Evaluating a Crystal Energy Landscape in the Context of Industrial Polymorph Screening

Abstract

To evaluate how the calculation of a crystal energy landscape can be used in the solid-form screening of pharmaceuticals, a Knowledge Transfer Secondment between GlaxoSmithKline (GSK) and University College London was established to carry out computational crystal structure prediction (CSP) and further guided experimentation on a molecule from GSK’s compound collection. The molecule chosen was 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)methyl]oxy)phenyl)methyl]-2-pyridinecarboxylic acid (GSK269984B) since the preliminary thermodynamic form screening had only identified one anhydrate, Form I. The calculations confirmed that Form I is the most thermodynamically stable form. The thermodynamically competitive computed structures all had very different conformations of GSK269984B, and further experiments were designed to attempt to generate these conformations in solution and hence the crystalline solid. The experimental screening generated four novel solvates which all eventually transformed to Form I, two of which could also be structurally characterized by single crystal X-ray diffraction. The molecular conformation (apart from the position of the polar proton) in all three crystal structures was, however, very similar. GSK269984B appears to have an unusually small number of solid forms because there is no kinetic barrier to crystallizing in the most stable conformation which corresponds to the most thermodynamically stable and densely packed structure.