Octanol water-saturated, titration

Scherrer, R. A. Crooks, S. L., Titrations in water-saturated octanol A guide to partition coefficients of ion pairs and receptor-site interactions, Quant. Struct.-Act. Relat. 8,59-62 (1989). 

The use of distribution coefficients for the QSAR treatment of ionizable compounds has been extended to consideration of ion-pair partitioning into biolipid phases. Two experimental methods for determining ion-pair partition coefficients are described. One is a single-phase titration in water-saturated octanol, in which case (for acids) log Pj = log P + pKa - pKa. The other is a two-phase titration (octanol/water) from which the ratio (P + 1)/(Pj + 1) can be calculated. An example outcome is that the uncoupling activity of phenols can be represented by an equation in log instead of log D and pKa. 

We decided to try a direct titration in water-saturated octanol. What we hoped to achieve, if not duplicating literature values, was to obtain partition coefficients proportional to "true" values so that regression analyses could be run and would be meaningful. Secondly, this should be a rapid method to assess structural features in a series for their effect on ion-pair partitioning. 

The advantages of the coulometric method are its simplicity of operation, its increased sensitivity, and the fact that it does not require a standardized reagent, such as water saturated 1-octanol, to calculate the water content but only to assess the accuracy of the instrument. The advantage of the volumetric method is that it permits the use of a wider range of very polar solvents as well as nonpolar solvents for dissolving the sample in the titration vessel. Furthermore, the volumetric titration vessel can be heated to enhance the dissolution of slightly soluble samples. Either the volumetric or the coulometric titration instrument can be joined with an oven (evaporation) or a distillation apparatus (azeotropic distillation). In this configuration, the moisture that is volatilized from the sample can be transported to the titrator with a dry gas and the evaporated water measured either coulometrically or volumetrically. The recent... 

The most common method for determining partition and distribution coefficients is the shake flask method. In this technique, the candidate drug is shaken between octanol (previously shaken together to presaturate each phase with the other) and water layers, from which an aliquot is taken and analyzed using UV absorption, HPLC or titration. In terms of experimental conditions, the value of the partition coefficient obtained from this type of experiment is affected by such factors as temperature, insufficient mutual phase saturation, pH and buffer ions and their concentration, as well as the nature of the solvents used and solute examined (Dearden and Bresnen 1988). 

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