Solubility measurement of polymorphic compounds via the pH-metric titration technique

In drug development, the thermodynamically most stable form of a compound is preferred because metastable forms are prone to transform to the stable form during processing, formulation, or storage [Guillory, J.K., 1999. Generation of polymorphs, hydrates, solvates, and amorphous solids. In: Brittain, H.G. (Ed.), Polymorphism in Pharmaceutical Solids. Marcel Dekker, New York, pp. 183–226]. It is therefore important to discover and characterize the stable form as early as possible. One of the most important properties to determine is thermodynamic solubility. However, due to compound and time constraints this solubility value is usually not determined until late in discovery. This report explores the ability of the pH-metric titration method to measure intrinsic solubility of the stable form of compounds that exist in one or more polymorphic forms. One metastable form and the stable form of eight compounds were examined. Intrinsic solubility was measured via pH-metric titration. The technique was performed on a larger scale in order to monitor polymorphic form changes by powder X-ray diffraction. Shake-flask solubility and corresponding X-ray diffraction data of each form was also determined. The results of this study indicate that, in general, when starting with a metastable polymorph, the pH-metric titration method is able to achieve the solubility of the stable form by the third titration, while the traditional shake-flask solubility method is unable to consistently determine the stable form solubility.