Lipophilic solvent systems

Examples of how the first condition can be met are given in Table II, which lists the slopes and intercept values of each equation of type (1) relating the least lipophilic solvent systems to octanol/water. The number of solute P values used to establish each equation is listed under... 

If hydrogen bonding could be accounted for separately, all of the slopes in the equations comparing the lipophilic solvent systems to octanol would be close to 1.0. For example, cyclohexane values correlate poorly with octanol values when all solutes are taken together. Even for phenols within the H-donor group, the correlation coefficient is only 0.76. However, if we add a log term which measures the hydrogen bonding capability of phenols (5), the correlation coefficient increases to 0.98 and the slope becomes 1.0. 

B In the lipophilic solvent system 2 the green-blue fluorescent ononin (Tl) remains close to the start additional blue fluorescent zones are found in the Rf range 0.2-0,45, The terpenes migrate to the lower R, range, detectable after treatment with the AS reagent. 

Very lipophilic bitter principles, such as quassin, absinthin and cnicin migrate unresolved up to the solvent front in screening system A a lipophilic solvent system is appropriate. 

Classification is possible after chromatography in the lipophilic solvent system toluene-ethyl acetate (93 7)... 

TLC-fingerprint analysis in a more lipophilic solvent system for the detection of terpenoids of essential oils and fatty acids ... 

As chronicled by Dearden [21], the association of compound lipophilicity with membrane penetration was first implied by Overton and Meyer more than a century ago. To enhance this understanding, lipophilicity measurements were initially performed using a variety of lipid phases [22], while the comprehensive review by Hansch et al. [23], with extensive data from literature and their own measurements, lent further support to the now accepted wide use of the octanol-water solvent system. 

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

The pH-metric technique used to determine partition coefficients was first used in the 1950s in solvent extraction of metal complexes [280-282], but it is in pharmaceutical research that it is most widely used thanks to the recent development of a fully automated and computer-controlled apparatus [125,283]. The potentiometric approach has been validated in various solvent systems [284-287], and it has become a relevant and expanding experimental technique to obtain lipophilicity descriptors [257,287-289]. 

Of particular interest when considering ionizable compounds is the difference of lipophilicity between the neutral species and one of its ionic forms, because ionization dramatically alters intramolecular interactions (such as electronic conjugation, internal ionic and hydrogen bonds, polarity, hydrophilic folding, and shielding). In a given solvent system, diff (log is approximately constant for compounds with similar chemical... 

QSARs based on ionic compounds have thus been dramatically restricted due to the neglect of ion partitioning, which consequently meant that no technique was dedicated to such measurements and that modeling never took account of ionic species. To become fully accepted, potentiometry and electrochemistry at the ITIES need now to prove interesting in QSARs. As numerous lipophilicity data of ionizable compounds become available, one can expect that solvatochromic equations for ions will soon be developed in various solvent systems, which would greatly facilitate QSAR studies. 

Most small organic molecules are soluble in mixed organic-aqueous solvents and can be easily analyzed using RPLC. However, there are some polar compounds which are not soluble in typical RPLC solvent systems or are unstable in an aqueous mobile phase system. These compounds can be analyzed on an RPLC column with a nonaqueous solvent system. This technique is called "nonaqueous reversed phase chromatography" (NARP).20-21 The NARP technique is primarily used for the separation of lipophilic compounds having low to medium polarity and a molecular weight larger than... 

Caron, G. Steyaert, G. Pagliara, A. Reymond, F. Crivori, P. Gaillard, P Carrupt, P.-A. Avdeef, A. Comer, J. Box, K. J. Girault, H. H. Testa, B., Structure-lipophilicity relationships of neutral and protonated P-blockers. Part I Intra and intermolecular effects in isotropic solvent systems, Helv. Chim. Acta. 82, 1211-1222 (1999). 

Since 1-octanol has certain limitations (see Section 1.3) many alternative lipophilicity scales have been proposed (see Figure 1.8). A critical quartet of four solvent systems of octanol (amphiprotic), alkane (inert), chloroform (proton donor) and propy-... 

