Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X-ray and Solid-State NMR


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.



subject category

Chemistry; Crystallography; Materials Science


Martins, ICB; Sardo, M; Santos, SM; Femandes, A; Antunes, A; Andre, V; Mafra, L; Duarte, MT

our authors


Authors acknowledge Fundacao para a Ciencia e a Tecnologia (FCT) for funding: Projects PTDC/CTM-BPC/122447/2010, RECI/QEQ-QIN70189/2012; for the awarded development Grant (IF/01401/2013) to L.M., for the postdoc grants SFRH/BPD/78854/2011, SFRH/BPD/65978/2009, and SFRH/BPD/64752/2009 awarded to V.A, M.S., and S.M.S., respectively, to the Ph.D. Grant SFRH/BD/93140/2013 awarded to I.C.B.M. and the funded R&D project EXPL/QEQ-QFI/2078/2013. This work was developed in the scope of projects CICECO-Aveiro Institute of Materials (ULD/CTM/50011/2013) and Centro de Quimica Estrutural- IST (UID/QUI/00100/2013) financed by national funds through the FCT/MEC and when applicable cofinanced by FEDER under the PT2020 Partnership Agreement. The Portuguese NMR Network (RNRMN) is also acknowledged.

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