The design and evaluation of an automated drug partitioning system for thermodynamic studies

Abstract

The measurement of partition coefficient data is now a routine part of drug research. Octanol-water partition values are used by Medicinal Chemists in studies on structure activity relations (Hansch Analysis). And in preformulation investigations partition coefficient values are determined at different pH to give insight into the absorption properties of a drug. Partition data also play an important role in the development of a group contribution approach to solution thermodynamics and the prediction of solution properties. The usual method of measuring partition coefficient values is the laborious shake-flask technique. The values determined from such batchwise determinations can be inaccurate and measurements at temperature considerably different to room temperature are often difficult. The derived data cannot normally be used to calculate the thermodynamic quantities; enthalpy and entropy. Consequently the utility of a rapid,continuous method for obtaining accurate partition data has been investigated. A commercially available Swedish apparatus (AKUFVE) has been used in recent years for studying the important factors in solvent extraction.This system has been evaluated using pharmaceutical systems. Briefly it consists of a mixer which provides rapid efficient contact between two immiscible solvents, a unique centrifugal separator that ensures rapid "absolute" separation of the two solvents and connections permitting sampling or on-stream measurement of the concentrations of solute in both solvent phases. Equilibrium is normally attained in a matter of minutes.The experiment conditions can be changed at will with the result that a temperature or pH profile can be determined in a few hours rather than over a period of days. The performance of the AKUFVE has been assessed using a range of compounds (alkyl phenols, weak acids, weak bases) at different solute concentration, temperature, pH, ionic strength, phase ratio. Three different solvents (octanol; cyclohexane; chloroform) and their mixtures have been examined. The derived partition values were compared with experimentally determined or literature values obtained in the conventional way. Ion-pair extraction systems and drugs undergoing simultaneous phase transfer and hydrolysis have also been investigated. The AKUFVE apparatus has been found to provide a rapid and accurate method for determining the partition coefficient values of drug substances in instances where a range of experimental conditions are investigated. For example solute concentration, pH, temperature. It can also be used to measure the partition coefficients of unstable substances. However, it is not suitable for simple routine one-off partition coefficient determination.