Studying conformational polymorphism in pharmaceutical solids using multidimensional solid-state NMR and electronic structure calculations

We propose a new method of determining aspects of molecular structure in polymorphic materials by using a combination of multidimensional solid-state NMR and molecular modeling via electronic structure calculations. The methodology is applied to a series of three conformational polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, referred to as the ROY compounds because of their red, orange and yellow colors. Chemical shift and dipolar coupling information obtained from these experiments vary noticeably between forms and is subsequently used to quantitatively determine aspects of local structure in these molecules, including the coplanar angle between the phenyl and thiophene rings. The accuracy of the information obtained from local field analysis and the model structure calculations demonstrates the capabilities of SSNMR as a quantitative structural analysis method