A New Straightforward Method for Lipophilicity (logP) Measurement using 19F NMR Spectroscopy

Summary

A novel and straightforward variation of the shake-flask method was developed for accurate lipophilicity measurement of fluorinated compounds by ¹⁹F NMR spectroscopy.

Abstract

Fluorination has become an effective tool to optimize physicochemical properties of bioactive compounds. One of the applications of fluorine introduction is to modulate the lipophilicity of the compound. In our group, we are interested in the study of the impact of fluorination on lipophilicity of aliphatic fluorohydrins and fluorinated carbohydrates. These are not UV-active, resulting in a challenging lipophilicity determination. Here, we present a straightforward method for the measurement of lipophilicity of fluorinated compounds by ¹⁹F NMR spectroscopy. This method requires no UV-activity. Accurate solute mass, solvent and aliquot volume are also not required to be measured. Using this method, we measured the lipophilicities of a large number of fluorinated alkanols and carbohydrates.

Introduction

Lipophilicity is a key physicochemical parameter of drug molecules which influences the properties of drug candidates in many aspects, including drug solubility, bioavailability, and toxicity¹. Lipophilicity is measured as the logarithm (logP) of the ratio of compound concentrations after partitioning between n-octanol and water. Optimal lipophilicity ranges have been proposed based on statistical data of orally administered drugs, of which the Lipinski's "rule of 5'' is the most famous example^2,3. Indeed, controlling lipophilicity has shown to be essential for ....

Protocol

1. Partitioning

1. Add 4,4,4-trifluorobutan-1-ol (compound X, ca. 6.0 mg) and 2,2,2-trifluoroethanol (reference compound, ca. 3.0 mg) to a 10 mL pear-shaped flask, dissolve in n-octanol (HPLC grade, ca. 2 mL), and add water (HPLC grade, ca. 2 mL).
   Note: This experiment is run in triplicate. Compound solubility in water and n-octanol must be checked. The amount of the compound used for partition must be carefully considered to avoid oversaturation of the compound in any layer. The mass ratio between compound X and reference compound ref must also be considered to avoid that the integral ratios of a given NMR sample are outside a 10/1 t....

Results

Two sets of data as control experiments are shown in Figure 2²¹. Using 2,2,2-trifluoroethanol as reference compound, logP values were obtained for 2-fluoroethanol and 3,3,3,2,2-pentafluoropropanol as -0.75 and +1.20, respectively (Figure 2A). Subsequently, the lipophilicity of 2-fluoroethanol was determined again but with 3,3,3,2,2-pentafluoropropanol as the reference (using its previous experimen.......

Discussion

The protocol described in the paper is a straightforward method for logP measurement of fluorinated compounds. This method is applicable to fluorinated compounds with a logP value from -3 to 3. For more hydrophilic (logP < -3) or lipophilic compounds (logP > 3), this method can still be used but will require much longer NMR experiment time as extended number of transients are needed to obtain a good signal-to-noise ratio. Hence, this is a limitation of the method. There is no r.......

Materials

Name	Company	Catalog Number	Comments
NMR (400 MHz) with Bruker 5 mm SEF probe	Bruker	n/a	AVIIIHD400
NMR (400 MHz) with Bruker 5 mm SMART probe	Bruker	n/a
DrySyn Snowstorm reactor	Asynt	ADS13-S
recirculating chiller	Asynt	n/a	model:Grant-LTC2
magnetic stirplate	Asynt	ADS-HP-NT
ACD/NMR processor software	ACD/Labs	n/a	ACD/NMR processor academic edition or ACD/Spectrus processor 2015