Cyclohexane/water partitioning system

Octanol-water log P values and the substituent constant n values derived from them have been covered in detail in the previous chapter by A1 Leo. It is of course undeniable that these descriptors have been hugely successful, but they are not the only partition coefficients that can be useful in describing molecular properties. The difference between octanol-water and cyclohexane-water partition coefficients (Alog P) has been shown to be useful in describing brain penetration, and it was proposed that a set of partition coefficients from four different partitioning systems would provide useful, complementary information in order to describe the properties of real membranes. The four partition systems involved water with the following second phases ... 

The quantitative descriptor of lipophilicity, the partition coefficient P, is defined as the ratio of the concentrations of a neutral compound in organic and aqueous phases of a two-compartment system under equilibrium conditions. It is commonly used in its logarithmic form, logP. Whereas 1-octanol serves as the standard organic phase for experimental determination, other solvents are applied to better mimic special permeation conditions such as the cyclohexane-water system for BBB permeation. Measurement of log P is described in Chapters 12 and 13 as well as in Ref [22]. 

The absolute solubilities and the partition coefficients of pheno-thiazine and of some of its derivatives in the systems heptane-water and cyclohexane-water have been determined. ... 

In the past 35 years or so, 1-octanol-water has been the most commonly used solvent system. It has been shown that for correlation with biological activity, organic solvents (such as 1-octanol) capable of forming hydrogen bonds usually givebetter correlation than those not capable (e.g., CCI4, cyclohexane, and other hydrocarbons). Extensive compilations on 1-octanol-water partition coefficient are available. 

Selection of the octanol-water system is often justified in part beeause, like biological membrane components, oetanol is flexible and contains a polar head and a nonpolar tail. Hence, the tendency of a drug molecule to leave the aqueous phase and partition into oc-tanol is viewed as a measure of how efficiently a drug will partition into and diffuse across biological barriers such as the intestinal membrane. Although the octanol-water partition coefficient is, by far, most commonly used, other solvent systems such as cyclohexane-water and chloroform-water systems offer additional insight into partitioning phenomena. 

Despite some good correlations with in vivo pharmacokinetics [105], log Pa/w seems to have only a limited performance in predicting brain-blood concentrations (log BB) [106— 109] or oral drug absorption [110]. The octanol-water system still has no serious rival, but alternative partition systems that might give a better description have been suggested and investigated. Notable attempts include the use of cyclohexane-water [111-113] or the use of A log P between octanol-water and cyclohexane-water [109,114,115]. 

Principles of Use. Solvent/water partition coefficients (Ksw) have been measured for numerous solutes in a targe variety of solvent systems. These K w values, like Kow, have found wide use in structure-activity correlations, especially for pharmaceuticals. Some of the more frequently used organic solvents are ethyl ether, n-butanol, chloroform, cyclohexane, benzene, and vegetable oils. In analogy with Eq. 1-1, KsW is defined as the ratio of the solute s concentration in the organic phase to that in the aqueous phase of the two-phase system at equilibrium. Low solute concentrations are employed in the measurement. 

Nonaqueous partition systems are for compounds which are slightly water-soluble but too polar for reversed-phase systems. The Bush and Zaffaroni systems for separation of steroids are included here. Polar stationary phases such as methanol-water [28], DMF, formamide or propylene glycol [29,30] combined with a suitable less polar mobile phase such as benzene, cyclohexane or CHCI3 are examples. 

A column partition chromatographic procedure for triamcinolone acetonide and related steroids has been worked out by Poet31, following essentially the procedure described by Smith et. al.13 The samp] e (40 mg) is fractionated on Celite (25 g) using a dioxane cyclohexane 2-methoxyethanol water 40 80 10 8 solvent system, followed by a methanol strip. The ultraviolet absorption of the eluate is monitored, and individual fractions are quantitated with isonicotinic acid hydrazide. The order of elution is 1,2-dihydrotriamcinolone acetonide, triamcinolone acetonide and finally triamcinolone (in the methanol strip). 

Figure 1 shows the aggregation behavior of AOT in liquid cyclohexane and supercritical fluid ethane. The systems are one-phase without added water. Surfactant aggregation is indicated by the solvatochromic probe pyridine A -oxide. Pyridine A -oxide was used because of its small size and large dipole moment (/x = 4.3 D), which allow it to partition to the center of reverse micelles instead of being trapped at the surfactant interface. This molecule is a blue shift indicator in that its U V absorption maximum shifts to lower... 

While it is fully miscible with water in all proportions, the partition coefficient in ternary mixtures of n-propanol with water and a possible entrainer such as cyclohexane or benzene is favourable to the hydrocarbon phase (Table 16.3). The lower values of partition coefficient are for those systems in which it is more likely to be economically advantageous to recycle part of the potential reflux to a phase separation with the feed. 

Figure 5.69 Experimental [3] and calculated partition coefficients of ethanol In the system water(l)-ethanol(2)-cyclohexane(3) at 298.15 K using UNIQUAC...

Since vitamin D and its metabolites are fat-soluble sterols, partition into organic solvents provides significant purification by removal of water-soluble contaminants. Solvent systems for extraction fall into two basic categories (see Table 4) [1] total lipid extraction, for example, methanol-chloroform-water (2 1 0 8) (83) or ethanol-water (9 1) (84), and [2] selective lipid extraction, for example, ether, ethylacet-ate-cyclohexane (1 1), hexane, dichloromethane, or hexane-isopropanol (1 2). 

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