Determination of the thermodynamics of the methyl group in solutions of drug molecules

Abstract

The contribution of the CH, group to the solution thermodynamics of drug molecules is dependent on whether it is attached to a ring system or is in the terminal position in an aliphatic chain. In the former case group contributions for CH, are very similar to those found for the CH2 group. For instance, in partition, the CH, group contribution (log FCH,) is in the range 0.65 to 0.28 (AG = 2.303 RT log FCHJ and is dependent on the polarity of the organic solvent. The contribution for the terminal aliphatic CH, is not equivalent to the mid chain CH, and a CH, correction factor or 1.14 to 1.34 kcal mol-l (4.77 to 5.61 kJ mol-l), has been calculated from alkane solubility data and partition studies. The additivity of group contributions and the correct choice of reference state are also discussed.Davis, Higuchi & Rytting (1972) have previously showed that the methylene group contribution to the thermodynamics of solutions of drug molecules could be obtained from activity coefficients, Henry's law constants and partition coefficient data. The free energy of transfer of the CH, group from water to organic solvent ranged from -850 to -450 cal mol-1 (1 cal mol-l = 4.186 kJ mol-l) depending on the nature of the solvent and differences in group values could be rationalized in terms of solvent polarity. In this paper the methyl group is considered.Many authors have assumed that the CH, and CH, contributions are identical (Hansch & Anderson, 1967;Kakovsky, 1957; Hersh, 1971). So that for an alkanol (CnH2n + ,OH)

Headspace concentrations of ethyl esters at different alcoholic strengths

“…For the ester group contribution the two lines have similar gradients (measured [1É16, SD \ 0É08 ; predicted [1É29, SD \ 0É03) but the measured set shows no signiÐcant di †erence for points at 0É5, 5, 10 and 17% ethanol (v/v). The energy contribution of the ester group at 0É5% (v/v) ethanol was calculated to be 6500 Jmol~1, but as calculated this included a correction factor for the end methyl group (Davis 1973a). A mean correction value of 4770 Jmol~1 was obtained from alkane solubility and was considered valid for partition studies provided that they involved reasonably non-polar solvents.…”

Peptide Hydrophobicity and Partitioning in Poly (ethylene glycol)/ Magnesium Sulfate Aqueous Two‐Phase Systems

“…Shanbhag and Axelsson (1975) suggested measuring hydrophobic interactions of proteins in aqueous environments by using aqueous two-phase partitioning. Zaslavsky et al (1978Zaslavsky et al ( , 1981Zaslavsky et al ( , 1984 suggested that the hydrophobic properties of aqueous two-phase systems could be quantified by the use of a AGCH2 value (Davis et al, 1972), which is the free energy of methylene group transfer between the phases. This free energy is a measure of the difference in partition coefficients in a homologous series of compounds between solutes differing in one chain length Both previous studies of peptide partitioning used the PEG/dextran system with an added buffer.…”

Independence of substituent contributions to the transport of small-molecule permeants in lipid bilayer

“…Therefore, they were estimated using the measured value for the unsubstituted compound, p-methylhippuric acid, and the functional group contributions obtained from the bulk solvent/water partition coefficients measured in the p-toluic acid series. The independence of functional group contributions to transfer free energies in bulk solvents is well established (4,5). The values for 4 bulk organic solvent/water systems (hexadecane, hexadecene, 1,9-decadiene, and 1-octanol) are shown in Table 1.…”

“…There is abundant evidence that the independence and additivity of functional group contributions can generally be assumed for bulk phase transfer free energies as determined from organic solvent/water partition coefficients (4,5), provided that appropriate nonadditivity corrections are made to account for chain branching or other steric factors, electronic effects, intramolecular hydrogen-bonding, etc. (6).…”