By NanoMEGAS SPRL
NanoMEGAS ground breaking electron diffraction study to solve complex Linagliptin crystal structure
Brussels, Belgium: – Researchers from NanoMEGAS SPRL, the world-leading instrumentation specialist and innovator in advanced electron diffraction technologies in Transmission Electron Microscopy (TEM), have lead-authored a study exploring use of direct electron detection camera for structure determination of nanocrystals of organic pharmaceutical compounds.
The study ‘Crystal Structure of Linagliptin Hemihydrate Hemiethanolate (C25H28N8O2)2(H2O)(C2H5OH) from 3D Electron Diffraction Data, Rietveld Refinement, and Density Functional Theory Optimization’ has been published in the American Chemical Society journal Crystal Growth and Design as part of a virtual special issue to mark the 50-year anniversary of the Rietveld Refinement Method.
This work was carried out as part of a project to determine the crystal structures of large-volume commercial pharmaceuticals, whose structures are still unknown even if high-quality powder diﬀraction is available in the Powder Diﬀraction File.
The study set out to solve the crystal structure of the potent dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin hemihydrate hemiethanolate (Linagliptin) that is used with diet and exercise to treat type-2 (non-insulin-dependent) diabetes.
In total, more than 30 linagliptin crystalline polymorphs have been described, together with other stable amorphous forms. Many patent applications related to linagliptin have been issued.
The NanoMEGAS team succeeded in fully characterizing the crystal structure of as received commercial reagent of linagliptin on the basis of 3D electron diffraction data, making Linagliptin is one of the largest organic structures to be solved ab initio by electron diffraction.
The structural studies were carried out by scientists from NanoMegas in Brussels in collaboration with scientists from the Center for Nanotechnology Innovation at the NEST Institute of Technology in Pisa, Italy, scientists from International Centre for Diffraction Data (ICDD) , USA and Scientists from North Central College, Illinois, USA.
The high quality data obtained allow the recognition of subtle symmetry reductions and of fine differences in the configuration of the two independent molecules that make up the structure. The structure was then further refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques.
The team discovered that the Linagliptin crystal structure is characterized by a zigzag array of molecules in the ab-plane, with a large number of weak hydrogen bonds linking the linagliptin molecules into a framework.
The water and ethanol molecules occupy channels parallel to the c-axis, and form hydrogen bonds to the framework. The two independent linagliptin molecules were found to have different conformations, which are very close in energy.
The current linagliptin hemihydrate hemiethanolate structure is very similar to the known linagliptin water/methanol/ethanol Form I already characterized by Dr. Reddy’s Laboratory. Although the two compounds are similar, they are not the same, so the current structure is a novel one.
Das, P.P., Andrusenko, I., Mugnaioli, E., Kaduk, J.A., Nicolopoulos, S., Gemmi, M., Boaz, N.C., Gindhart, A.M. and Blanton, T. (2021). Crystal Structure of Linagliptin Hemihydrate Hemiethanolate (C25H28N8O2)2(H2O)(C2H5OH) from 3D Electron Diffraction Data, Rietveld Refinement, and Density Functional Theory Optimization. Crystal Growth & Design, 21(4), pp.2019–2027. doi:10.1021/acs.cgd.0c01379.
Brussels-based instrumentation hardware and software manufacturer NanoMEGAS SPRL (NM) is a specialist and innovator in advanced electron diffraction technologies in Transmission Electron Microscopy (TEM), with exciting applications for the pharmaceutical industry.
NanoMEGAS produces and distributes hardware and software solutions for TEM applications that can be used for academic and industrial characterization of nanocrystalline and amorphous nanomaterials for pharmaceuticals and for polymorphic analysis. NM also provides scientific consulting for pharmaceutical companies wishing to characterize nano-crystalline and amorphous pharmaceuticals.
NanoMEGAS was founded in 2004 by a team of scientists and experts in the field of electron crystallography and catalysis. Inspired by pioneering work carried out on electron crystallography using precession electron diffraction at Bristol, UK at 1996 the NanoMEGAS team was first to develop and market its “spinning star” universal precession device for TEM in 2004. Today, there are more than 220 installations worldwide and more than 1500 scientific publications related with NanoMEGAS applications & instrumentation in various fields, including pharmaceuticals.
Learn more at https://nanomegas.com
Results of study showing (a) asymmetric unit of Linagliptin hemihydrate hemiethanoate, with the atom numbering, (b) Crystal structure of Linagliptin, viewed down the c-axis, (c) comparison of the two independent molecules in Linagliptin, and (d) comparison of the two independent molecules in Linagliptin, after invoking inversion and flexibility options. Finally (e) the Hirshfeld surface of linagliptin showing intermolecular contacts longer than the sums of the van der Waals radii colored blue, contacts shorter than the sums of the radii colored red and contacts equal to the sums of radii as white.