Chloroform/water partitioning

Cieplak, P., Caldwell, J. W., Kollman, P. A., Molecular mechanical models for organic and biological systems going beyond the atom centered two body additive approximation aqueous solution free energies of methanol and IV-methyl acetamide, nucleic acid base, and amide hydrogen bonding and chloroform/water partition coefficients of the nucleic acid bases, J. Comput. Chem. 2001, 22, 1048-1057... 

Table 11.3 Absolute free energies of solvation (kcal mol ) and chloroform/water partition coefficients (logio units) for nucleic acid bases at the SM5.4/AM1 Icvcf ...

The similar accuracies of different well-parameterized continuum models implies that they will also perform similarly for the computation of partition coefficients, and that has proven to be the case in most studies to date (see, for example, Bordner, Cavasotto, and Abagyan 2002 and Curutchet et al. 2003b). In Table 11.4 the previously presented SMx results for the chloroform/water partitioning of die methylated canonical nucleic acid bases are compared to results from die MST-ST/HF/6-31G method, and also to purely electrostatic results obtained using a multipole expansion SCRF method. As the latter does not include any accounting for non-electrostatic effects, its performance is significantly degraded compared to the other two. 

When measured at a temperature of 25°C, the ethyl ether / water partition coefficient of mandelic acid was reported as log P = 0.137 [7]. The chloroform / water partition coefficient at the same temperature was reported as -1.32, demonstrating the hydrophilic nature of the compound. 

Mechanical Models for Organic and Biological Systems Going Beyond the Atom Centered Two Body Additive Approximation Aqueous Solution Free Energies of Methanol and N-Methyl Acetamide, Nucleic Acid Base, and Amide Hydrogen Hydrogen Bonding and Chloroform/Water Partition Coefficients of the Nucleic Acid Bases. 

Glyceryl trinitrate, a volatile dmg with a chloroform/water partition coefficient of 109, diffuses from simple tablet bases into the walls of plastic bottles and into plastic liners used in packaging tablets. This partitioning can be prevented if there is included in the tablet formulation an agent (such as polyoxyethylene glycol) which complexes with the dmg substance, thereby increasing its affinity for the tablet phase - in other words, reducing its... 

In 1899 Overton (13) and Meyer (1 ) correlated narcotic activity with lipid solubility (chloroform-water partition coefficients) of a wide variety of non-ionized compounds. They found that narcotic activity increased with increasing lipophilicity until lipid solubility became so high that the substance was virtually water insoluble. They also found that these compounds penetrated tissue cells as though the membranes were lipid in nature. This is the first reported correlation between partition coefficients and biological activity. A second major development in QSAR occurred in 1939 when Ferguson (15) was able to calculate toxic concentrations of a series of compounds from solubility and vapor pressure data. 

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. 

Avdeef, A. Barrett, D. A. Shaw, P. N. Knaggs, R. D. Davis, S. S.,Octanol-, chloroform-, and PGDP-water partitioning of morphine-6-glucuronide and other related opiates, J. Med. Chem. 39, 4377 1381 (1996). 

A second physicochemical parameter influencing chemical penetration through membranes is the relative lipid solubility of the potential toxicant that can be ascertained from its known partition coefficient. The partition coefficient is a measure of the ability of a chemical to separate between two immiscible phases. The phases consist of an organic phase (e.g., octanol or heptane) and an aqueous phase (e.g., water). The lipid solvent used for measurement is usually octanol because it best mimics the carbon chain of phospholipids, but many other systems have been reported (chloroform/water, ether/water, olive oil/water). The lipid solubility and the water solubility characteristics of the chemical will allow it to proportionately partition between the organic and water phase. The partition coefficients can be calculated using the following equation ... 

Thus, Caverley and Unwin [158] have described a rapid and sensitive technique for the determination of residues of the fungicides, furalaxyl and met-alaxyl in plants. Plants are macerated with acetone and after filtration and dilution with water, partitioned with chloroform. The extracts are subjected to GC with a nitrogen-specific detector after removal of chloroform and dissolution in acetone. Recoveries are generally better than 80%, with detection limits of 0.1 mg/kg for lettuce. 

