Crystal Structure of Linezolid

Tanaka, Rumiko; Hirayama, Noriaki

doi:10.2116/analscix.24.x43

Cited by 6 publications

(8 citation statements)

References 3 publications

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“…The structure could have been solved in space group P2 1 /n with disordered C4 and C5 atoms (with attached hydrogens), but this space group does not correspond to the chemical nature of linezolid molecule and such structure's initial refinement parameters were significantly worse. This situation is similar to the one observed in the crystal of LIN form III, determined in the space group P1 with two molecules in an asymmetric unit (CCDC refcode TIYQAU) (Tanaka & Hirayama, 2008).…”

Section: Lin:ga:h 2 O Cocrystalsupporting

confidence: 85%

“…Then, in each case the same geometry optimization procedure was repeated for crystal structures of the coformers used to prepare the cocrystals. The following crystal structures were used: linezolid form II (CSD refcode TIYQAU01) (Maccaroni et al, 2008), linezolid form III (CSD refcode TIYQAU) (Tanaka & Hirayama, 2008), benzoic acid (CSD refcode BENZAC13) (Cai & Katrusiak, 2012), p-hydroxybenzoic acid (CSD refcode JOZZIH01) (Du et al, 2018), monoclinic polymorph of 2,6-dihydroxybenzoic acid (CSD refcode LEZJAB01) (MacGillivray & Zaworotko, 1994), triclinic polymorph of monohydrate of 3,4-dihydroxybenzoic acid (CSD refcode BIJDON03) (Horneffer et al, 1999), monohydrate form I of gallic acid (CSD refcode KONTIQ01) (Okabe et al, 2001). In each case stabilization energy was calculated as a difference between total energy of a cocrystal and a sum of total energies of pure components in the respective stoichiometric ratios.…”

Section: Castep Calculationsmentioning

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: Lin:ga:h 2 O Cocrystalsupporting

confidence: 85%

Section: Castep Calculationsmentioning

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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“… Superposition of the found global linezolid gas phase minimum (AMBER on the left and OPLS-AA on the right) with the linezolid bioactive conformation (green). The OPLS-AA force field reproduces the conformation linezolid adopts in the solid state [ 38 ] or complexed by a transporter protein [ 39 ]. …”

Section: Overall Strategymentioning

confidence: 99%

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

Grunenberg

Licari

2016

Beilstein J. Org. Chem.

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SummaryWe propose several new and promising antibacterial agents for the treatment of serious Gram-positive infections. Our predictions rely on force field simulations, supervised by first principle calculations and available experimental data. Different force fields were tested in order to reproduce linezolid's conformational space in terms of a) the isolated and b) the ribosomal bound state. In a first step, an all-atom model of the bacterial ribosome consisting of nearly 1600 atoms was constructed and evaluated. The conformational space of 30 different ribosomal/oxazolidinone complexes was scanned by stochastic methods, followed by an evaluation of their enthalpic penalties or rewards and the mechanical strengths of the relevant hydrogen bonds (relaxed force constants; compliance constants). The protocol was able to reproduce the experimentally known enantioselectivity favoring the S-enantiomer. In a second step, the experimentally known MIC values of eight linezolid analogues were used in order to crosscheck the robustness of our model. In a final step, this benchmarking led to the prediction of several new and promising lead compounds. Synthesis and biological evaluation of the new compounds are on the way.

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“…LZD form IV belongs to the triclinic crystal system with space group of P 1 and its unit-cell parameters are a = 6.5885 Å, b = 10.977 Å, c = 12.919 Å, α = 69.313°, β = 88.17°, and γ = 74.23°. The space group is P 1 (Tanaka and Hirayama, 2008). Excipients besides the active drug substance commonly used in the tablet formulation were also provided by Zhejiang Huadong Pharmaceutical Co., LTD.…”

Section: Methodsmentioning

confidence: 99%

Determination of minor quantities of linezolid polymorphs in a drug substance and tablet formulation by powder X-ray diffraction technique

Sun

Zhou

et al. 2017

Powder Diffr.

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Linezolid (LZD) is one of the first commercially available synthetic oxazolidinone antibiotics and is widely used for the treatment of multidrug-resistant Gram-positive bacterial infection. LZD was found to have five polymorphic forms. The most stable and commercialized polymorphs are known as forms II and IV. Trace content of form II in LZD form IV will cause to transition LZD form IV to II rapidly. Powder X-ray diffraction (PXRD) methods were evaluated for the determination of the polymorphic content of the drug substance and drug product. The estimated limit of detection values of the single peak method for LZD polymorph form II in drug substance and tablet formulation were 0.4 and 0.6%, respectively, while the limit of detection value of Rietveld Refinement (full-profile fitting) evaluated LZD polymorph form II in drug substance was 0.2%. The results clearly show that levels <1 wt.% (in active pharmaceutical ingredients) and 2 wt.% (in tablets) LZD form II in form IV can be detected and quantified by PXRD. Validation of the analytical method proved that the method is repeatable, sensitive, and accurate.

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Crystal Structure of Linezolid

Cited by 6 publications

References 3 publications

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

Determination of minor quantities of linezolid polymorphs in a drug substance and tablet formulation by powder X-ray diffraction technique

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