Crystal structure prediction could have helped the experimentalists with polymorphism in benzamide

Thun, Juergen; Schoeffel, Markus; Breu, Josef

doi:10.1080/08927020802208943

Cited by 18 publications

(16 citation statements)

References 31 publications

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“…Recently, clonixin was found to form a solvate with N,N-dimethylformamide. 13 Polymorphism is important both theoretically (CSP) 14,15 and practically. [16][17][18][19] Polymorphism is of particular signicance in pharmaceuticals because different forms of the same API (Active Pharmaceutical Ingredient) may have different kinetic, thermodynamic, surface, mechanical, and packaging properties, which can affect clinical formulation and eventual bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Solution growth and thermal treatment of crystals lead to two new forms of 2-((2,6-dimethylphenyl)amino)benzoic acid

Zhoujin

et al. 2018

RSC Adv.

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We report the discovery of two new forms (II and III) of a potential non-steroidal anti-inflammatory and thyroid drug, 2-((2,6-dimethylphenyl)amino)benzoic acid (HDMPA) through solution growth and thermal treatment of crystals. Form II has been discovered through crystal growth in a variety of solvents, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Form II converts into form III upon thermal treatment, as indicated by the phase behavior study of form II with differential scanning calorimetry (DSC). Form III has been characterized by IR, Raman and PXRD. Conformational flexibility of the molecule seems to lead to the polymorphism of the system. A conformational scan shows the conformational minima correspond to the conformers in the polymorphs. Lattice energy calculations show energies of À48.14 and À50.31 kcal mol À1 for forms I and II, providing information on the relative stability for each form. Hirshfeld analysis revealed that

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Section: Introductionmentioning

confidence: 99%

Solution growth and thermal treatment of crystals lead to two new forms of 2-((2,6-dimethylphenyl)amino)benzoic acid

Zhoujin

et al. 2018

RSC Adv.

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“…6 Form II is not observed anywhere in the CSP results as is the case for previous CSP studies. 8 Validation by geometry optimization of the original Pba2 structure in the DFT-D potential results in a heavy distortion of 0.88 Å RMSCD, which is well above the threshold of 0.35 Å, thus strongly indicating a problem with the Pba2 structure. 16,17 The geometry optimization highlights a very short carbon−carbon contact of 2.7 Å, which relaxes to 3.6 Å upon geometry optimization ( Figure S1).…”

Section: Resultsmentioning

confidence: 94%

“…In a specific attempt to predict form II, the reported experimental space-group symmetry has been included in a CSP study but without success. 8 In 2013, Ectors et al used computational methods to support the idea that the N and O atoms of the amide group in the crystal structure of form II, which was determined from PXRD data, may have been swapped. 11 Finally, computational methods have been used to suggest a hypothetical polymorph of benzamide, but no details have been released.…”

Section: Introductionmentioning

confidence: 99%

Revision of the Crystal Structure of the First Molecular Polymorph in History

Johansson

Streek

2016

Crystal Growth & Design

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Despite being the earliest reported case of polymorphism in a molecular crystal, the unstable form II of benzamide has thus far evaded thorough structural characterization because collection of experimental data at atomic resolution has proven extremely challenging. Using a highly validated computational crystal structure prediction (CSP) method based on dispersion-corrected density functional theory, we correctly predict the stable form I with the lowest energy among all sampled structures and its polytypic form III with slightly higher energy. From Rietveld refinement of selected CSP models against synchrotron X-ray powder diffraction data of the historical polymorph, we are able to identify a subtle weakness in the available experimental data and arrive at a revised structure of form II. The revised crystal structure is the first benzamide structure to form catemers rather than dimers and possesses the rare space-group symmetry Fdd2 with two molecules in the asymmetric unit, which is necessary to support the new hydrogen bonding network. This rare space group is only found in the CSP by a complete structural search in all 230 space groups with one or two molecules in the asymmetric unit.

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“…16 The three structurally characterized forms of benzamide, however, all show the same hydrogen bonding motifs: Dimers are aligned via further hydrogen bonds to ribbons. 17 Attempts to crystallize this predicted form have, however, so far been unsuccessful, most likely because of the pronounced stability of the dimers even in highly polar solvents. 12,13 For this reason, the polymorph selection is expected to be little in-fluenced by the choice of solvent.…”

Section: Introductionmentioning

confidence: 99%

Thermoanalytical Evidence of Metastable Molecular Defects in Form I of Benzamide

Butterhof

Martin

Ectors

et al. 2012

Crystal Growth & Design

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von Liebig discovered the first case of molecular polymorphism when crystallizing benzamide in 1832. 1 So far only microcrystalline mixtures of metastable phases with the thermodynamically stable form I were available. Optimizing the conditions for crystal growth now gave access to single crystals of the metastable form III which allowed for a detailed comparison of form I and form III by Raman and IR spectroscopy and thermoanalysis. Surprisingly, in the course of detailed DSC measurements for form I an endothermic peak prior to melting was observed. As proven by temperature dependent powder diffraction, thermal microscopy, MDsimulations, and solid-state NMR this pre-melting thermosignal is not related to an enantiotropic phase transition of form I into form III with a transition temperature close to the melting point.

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Crystal structure prediction could have helped the experimentalists with polymorphism in benzamide

Cited by 18 publications

References 31 publications

Solution growth and thermal treatment of crystals lead to two new forms of 2-((2,6-dimethylphenyl)amino)benzoic acid

Solution growth and thermal treatment of crystals lead to two new forms of 2-((2,6-dimethylphenyl)amino)benzoic acid

Revision of the Crystal Structure of the First Molecular Polymorph in History

Thermoanalytical Evidence of Metastable Molecular Defects in Form I of Benzamide

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