Solid state studies of pharmaceutically important molecules and their derivatives

Abstract

The research described in this thesis provides important information about the solid state behavior of amides of bile acids with potential pharmaceutical activity. Polymorph/ solvate screening and structural characterization for nine bile acid derivatives consisting of bile acids with varying amounts of hydroxyl groups and a selection of small molecules combined via an amide linkage was performed. Two of the studied compounds were shown to be polymorphic, and hydrates/solvates were identified for six amides. Detailed structural characterization for the isolated solid state forms was performed using a wide selection of experimental methods, including single crystal and powder X-ray diffraction, solid state NMR spectroscopy, optical spectroscopy, and thermoanalytical methods. Information about the solid state structures of molecules with potential pharmaceutical activity is important, since different crystal forms may possess different chemical, physical, and pharmaceutical properties. Infinite crystal calculations were conducted for a series of three nitrogen heterocycles in order to compare the single crystal structures to SS-NMR data. Optimization of hydrogen atom positions was proven to be essential to reproduce the solid state NMR chemical shielding data starting from single crystal X-ray structures. Moreover, the ability of the NMR-CASTEP program to reliably predict SS-NMR chemical shifts for nitrogen heterocycles was demonstrated. Pharmacological applications of aminopyridines, basic aspects of polymorphism and its significance in pharmacology, and analytical methods in crystal form characterization are briefly summarized in the literature review.