Nuclear Magnetic Resonance Method for Measuring Water Solubility of Organic Compounds

Water solubility measurements are required in drug discovery, in toxicological or environmental studies, and in developing industrial processes which employ extractions or crystallizations. The gold-standard shake-flask method is tedious and takes at least 24 h. We developed a nuclear magnetic resonance (NMR) method for automation, which has the same accuracy and solubility range as the shake-flask method, but a measurement can be made faster, since the analysis does not require separation of the phases. Samples of saturated solutions are analyzed in the presence of excess solute, since the NMR spectra do not show signals for the dispersed solids, and they tend to show separate signals for the dissolved and dispersed liquids. Spectra are acquired with water suppression, using a pulse sequence appropriate for quantitation. A sample of water is used as the external reference, and the concentration of the solute is determined using the PULCON relationship. An evaluation of the method in terms of selectivity, accuracy, precision, and limit of quantitation is presented in detail.

Automated summary

Water solubility measurements are essential in drug discovery, toxicological or environmental studies, and industrial processes. We developed an automated NMR method that provides accurate results with a wide solubility range, and it is faster than the traditional shake-flask method. By analyzing saturated solutions with excess solute, the NMR spectra can distinguish between dissolved and dispersed liquids. Evaluation of the method's selectivity, accuracy, precision, and limit of quantitation is presented.