The Reversible Proxibarbal‐Valofan Isomerisation. Part I. Kinetic and thermodynamic studies in aqueous solutions

Abstract

The tautomerisation between proxibarbal (I) and the two diastereoisomers of valofan, IIX and IN, was investigated in aqueous solutions, and various rate and equilibrium constants wefe calculated by compartmental analysis. The proportion of I at equilibrium was found to increase with pH, and indeed, the two equilibrium constants are linear functions of pH. In contrast, the equilibrium-concentration ratio of IIY/IIX was close to 63 :37 and remained constant in the pH range investigated. The ratc constants were also determined as a function of temperature, allowing calculation of the thermodynamic parameters. Under physiological conditions, the difference in free energy favouring I us. IIX and IIY is 6.7 and 5.4 kl.mol-', respectively.

The Reversible Proxibarbal‐Valofan Isomerisation. Part II. Kinetic studies in a biphasic octanol/water system

“…-A comparison of the previous [3] and present study reveals some marked differences in the proxibarbal/valofan isomerisation in H,O and octanol/H,O systems. Firstly, the overall rate of reaction is considerably slower in biphasic systems due to partitioning into a solvent where the reaction is very slow.…”

“…In aqueous solutions under physiological conditions, the interconversion reaches a proxibarbal/valofan equilibrium of 84:16 with half-lives in the range 20-40 min [3]. The reaction also occurs in biological systems and is of particular importance for the human metabolism of these drugs [4-71.…”

“…During each experiment, 8-10 tubes were collected at various time intervals and immediately centrifuged at 1000 rpm for 1 min. The phases were then carefully separated, and both were analysed for compounds I, IIX, and IIY as described in [3]. Following the analysis of each octanolic sample, the non-eluted octanol had to be removed by washing the HPLC column with MeOH (1.5 ml/min for 4 min) and reconditioning it with the usual eluent for 10 min.…”

“…four rate constants of isomerisation and six rate constants of partitioning. The ten rate constants were calculated by compartmental analysis of experimental data using the LINDE package as previously described [3]. In a number of cases, the rate constants were repeatedly calculated from the same set of data, starting the optimisation from various initial values.…”