Structure Refinements of Pharmaceupticals by New NMR Crystallography Methods
Title: Structure Refinements of Pharmaceupticals by New NMR Crystallography Methods
SNIC Project: SNIC 2022/5-213
Project Type: SNIC Medium Compute
Principal Investigator: Mattias Edén <>
Affiliation: Stockholms universitet
Duration: 2022-04-28 – 2023-05-01
Classification: 10402 10407


The project “Access to potent medical drugs through polymorph-specific crystallization enabled by ionic liquids” aims at steering the crystallization of polymorphic pharmaceuptical compounds for obtaining a specifically targeted form. As one part of this project, funded by the Knut & Alice Wallenberg foundation, we will utilize and further refine a very recently developed solid-state NMR crystallography method [1]. Relative to previous NMR crystallography approaches, this protocol offers effortless estimates of entire sets of (for instance) 13C-1H and 1H-1H interatomic distances from polycrystalline powders; these experimental data may then be used for assessing a large number of potential structure models, which may be generated by any experimental or modeling technique. The protocol extracts sets of interatomic distances by the analysis of one sole 2D NMR spectrum, where we will particularly target the experimentally determined sets of 1H-1H distances in pharmaceuptical compounds for structure validations. Moreover, we will ourselves refine previously reported diffraction-derived structures of several drug molecules, as well as co-crystals thereof, by employing plane-wave density functional theory (DFT) calculations and/or ab initio molecular dynamics (AIMD) simulations, followed by their direct validations against the NMR crystallography protocol. Further assessments will also be made by using traditional NMR crystallography procedures that contrasts experimental 1H, 13C, and 15N chemical shift-tensor parameters with those calculated by the gauge including projector augmented wave (GIPAW) method applied to the DFT-refined structure. References: [1] Refined Structures of O-Phospho-L-Serine and its Calcium Salt by New Multinuclear Solid-State NMR Crystallography Methods; R. Mathew, B. Stevensson, M. Edén, J. Phys. Chem. B, 125, 10985−11004 (2021)