Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X-ray and Solid-State NMR
authors Martins, ICB; Sardo, M; Santos, SM; Femandes, A; Antunes, A; Andre, V; Mafra, L; Duarte, MT
nationality International
journal CRYSTAL GROWTH & DESIGN
keywords VARIABLE CHAIN-LENGTH; CO-CRYSTALS; DICARBOXYLIC-ACIDS; COCRYSTALS; CRYSTALLOGRAPHY; CARBOXYLATES; DIFFRACTION; SOLUBILITY; MECHANISM; ADDUCTS
abstract The reactivity of the active pharmaceutical ingredient azelaic acid (AA) with carboxylic acid, alcohol, amine, and amide based co-formers was screened. Five new multicomponent crystal forms of AA were obtained by liquid assisted grinding and conventional solution methods. The obtained forms: (i) a co-crystal with 4,4'-bipyridine (AA:BIP, 1), (ii) an anhydrous and an hydrated molecular salt with piperazine (AA:PIP, 2 and 3), and (iii) two anhydrous molecular salts with morpholine (AA:MORPH, 4) and 1,4-diazobicyclo[2.2.2]octane (AA:DABCO, 5), were fully characterized by X-ray diffraction and solid-state (SS) NMR. In all new forms the carboxylic-carboxylic R-2(2)(8) homosynthon present in AA is broken, and NH2 center dot center dot center dot O-COOH or +NH2 center dot center dot center dot O-COO-hydrogen bonds (HBs) become the fundamental pillars in the new supramolecular arrangements. The X-ray structure of 4 exhibits a static disorder in the hydrogen atoms engaged in an HB between two COOH moieties of AA. Density functional theory geometry optimization of the hydrogen positions followed by GIPAW-DFT calculations of H-1 chemical shifts showed that such disordered atoms refer to O center dot center dot center dot H center dot center dot center dot O hydrogens, roughly equidistant from both proton acceptor and donor atoms. SSNMR detected unusually strong HBs associated with such disordered hydrogens through the presence of H-1 resonances shifted to very high frequencies (up to ca. 20.1 ppm). These results clearly show the advantageous use of both X-ray diffraction and SSNMR techniques for structural elucidation. We concluded that the hydrated piperazine salt 3 readily converted to 2 at ambient RH and that their thermal behavior is strongly determined by both the supramolecular arrangement and strength of HB network. Piperazine salt 2 presents an improved aqueous solubility bestowing a promising opportunity to avoid the use of alcoholic solutions in the final formulations.
publisher AMER CHEMICAL SOC
issn 1528-7483
year published 2016
volume 16
issue 1
beginning page 154
ending page 166
digital object identifier (doi) 10.1021/acs.cgd.5b01057
web of science category Chemistry, Multidisciplinary; Crystallography; Materials Science, Multidisciplinary
subject category Chemistry; Crystallography; Materials Science
unique article identifier WOS:000367963400018
  ciceco authors
  impact metrics
journal analysis (jcr 2017):
journal impact factor 3.972
5 year journal impact factor 3.880
category normalized journal impact factor percentile 77.120
dimensions (citation analysis):
altmetrics (social interaction):



 


Sponsors

1suponsers_list_ciceco.jpg