Cyclohexane/water partition coefficient

Dearden JC, Roberts MJ. Cyclohexane-water partition coefficients of some pharmaceuticals. J Pharm Pharmacol 1989 41 102P. 

In this equation Kcw is the cyclohexane/water partition coefficient and IM values are hydrogen bonding corrections for specific functional groups in the solute. The IH values are given in Table 1-10. Note that the correlation coefficient (r) for Eq. 1-38 (0.967) is significantly better than for Eq. 1-7 (0.761) for H donors but is about the same as for Eq. 1-18 (0.957) for H acceptors. 

HPLC/RT = high-pressure liquid chromatography/retention time IH = correction factor for hydrogen bonding in Eq. 1-38 Kcw = cyclohexane/water partition coefficient in Eq. 1-38... 

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 blood-brain barrier penetration of Hj receptor antihistaminics has been correlated with A log P, the difference between n-octanol/water and cyclohexane/ water partition coefficients (eqs. 23 and 24, chapter 3.1) [199, 200]. An even better correlation could be obtained by using Aaik, a hydrogen-bonding capability parameter, and V, the van der Waals volume (eq. 169) [773]. 

The practicality of both approaches is open to question in view of the potential toxicity of the co-solvents and electrolytes. The order of interaction of prostaglandins with the non-ionic surfactant C12E23 was PGEi > PGE2 > PGF2 [220] which corresponds to the order of their cyclohexane/water partition coefficients. 

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. 

The elution strength of hybrid micellar mobile phases was measured for a number of organic additives (alcohols, alkane diols, alkanes, alkylnitriles, and dipolar aprotic solvents, such as dimethyl sulfoxide and dioxane) added to micellar SDS, CTAC, and Brij-SS. Benzene and 2-ethylanthraquinone were used as probe compounds. The presence of alcohols, alkane diols, alkylnitriles, and dipolar aprotic solvents produced a diminution of the retention times, reaching remarkable levels for the most hydro-phobic compound (2-ethylanthraquinone). The observed elution strength order roughly paralleled the octanol-water partition coefficients of the additives, Rq/w (Fig- 2), or their ability to bind to micelles, am- In contrast, alkanes (pentane, hexane, and cyclohexane) had relatively little effect on the retention. 

Elimination of 2,3,3 -trichlorobiphenyl, DDE, and y-hexa-chloro[flflaeee] cyclohexane from larvae of the midge Chironomus riparius was generally greater in sediments with higher organic content, and a significant correlation was found between the rate of elimination and the octanol / water partition coefficient of the compounds (Lydy et al. 1992). 

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. 

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. 

The hydrogen-bonding ability 1 of different functional groups was first defined by Seiler (Table 3) [191] as the difference between cyclohexane/water and n-octanol/water partition coefficients (eq. 22). 

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 concept of measuring such rates is not new, particularly in the pharmaceutical field. Van de Waterbeemd [14] measured rates of transfer of various drugs from octanol to water and empirically related these rates to the partition coefficient. Similarly Brodin [15], using a different experimental method, obtained rates of transfer for another series of compounds between cyclohexane and water. The rotating diffusion cell has been introduced for similar purposes [16-18]. It is necessary to look into the broader background of liquid-liquid interfacial kinetics, in order to illustrate aspects of the issues under consideration. The subject has been reviewed in part by Noble [19]. 

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. ... 

Two-phase experiments. We conducted a photolysis experiment in which 1-naphthol was dissolved in a small amount of cyclohexane and layered over a pH 7 buffer. The partition coefficient for 1-naphthol between these two solvents favored cyclohexane by about 5 1. In this experiment, UV spectral data indicated that to some extent the photoreactions developed product distributions that would have occurred if the other phase had been absent. Thus, in the water layer, which did not contain much 1-naphthol to begin with because of the unfavorable partition coefficient, the usual maximum at 264 nm appeared and increased in intensity as it did in the single-phase aqueous experiments. In the cyclohexane layer, the loss of the 292-nm maximum for l-naphthol was observed as before, but a minor peak at 270 nm could also be observed. Also, the end absorption intensity decreased with time, probably because nonpolar photooxidation products were... 

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. 

The second criterion for the selection of a proper organic solvent was its effects on the enzyme activity and stability. Seven organic solvents were tested, chloroform, cyclohexane, n-hexane, n-octane, isooctane, dodecanol, and n-decane, with logP values of 2.0, 3.2, 3.5, 4.5, 4.5, 5.0, and 5.6, respectively. The logP of a solvent, the logarithm of the partition coefficient of the solvent in a standard mixture of 1-octanol and water, is a parameter often used for predicting its biocompatibility, and is usually more indicative of the dissolved solvent. 

Figure 3.7 Relation between percentage solvent present in a deposited film and the partition coefficient in a cyclohexane/water blend...

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...

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