Deciphering the Topology of Sitagliptin Using an Integrated Approach

Determining the structure of sitagliptin is crucial for
ensuring
its effectiveness and safety as a DPP-4 inhibitor used to treat type
2 diabetes. Accurate structure determination is vital for both drug
development and maintaining quality control in manufacturing. This
study integrates the advanced techniques of solid-state nuclear magnetic
resonance (NMR) spectroscopy, three-dimensional (3D) electron diffraction,
and density functional theory (DFT) calculations to investigate the
structural intricacies of sitagliptin. Solid-state NMR provides detailed
information on the molecular environment, revealing insights into
the atomic-level structure. The DFT calculations complement these
experimental findings by offering theoretical insights into the electronic
structure and helping validate the NMR data. Dynamic nuclear polarization
has recently emerged as a cornerstone approach to enhance the sensitivity
of solid-state NMR spectroscopy under magic angle spinning (MAS),
opening unprecedented analytical opportunities. In this work, we incorporated
the latest state-of-the art dynamic nuclear polarization NMR into
3D ED NMR crystallography. The findings from this study have important
implications for the pharmaceutical industry, particularly in enhancing
the precision of drug development and ensuring the high quality of
diabetes treatments. Overall, this combined methodological approach
not only advances the structural characterization of sitagliptin but
also sets a precedent for analyzing other pharmaceutical compounds
of similar complexity.