Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry

Wielgus, Ewelina; Paluch, Piotr; Frelek, Jadwiga; Szczepek, W. J.; Potrzebowski, Marek J.

doi:10.1002/jps.24606

Cited by 8 publications

(12 citation statements)

References 32 publications

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“…In the spectrum of form II resonances originating from morpholine ring carbon atoms (C13-C16) are significantly broadened, whereas in the spectrum of form III they are not observed. This was observed before and associated with temperature-dependent molecular dynamics of this ring present in both analyzed forms (Wielgus et al, 2015). In addition, in the spectrum of form II the resonance originating from C9 is also broadened and has significantly lower intensity, which can be attributed to the coupling between 13 C and 19 F nuclei.…”

Section: Resultssupporting

confidence: 65%

“…Note, however, that shorter heating times at this temperature led to a mixture of forms II and III. The assignment in the presented spectra was done of the basis of the literature data (Wielgus et al, 2015), and validated against the calculated 13 C shielding constants for both forms of LIN (see Table S3 and Fig. S11 for the calculated values and regression curves showing the agreement between experimental and theoretical data).…”

Section: Resultsmentioning

confidence: 99%

“…1), a wide-range antibiotics used mainly to treat infections caused by resistant strains of Gram-positive bacteria (Moellering, 2003;Abou Hassan et al, 2016). To date, crystal structures of two polymorphic forms of LIN are known, orthorhombic form II (Maccaroni et al, 2008), which is a commercially available form, and triclinic form III (Rao & Reddy, 2005;Tanaka & Hirayama, 2008), which is also mistakenly referred to in the literature as form IV (Wielgus et al, 2015). These two polymorphs are enantiotropic, with the stable form II undergoing transformation to the metastable form III by heating to a temperature between 120 C and 140 C for the appropriate amount of time (Maccaroni et al, 2008;Bergren, 2003;Rao & Reddy, 2005;Frelek et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Khalaji

Wróblewska

Wielgus

et al. 2020

Acta Crystallogr B Struct Sci Cryst Eng Mater

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In a search for new crystalline forms of linezolid with modified thermal properties five cocrystals of this wide range antibiotic with aromatic acids were obtained via mechanochemical grinding and analyzed with single crystal X-ray diffraction, solid-state NMR spectroscopy, powder X-ray diffraction and DSC measurements. The coformers used in this study were benzoic acid, p-hydroxybenzoic acid, protocatechuic acid, γ-resorcylic acid and gallic acid. In each of the cocrystals distinct structural features have been found, including a variable amount of water and different heterosynthons, indicating that there is more than one type of intermolecular interaction preferred by the linezolid molecule. Basing on the frequency of the observed supramolecular synthons, the proposed hierarchy of the hydrogen-bond acceptor sites of linezolid (LIN) is C=Oamide > C=Ooxazolidone > C—O—Cmorpholine > C—N—Cmorpholine > C—O—Coxazolidone. In addition, aromatic–aromatic interactions were found to be important in the stabilization of the analyzed structures. The obtained cocrystals show modified thermal properties, with four of them having melting points lower than the temperature of the phase transition from linezolid form II to linezolid form III. Such a change in this physicochemical property allows for the future application of melting-based techniques of introducing linezolid into drug delivery systems. In addition a change in water solubility of linezolid upon cocrystalization was evaluated, but only in the case of the cocrystal with protocatechuic acid was there a significant (43%) improvement in solubility in comparison with linezolid.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Khalaji

Wróblewska

Wielgus

et al. 2020

Acta Crystallogr B Struct Sci Cryst Eng Mater

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“…LIN crystallizes in one of two well-characterized polymorphic anhydrous forms, namely, form II and form III. − Form II is more thermodynamically stable than form III and is characterized as having one LIN molecule in an asymmetric part of a crystallographic unit cell in contrast to LIN form III, which crystallizes with two symmetric independent molecules in an asymmetric part of a unit cell. In our grinding experiments, both forms were tested for the cocrystal formation with the considered coformers and the influence of the polymorphic form taken for the reaction on its outcome is described in one of the following sections.…”

