Towards the improvement of physicochemical properties of Tolvaptan via crystal engineering

Abstract

The aim of this study is to alter the physicochemical properties (e.g. solubility, and melting point) of tolvaptan (Samsca庐) an oral non-peptide arginine vasopressin V2 receptor antagonist via crystal engineering methods. In this thesis, the solubility of tolvaptan in water was altered by the employment of crystal engineering methods including the screening for polymorphs, solvates and cocrystals. Cocrystal screening by liquid assisted grinding identified L-malic acid as a possible cocrystal former with tolvaptan. Polymorph screening identified a number of solid forms having different melting points. Powder X-ray diffraction analysis still needs to be carried out to confirm the identity of these forms. Solid-solid transformations observed by thermal microscopy have been linked to changes in the conformation of the saturated part of the benzazepine fragment. This can be used as a solvent free pathway to access new polymorphs.