Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: Crystal structures and multinuclear solid-state NMR

Vogt, Frederick G.; Katrincic, Lee M.; Long, Stacey T.; Mueller, Ronald L.; Carlton, Robert A.; Sun, Yang; Johnson, Matthew N.; Copley, Royston C. B.; Light, Mark E.

doi:10.1002/jps.21336

Cited by 31 publications

(19 citation statements)

References 68 publications

(142 reference statements)

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“…Some early computational work (aimed at benchmarking and validation) included F 2 as test molecule, which proved to be challenging [26][27][28]. Interest in modeling 19 F shifts has steadily continued, and several papers have appeared in the last decade aimed at general structural issues, solution chemistry and physical organic chemistry, [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] solid-state issues (especially the prediction of chemical shift tensors), [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] J-couplings [65][66][67][68][69][70][71][72]…”

Section: Introductionmentioning

confidence: 99%

Computational 19F NMR. 1. General features

2012

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Fluorine-19 NMR chemical shifts have been calculated for a wide variety of fluorine-containing inorganic and organic molecules by relativistic DFT methods. The agreement with experimental values, spanning the whole range from ClF to FOOF, is satisfactory but somewhat less accurate than for comparable light nuclei. 19 F shifts in uranium chlorofluorides have been analyzed in detail, and the poor agreement with experiment is partly rationalized.

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Section: Introductionmentioning

confidence: 99%

Computational 19F NMR. 1. General features

2012

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“…To extract structural information from correlation spectroscopy, we extend the 1 H detection to a 2D mode. 1 H double quantum (DQ) correlation experiment utilizing back-to-back (BABA) excitation and reconversion pulse scheme has shown the capability of detecting close contacts of up to 5 Å in pharmaceutical solids. ,,, The 2D 1 H– 1 H spectra of pure CLF and HPMCP are included in Figure , panels A and B, respectively, which show the correlation between aliphatic and aromatic protons. Hypothetically, the formation of CLF–HPMCP ASD involves proton transfer from −COOH of polymer to N α of CLF.…”

Section: Resultsmentioning

confidence: 99%

Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions

et al. 2016

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It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D H-H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.

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“…Interestingly, it was found that some polymorphs were significantly absorbed even though rifaximin had been previously considered to be a nonabsorbable drug substance. X‐ray diffraction solid‐state NMR techniques have been used to analyze the structures of two enantiotropically‐related, nonsolvated polymorphs of {4‐(4‐chloro‐3‐fluorophenyl)‐2‐[4‐(methyloxy)phenyl]‐1,3‐thiazol‐5‐yl} acetic acid,58 and the orthorhombic and triclinic polymorphs of linezolid 59. A quantitative X‐ray diffraction method for analysis of mixtures of clopidogrel bisulfate polymorphs has been reported, with 1.0–1.5% (w/w) being found for the limit of quantitation 60…”

Section: Structural Characterization and Properties Of Polymorphs Andmentioning

confidence: 99%