Calculation of partition coefficient of an unstable compound using kinetic methods.

A stirred transfer cell containing equal volumes of light liquid paraffin and an aqueous phase at 37 degrees was used to demonstrate the feasibility of calculating the partition coefficient of an unstable compound by kinetic analysis. Cyclohept-2-enone was chosen since it is a neutral molecule and, therefore, should have a pH-independent oil-water partition coefficient, KD. Moreover, this cyclic alpha, beta-unsaturated ketone undergoes hydrogen-ion-catalyzed hydration but is sufficiently stable at neutral pH to determine KD. The model system chosen represents first-order transfer between the aqueous (C1) and organic (C2) phases with simultaneous, reversible, first-order hydration. The transfer constants k'12 and k'21, were determined at 37 degrees in the absence of degradation where asymptotic values for C1 agreed with the observed equilibrium values in nonkinetic partitioning studies. The first-order rate constants for hydration in 0.1 N HCl were determined at 37 degrees in the absence of the organic phase. Partitioning with simultaneous hydration when was studied using 0.1 N HCl and light liquid paraffin. Data were analyzed by nonlinear regression based on the equation for C1 as a function of time. The values for k'12 and k'21 from these experiments were comparable to the estimates obtained under stable conditions. This agreement demonstrates that simultaneous degradation and partitioning can be analyzed for k'12 and k'21, thus permitting calculation of the partition coefficient (i.e., KD = k'12/k'21) that would be observed if the drug were stable.