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

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• 作者：Inês C. B. Martins ; Mariana Sardo ; Sérgio M. Santos ; Auguste Fernandes ; Alexandra Antunes ; Vania André ; Luís Mafra ; M. Teresa Duarte
• 刊名：Crystal Growth & Design
• 出版年：2016
• 出版时间：January 6, 2016
• 年：2016
• 卷：16
• 期：1
• 页码：154-166
• 全文大小：738K
• ISSN：1528-7505

文摘

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 R₂²(8) homosynthon present in AA is broken, and NH₂···O_COOH or ⁺NH₂···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 ¹H chemical shifts showed that such disordered atoms refer to O···H···O hydrogens, roughly equidistant from both proton acceptor and donor atoms. ¹H SSNMR detected unusually strong HBs associated with such disordered hydrogens through the presence of ¹H 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.