Most log P values are determined with 1-octanol as the nonpolar solvent. Sometimes octanol-water partition coefficients are denoted Pow to make the nonpolar solvent more explicitly clear. Octanol effectively imitates many lipid membranes, especially those in the small intestine, where most drugs are absorbed. Other solvents are better suited to model other tissues in the body. Chloroform is more polar than octanol and simulates partitioning in oral tissues. Olive oil is less polar than octanol and models the blood-brain barrier. 

Table 1.2 Comparison of barbiturate absorption in rat colon and partition coefficient (chloroform/water) of undissociated drug.

The concentration of the weak acid or of the weak base can be determined by distribution between water and another solvent, such as benzene or chloroform the partition coefficient of the acid or base between the water and the other solvent must, of course, be known. The degree of hydrolysis may then be calculated from the concentration of the salt and the determined concentration of the weak acid or base. An example of such a salt is aniline hydrochloride. This is partially hydrolysed into aniline and hydrogen chloride. On shaking the aqueous solution with benzene the aniline will distribute itself between the water and benzene in the ratio of the distribution coefficient. The initial concentration of aniline hydrochloride is known, the concentration of the free aniline in the aqueous solution can be computed from that found in the benzene solution, and from this the total concentration of aniline, produced by hydrolysis, is deduced. Sufficient data are then available for the calculation of the degree of hydrolysis. 

Membranes Inhalation anaesthetics (diethylether, chloroform, and their more modem replacements). The mode of action of these was enshrouded in mystery for a long time, but accumulating evidence now supports direct interaction with several ion channels. Nevertheless, there is a remarkably close correlation between the ability of these agents to partition into lipid membranes, as measured by their oil-water partition coefficients, and their narcotic activity so, in a sense, cell membranes may be considered the targets of these agents. 

Passive diffusion of sulfonamides into human red cells is determined by plasma dmg binding and lipid solubility. Apparent partition coefficients between chloroform and water at pH 7.4 show an almost linear relation with penetration constant for sulfonamides and a number of other acids. Penetration rates of sulfonamides into the aqueous humour and cerebrospinal fluid also correlate with partition coefficients (Fig. 5.11) moreover, as can be seen from the data in Fig. 5.12, the antibacterial effects of fatty acids and esters towards B. subtilis correlate with octanol/water partition coefficients. 

Before the advent of commercially available methods, it was common to use two-phase, liquid-liquid partition with organic solvents and solvent mixtures, including methylene chloride, hexane, diethyl ether, ethanoi/chloroform/water, methylene chloride/methanol, hexane/isopropanoi, and cydohexane/ethyl acetate. Ethanol and methanol... 

Moreover, A log P was proposed as a molecular descriptor for modeling hydrogen bonding capacity it corresponds to the difference between the partition coefficient experimentally determined in octanol/water (log Pow) and partition coefficients determined in other systems, such as octanol/water-heptane/water (logPaijj) systems and octanol/water-chloroform/water (log PCH3C1) systems [El Tayar, Tsai et al, 1991b Winiwarter, Ax et al., 2003]. 

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. 

During the bioactivity-guided fractionation of an MEK extract, it was first partitioned between hexane and 80% aqueous methanol. Water was then added to the 80% aqueous methanol fraction to give 60% aqueous methanol and this was extracted thoroughly with chloroform. If the bioactive compounds were not extracted with chloroform the aqueous layer was subsesquently extracted with ethyl acetate. If a methanol extract was found to be active it was first subjected to an rr-butanol/water partition. The n-butanol layer, which usually contained the active compound(s), was then evaporated and treated in a manner similar to that used for an MEK extract described above. 

Table 9.3. Comparison of Barbiturate Absorption in Rat Colon and Partition Coefficient (Chloroform/Water) of Undissociated Drug...

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