Structural Refinement of Carbimazole by NMR Crystallography.

Andrea Scarperi,Marco Geppi,Francesca Martini,Elisa Carignani,Aleksandra Pajzderska,Giovanni Barcaro

doi:10.3390/molecules26154577

Abstract

The characterization of the three-dimensional structure of solids is of major importance, especially in the pharmaceutical field. In the present work, NMR crystallography methods are applied with the aim to refine the crystal structure of carbimazole, an active pharmaceutical ingredient used for the treatment of hyperthyroidism and Grave’s disease. Starting from previously reported X-ray diffraction data, two refined structures were obtained by geometry optimization methods. Experimental 1H and 13C isotropic chemical shift measured by the suitable 1H and 13C high-resolution solid state NMR techniques were compared with DFT-GIPAW calculated values, allowing the quality of the obtained structure to be experimentally checked. The refined structure was further validated through the analysis of 1H-1H and 1H-13C 2D NMR correlation experiments. The final structure differs from that previously obtained from X-ray diffraction data mostly for the position of hydrogen atoms.

Highlights

In the determination of the solid-state structure of crystalline compounds, NMR crystallography [1] has gradually grown in importance and is considered complementary and supplementary to X-ray diffraction crystallography, the established leading technique in the field
We performed differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) in order to obtain a basic characterization of our carbimazole sample
The carbimazole sample was subjected to a preliminary screening, which confirmed the equivalence between its crystalline form and the form previously described in the literature and characterized by X-ray diffractometry (XRD) [42,43]

Summary

Introduction

In the determination of the solid-state structure of crystalline compounds, NMR crystallography [1] has gradually grown in importance and is considered complementary and supplementary to X-ray diffraction crystallography, the established leading technique in the field. NMR techniques can cope with some limitations of X-ray diffractometry (XRD), such as the requirement of high quality and large single crystals. Powder X-ray diffraction (PXRD) can be applied in this case, but solving structure from PXRD still remains a challenging operation and the obtained structures are usually of lower quality than those derived from single crystal diffraction data. Hydrogen atoms are poorly localized by XRD, as diffractometric techniques locate the centroid of the electron density, not the nuclear positions. NMR is intrinsically sensitive to the nuclear species and provides chemically selective information. The positions and interactions of hydrogen atoms can be finely probed by 1H NMR, and exploiting heteronuclei, such as 13C, 14/15N, 31P and others

Methods

Results

Conclusion