Section: Introductionmentioning

confidence: 99%

Virtual Cocrystal Screening Methods as Tools to Understand the Formation of Pharmaceutical Cocrystals—A Case Study of Linezolid, a Wide-Range Antibacterial Drug

Khalaji

Potrzebowski

Dudek

2021

Crystal Growth & Design

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Experimental mechanochemical screening of cocrystals with linezolid (LIN) resulted in the formation of six new crystal phases, including three neat cocrystals and three cocrystal hydrates, in addition to seven previously described cocrystals. In an attempt to understand the factors governing the formation of these phases, different experimental conditions of the mechanochemical reactions (polymorphic forms of LIN and presence of different solvents to create liquid-assisted grinding conditions) were tested and the results were compared with the predictions from three commonly used virtual cocrystal screening tools: molecular complementarity, hydrogen bond propensity, and molecular electrostatic potential maps. It is shown that these three methods can be used to help understand a molecule’s preferences to form cocrystals with particular coformers. The influence of molecular conformation on the outcome of the predictions is also evaluated. A comparison between the prediction methods indicates that while considering a set of similar coformers, the approach based on molecular electrostatic potential maps seems to be more consistent with the experimental results than molecular complementarity and hydrogen bond propensity tools. Instead, these two latter approaches are recommended at the early stages of coformer selection. In addition, intermolecular energy contribution (lattice energy) to the total energy of crystal forms of coformers was found to be indicative of the feasibility of cocrystal formation in the case of coformers capable of forming similar supramolecular synthons.

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“…labile drugs or those with required chiral purity [ 10 – 14 ]. Similar approaches to the identification of oxazolidinone analogues have been reported in the literature for linezolid and tedizolid [ 15 – 17 ]. However, so far, no reports have described the comprehensive characterisation of intermediate products which are important for the chiral pool synthesis of RAD by spectroscopic methods.…”

Section: Introductionmentioning

confidence: 83%

Comprehensive spectral identification of key intermediates to the final product of the chiral pool synthesis of radezolid

Michalska

Bednarek

Gruba

et al. 2017

Chemistry Central Journal

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Radezolid (RAD, 12), biaryl oxazolidinone, was synthesised with small modifications according to the methods described in the literature. The pharmacological activity is observed only for (S)-enantiomer, therefore its synthesis is oriented towards obtaining a single isomer of required purity and desired optical configuration. The intermediate products of RAD synthesis were characterised using 1H- and 13C-NMR, as well as the 2D correlation HSQC and HMBC (2, 5, 9, 10), furthermore studied using infrared radiation (FT-IR), Raman scattering (3, 5, 9), and electronic circular dichroism (ECD) (5, 12) spectroscopy. Each technique provides a unique and specific set of information. Hence, the full spectral characteristics of key intermediates obtained from the chiral pool synthesis to the finished product of RAD were summarised and compared. For a more accurate analysis, and due to the lack of reliable and reproducible reference standards for intermediate products, their vibrational analysis was supported by quantum chemical calculations based on the density functional theory (DFT) utilising the B3LYP hybrid functional and the 6-311G(d,p) basis set. Good agreement was observed between the empirical and theoretical spectra.Graphical abstractComprehensive spectral identification (ECD, NMR, FT-IR, Raman) of key intermediates of the chiral pool synthesis of radezolid. Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-017-0309-x) contains supplementary material, which is available to authorized users.

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Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry

Cited by 8 publications

References 32 publications

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Virtual Cocrystal Screening Methods as Tools to Understand the Formation of Pharmaceutical Cocrystals—A Case Study of Linezolid, a Wide-Range Antibacterial Drug

Comprehensive spectral identification of key intermediates to the final product of the chiral pool synthesis of radezolid

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