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

Abstract

The contribution of the CH3 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 CH3 are very similar to those found for the CH2 group. For instance, in partition, the CH3 group contribution (log Fch3) is in the range 0.65 to 0.28 (ΔG = 2.303 RT log Fch3) and is dependent on the polarity of the organic solvent. The contribution for the terminal aliphatic CH3 is not equivalent to the mid chain CH2 and a CH3 correction factor or 1.14 to 1.34 kcalmol−1 (4.77 to 5.61 kJmol−1), 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.