Among the large number of existing lipophilicity parameters [31], the descriptor frequently estimated by in silica methods is the partition coefficient of a solute between 1-octanol and water, expressed as log Poet [32]. However, lipophilicity determination in different solvent systems, such as alkane/water system, proved its utility in (Q)SAR studies and therefore some predictive methods also emerged in this field. Many publically available databases include numerous experimental values collected through the literature the quality of the experimental data represents the cornerstone of most of the models developed to predict lipophilicity. 

Different balance between intermolecular forces can be accessible via partition coefficients measured in solvents systems other than the traditional 1-octanol/water. Therefore there was a growing interest in the partition processes in several solvent/ water systems [64, 65] and in particular the critical quartet of solvents which was designed to merge the main information about a solute concerning its partition and transport. Only a few studies have been performed to characterize the lipophilicity profile of new chemical entities in different solvent/water systems and consequently the number of methods attempting to model such partitioning systems is limited. 

System 2 is quite non-polar and useful for discriminating between highly lipophilic bases, which include many of the antihistamines and narcotics, and sympathomimetic bases, which are often quite polar and move very little in mobile phase 2. The use of selective solvent systems is often combined with use of location agents that are selective for nitrogenous drugs. 

To design for selectivity, then, one should follow the relationship between selectivity and the difference in log P between two relevant solvent systems, and maximize this difference by choice of appropriate substitution. Young et al. (1988) have made use of A log P between octanol and cyclohexane systems to model successfully accumulation in brain tissue, giving support to this new, QSAR-based approach to selectivity enhancement. Related to this approach is the older and well-established principle that for keeping drugs away from the CNS, one should design them to have lipophilicity either much less than, or much greater than, a log P value of 2.0 in the octanokwater system (Hansch et al., 1987 see also Section 2.3.1). 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

Denmark has developed a practical dioxirane-mediated protocol for the catalytic epoxidation of alkenes, which uses Oxone as a terminal oxidant. The olefins studied were epoxidized in 83-96% yield. Of the many reaction parameters examined in this biphasic system, the most influential were found to be the reaction pH, the lipophilicity of the phase-transfer catalyst, and the counterion present. In general, optimal conditions feature 10 mol% of the catalyst l-dodecyl-l-methyl-4-oxopiperidinium triflate (30) and a pH 7.5-8.0 aqueous-methylene chloride biphasic solvent system [95JOC1391]. 

Experimental results suggest that hydrophillic proteins tend to be solubilized within the water core of the reversed micelles, while lipophilic biomolecules can either stay in the interface or even partially exposed to the organic phase.45 Because of the protection offered by the reversed micelles, proteins were shown to maintain their functional properties.47 The retention of bioactivity depends strongly on the solvent system and it is usually not 100%.45... 

The next important step is to establish some sort of lipophilic order in the solvent systems. At one time or another, various parameters have been proposed for such a scale—dipole moment, dielectric constant, solubility parameter, among others. For this particular application, we found that the solvents lipophilic character could be measured by its inability to accommodate water molecules—i.e.y lipophilicity of a solvent can be measured by the reciprocal of the concentration in moles/liter of dissolved water at saturation. 

Table I shows that when the solvent systems are ordered in this way, the primary butanols are the least lipophilic and oleyl alcohol is the most lipophilic of the solvents in the left column. Up to this point, the partition coefficients of various solutes are accommodated by Equation 1. The separation of the solvents in the right-hand column as more lipophilic is somewhat arbitrary, of course, but the partition coefficients measured in these systems are poorly correlated with any of the systems in the left column and generally cannot be correlated well with each other.

A linear relationship between log P s will exist if one of two requirements is met the primary solvation forces in the two solvent systems can be so similar that a variety of lipophilic and hydrophilic solute groups are accommodated proportionately, or the structural differences in the solute set being considered are such that one of the right hand terms in Equation 2 is essentially constant. The latter condition often applies to a homologous series where the hydrophilic group (an OH or C02H) contributes a constant component to the total transfer free energy. 

The data in Table VI show how the intercept value for each of the donor equations can also be used as a measure of the lipophilicity of the solvents. The intercept in the equation for any solvent system is the log F in that system for any solutes which are distributed equally between water and octanol—i.e., solutes where log F(0ct) = 0. Therefore, a negative intercept means the solvent is more lipophilic than octanol, and a positive intercept means it is less lipophilic. This is more apparent when considering a homologous series—e.g., the carboxylic acids as shown in Table VI. 

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