An NMR crystallography investigation of furosemide

Zilka, Miri; Yates, Jonathan R.; Brown, Steven P.

doi:10.1002/mrc.4789

Cited by 9 publications

(5 citation statements)

References 64 publications

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“…We emphasize that our approach relies on chemical shielding differences (Δδ) and thereby avoids the issue of referencing the calculated values. ,− However, to allow for comparison to the RMSE method, calculated NMR chemical shieldings, σ calc , were converted into isotropic chemical shifts (δ iso,calc ) using eq , where σ ref is the reference shielding (30.0 ppm for 1 H and 169.9 ppm for 13 C), , and the gradient ( m ) was set to minus one; this is equivalent to taking the sum of the experimental chemical shifts and the GIPAW calculated absolute isotropic chemical shieldings δ iso , calc = σ ref + m × σ calc …”

Section: Methodsmentioning

confidence: 99%

“…The integration of solid-state NMR data and ab initio calculations of NMR parameters in NMR crystallography presents a valuable approach for determining crystal structures. − ,− Requiring a good starting structural model that is geometry optimized before the calculation of NMR parameters, NMR crystallography is now widely employed in academia and increasingly in industry, particularly to refine and improve the quality of structures derived from both single-crystal and powder X-ray diffraction data. − ,− ,,, NMR crystallography can also be used to determine crystal structures de novo without X-ray diffraction data by finding the model from a CSP ,,− campaign whose calculated properties are most consistent with the experimental NMR data. ,− ,,,,− Chemical shifts for proposed model structures are calculated, usually using the gauge-including projector augmented wave (GIPAW) method, − and compared directly with experimentally measured solid-state NMR chemical shifts, with only the correct model expected to pass the given thresholds of agreement for the root mean squared error (RMSE). ,,, …”

Section: Introductionmentioning

confidence: 99%

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Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

Rahman,

Dannatt,

Blundell

et al. 2024

J. Phys. Chem. A

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The Δδ regression approach of Blade et al. [J. Phys. Chem. A 2020, 124(43), 8959−8977] for accurately discriminating between solid forms using a combination of experimental solutionand solid-state NMR data with density functional theory (DFT) calculation is here extended to molecules with multiple conformational degrees of freedom, using furosemide polymorphs as an exemplar. As before, the differences in measured 1 H and 13 C chemical shifts between solution-state NMR and solid-state magicangle spinning (MAS) NMR (Δδ experimental ) are compared to those determined by gauge-including projector augmented wave (GIPAW) calculations (Δδ calculated ) by regression analysis and a ttest, allowing the correct furosemide polymorph to be precisely identified. Monte Carlo random sampling is used to calculate solution-state NMR chemical shifts, reducing computation times by avoiding the need to systematically sample the multidimensional conformational landscape that furosemide occupies in solution. The solvent conditions should be chosen to match the molecule's charge state between the solution and solid states. The Δδ regression approach indicates whether or not correlations between Δδ experimental and Δδ calculated are statistically significant; the approach is differently sensitive to the popular root mean squared error (RMSE) method, being shown to exhibit a much greater dynamic range. An alternative method for estimating solution-state NMR chemical shifts by approximating the measured solution-state dynamic 3D behavior with an ensemble of 54 furosemide crystal structures (polymorphs and cocrystals) from the Cambridge Structural Database (CSD) was also successful in this case, suggesting new avenues for this method that may overcome its current dependency on the prior determination of solution dynamic 3D structures.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

Rahman,

Dannatt,

Blundell

et al. 2024

J. Phys. Chem. A

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“…In contrast, NMR chemical shifts are local probes of local atomic environments around nuclei and thus do not require such long-range order. This has allowed the combined use of solid-state NMR, crystal structure prediction (CSP) protocols, and chemical shift computations using density function theory (DFT) for structure determination in a variety of powdered and disordered solids. − …”

Section: Introductionmentioning

confidence: 99%

Chemical Shift-Dependent Interaction Maps in Molecular Solids

Cordova

Emsley

2023

J. Am. Chem. Soc.

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Structure determination of molecular solids through NMR crystallography relies on the generation of a comprehensive set of candidate crystal structures and on the comparison of chemical shifts computed for those candidates with experimental values. Exploring the polymorph landscape of molecular solids requires extensive computational power, which leads to a significant bottleneck in the generation of the set of candidate crystals by crystal structure prediction (CSP) protocols. Here, we use a database of crystal structures with associated chemical shifts to construct three-dimensional interaction maps in molecular crystals directly derived from a molecular structure and its associated set of experimentally measured chemical shifts. We show how the maps obtained can be used to identify structural constraints for accelerating CSP protocols and to evaluate the likelihood of candidate crystal structures without requiring DFT-level chemical shift computations.

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“…Solid-state NMR can be used to gain insights into crystallographic disorder occurring in bulk pharmaceuticals ,− and can be combined with gauge-including projector-augmented-wave (GIPAW) calculations to verify and refine the crystal structure, that is, NMR crystallography. ,,,− As a technique that observes the bulk sample, solid-state NMR can be used to validate the occurrence of crystallographic disorder and determine its nature. ,, The disorder caused by dynamics can be investigated by solid-state NMR, − offering qualitative information through line-shape analysis, chemical shift measurement, and dipolar coupling measurements. , In addition, quantitative information on the thermodynamic parameters of the dynamics can be obtained through relaxation time measurements. ,,, There are limits to the ability of solid-state NMR to investigate disorder, which may arise due to the nature of the technique. Examples of this may arise from an insufficient resolution required to adequately resolve the crystallographic disorder, the disorder involving unreceptive nuclei or potentially missing the presence of dynamics occurring at a timescale distinct from that of the one-dimensional NMR experiment.…”

Section: Introductionmentioning

confidence: 99%

Combining X-ray and NMR Crystallography to Explore the Crystallographic Disorder in Salbutamol Oxalate

Al-Ani

Szell

Rehman

et al. 2022

Crystal Growth & Design

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Salbutamol is an active pharmaceutical ingredient commonly used to treat respiratory distress and is listed by the World Health Organization as an essential medicine. Here, we establish the crystal structure of its oxalate form, salbutamol oxalate, and explore the nature of its crystallographic disorder by combined X-ray crystallography and 13 C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR. The *C−OH chiral center of salbutamol (note that the crystal structures are a racemic mixture of the two enantiomers of salbutamol) is disordered over two positions, and the tert-butyl group is rotating rapidly, as revealed by 13 C solid-state NMR. The impact of crystallization conditions on the disorder was investigated, finding variations in the occupancy ratio of the *C−OH chiral center between single crystals and a consistency across samples in the bulk powder. Overall, this work highlights the contrast between investigating crystallographic disorder by X-ray diffraction and solid-state NMR experiment, and gauge-including projector-augmented-wave (GIPAW) density functional theory (DFT) calculations, with their combined use, yielding an improved understanding of the nature of the crystallographic disorder between the local (i.e., as viewed by NMR) and longer-range periodic (i.e., as viewed by diffraction) scale.

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An NMR crystallography investigation of furosemide

Cited by 9 publications

References 64 publications

Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

Chemical Shift-Dependent Interaction Maps in Molecular Solids

Combining X-ray and NMR Crystallography to Explore the Crystallographic Disorder in Salbutamol Oxalate

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