Organic-soluble lanthanide chelates have been used to probe lipophillic systems. The compound 4-(4-dipentylamino-( )- S-styryl)-l-(2,2,2-trifluoroethyl)pyridinium perchlorate (22) was employed as a probe in dimyristoylphosphatidylcholine vesicles. Probe molecules assembled in the inner and outer shells of the vesicle as evidenced by the presence of two signals in the NMR spectrum (376 MHz). Even though addition of Eu(fod)3 promoted vesicle fusion, only one of the signals shifted. The shifted signal was likely from the probe molecule on the outer shell, as the internal P signal of the phospholipid did not shift in the presence of Eu(fod)3 ". 

Enhanced drug stability (protection against oxidation, photodegradation, and hydrolysis in lipophilic systems). 

The ability of flavonoids to enhance the resistance to oxidation and to terminate free-radical chain reactions in lipophilic systems can be monitored using low-density lipoproteins (LDL) as a model (Rice-Evans et al., 1996). The LDL oxidation is initiated either by copper or by a peroxyl radical [2,2 azobis(2-amidinopropane hydrochloride) (AAPH)] (Abuja et al., 1998). Hexanal liberated from the decomposition of oxidized n-6 polysaturated fatty acids in LDL may be determined by static headspace gas chromatography (Frankel and Meyer, 1998). Also, bleaching of P-carotene (Velioglu et al., 1998 Fukumoto and Mazza, 2000) and the tracing by HPLC (Fukumoto and Mazza, 2000) of malonaldehyde formed in lipid emulsion systems in the presence of iron (Tsuda et al., 1994) have been used to measure antioxidants in lipophilic systems. 

A survey of acute oral toxicity, as measured by the 50% lethal dose (LD j) test, demonstrated that of4461 colorants tested, only 44 had an LD-,j< 250 mg kg and that 3669 exhibited practically no acute toxicity (LD > 5 g kg ). The rest fell somewhere between these two levels. The evaluation of these colorants by chemical classification revealed that the most toxic ones were found among the diazo (mostly benzidine derivatives) and the cationic dyes. It is widely known that some general cationic compounds have toxic properties. Pigments and vat dyes by comparison were discovered to have extremely low acute toxicity - presumably due to their insolubility/very low solubility in water and in lipophilic systems. 

Organomercury compounds derive their toxicity from their solubility in both aqueous and lipophilic systems. They primarily affect the central nervous system. The reversible ionic/covalent bonding in organomercury compounds distributes them in the body. Thus, water-soluble species such as 3 are converted in the stomach into lipophilic 5 (cf. Eq. 8) X = [N03]-, etc., where they are then absorbed. 

The introduction of low quantities of surfactants (50 to 125 ppm) helps solve these two problems. The surfactant molecule has a lipophilic organic tail and a polar head that is adsorbed selectively on the metal walls of the admission system. These products have a double action ... 

Emulsifiers are classified by the hydrophilic—lipophilic balance (HLB) system. This system indicates whether an emulsifier is more soluble in water or oil, and for which type of emulsion (water-in-oil or oil-in-water) it is best suited. Emulsifiers having alow HLB value are more oil soluble, and are better suited for water-in-oil appHcations such as margarine. Conversely, emulsifiers having a high HLB value are more water soluble, and function more effectively in oil-in-water emulsions such as ice cream (34). The use of this system is somewhat limited because the properties of emulsifiers are modified by the presence of other ingredients and different combinations of emulsifiers are needed to achieve a desired effect. The HLB values of some common emulsifiers are given (35). 

The amino group is readily dia2oti2ed in aqueous solution, and this reaction forms a basis for the assay of sulfas. Aldehydes also react to form anils, and the yellow product formed with 4-(dimethylamino)hen2a1dehyde can be used for detection in thiu-layer and paper chromatography. Chromatographic retention values have been deterrnined in a number of thiu layer systems, and have been used as an expression of the lipophilic character of sulfonamides (23). These values have corresponded well with Hansch lipophilic parameters determined in an isobutyl alcohol—water system. 

Catalyst Cation. The logarithms of extraction constants for symmetrical tetra- -alkylammonium salts (log rise by ca 0.54 per added C atom. Although absolute numerical values for extraction coefficients are vastly different in various solvents and for various anions, this relation holds as a first approximation for most solvent—water combinations tested and for many anions. It is important to note, however, that the lipophilicity of phenyl and benzyl groups carrying ammonium salts is much lower than the number of C atoms might suggest. Benzyl is extracted between / -propyl and -butyl. The extraction constants of tetra- -butylammonium salts are about 140 times larger than the constants for tetra- -propylammonium salts of the same anion in the same solvent—water system. 

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