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Title: | Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X-ray and Solid-State NMR |
Author: | Martins, Ines C. B. Sardo, Mariana Santos, Sergio M. Femandes, Auguste Antunes, Alexandra Andre, Vania Mafra, Luis Teresa Duarte, M. |
Keywords: | VARIABLE CHAIN-LENGTH CO-CRYSTALS DICARBOXYLIC-ACIDS COCRYSTALS CRYSTALLOGRAPHY CARBOXYLATES DIFFRACTION SOLUBILITY MECHANISM ADDUCTS |
Issue Date: | 2016 |
Publisher: | AMER CHEMICAL SOC |
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. |
Peer review: | yes |
URI: | http://hdl.handle.net/10773/20857 |
DOI: | 10.1021/acs.cgd.5b01057 |
ISSN: | 1528-7483 |
Publisher Version: | 10.1021/acs.cgd.5b01057 |
Appears in Collections: | CICECO - Artigos |
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