Deciphering the Topology of Sitagliptin Using an Integrated Approach.

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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.