Thermodynamic solubility measurement without chemical analysis

Abstract

In this work, the optical imaging based single particle analysis (SPA) and the gold standard shake-flask (SF) solubility methods are compared. We show that to analyze pharmaceutical compounds spanning 7 log units in solubility and a diverse chemical space with limited resources, several analytical techniques are required (HPLC-UV, LC-MS, refractometry and UV–Vis spectrometry), whereas solely the SPA method is able to analyze all the same compounds. SPA experiments take only minutes, while for SF, it may take days to reach thermodynamic equilibration. This decreases the time span needed for the solubility experiment from initial preparations to obtaining the result from roughly three days to less than three hours. The optimal particle size for SPA ranges from approximately one to hundreds of microns. Challenges include measuring large particles, very fast dissolving compounds and handling small sample sizes. Inherent exclusion of density from the SPA measurement is a potential source of error for compounds with very low or high density values. The average relative difference of 37 % between the two methods is very good in the realm of solubility, where 400 % interlaboratory reproducibility can be expected.