resumo
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.
palavras-chave
VARIABLE CHAIN-LENGTH; CO-CRYSTALS; DICARBOXYLIC-ACIDS; COCRYSTALS; CRYSTALLOGRAPHY; CARBOXYLATES; DIFFRACTION; SOLUBILITY; MECHANISM; ADDUCTS
categoria
Chemistry; Crystallography; Materials Science
autores
Martins, ICB; Sardo, M; Santos, SM; Femandes, A; Antunes, A; Andre, V; Mafra, L; Duarte, MT
nossos autores
Inês Catarina Batista Martins
Estudante de doutoramento
Luís Mafra
Investigador Principal
Mariana Coutinho Sardo
Investigador Auxiliar
Sérgio Miguel Fernandes dos Santos
Investigador Auxiliar
Vânia Mafalda de Oliveira André
Bolseiro de pós-DoutoramentoProjectos
Polymorphism in pharmaceuticals: new insights from NMR Crystallography (EXPL/QEQ-QFI/2078/2013)
agradecimentos
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.