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Structural and computational insights into the enhanced solubility of dipfluzine by complexation: salt and salt-cocrystal

Abstract

Dipfluzine (DF) is a diphenylpiperazine calcium channel blocker with poor solubility. In the present work, cocrystal/salt screening experiments resulted in two salts and one salt-cocrystal of DF with carboxylic acid coformers namely fumaric acid (H2FA), 2-hydroxybenzoic acid (2-HBA) and 4-hydroxybenzoic acid (4-HBA). Since DF is susceptible of cocrystallization with acids, the present work concentrated on the solubilisation of the synthesized molecular adducts from diverse structures and energies. All the newly crystalline products were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and fourier transform infrared spectroscopy (FT-IR). Structure analysis reveals that the DF presents uniform mono-protonation and charge-assisted hydrogen bonded to coformers, and the hydrogen bonding preference of the coformers governs the supramolecular architectures of the solid adducts, that is, the complexes containing H2FA and 4-HBA, which preferred to form intermolecular hydrogen bonds, were extended to high dimensional 1-D chain and 2-D meso-helical layer, whereas the 2-HBA introduced salt showed a discrete structure by virtue of its common intramolecular connectivity. Solubility determinations suggested complexation was able to increase the solubility of DF in various media. Furthermore, the lattice energy calculations were carried out on pure DF, complexed salts and salt-cocrystal using CRYSTAL14 software at the DFT (B3LYP) level based on the single crystal structures. The correlation of supramolecular structures, lattice energies and solubilities were discussed in detail.

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Publication details

The article was received on 05 Apr 2018, accepted on 01 Aug 2018 and first published on 01 Aug 2018


Article type: Paper
DOI: 10.1039/C8NJ01576G
Citation: New J. Chem., 2018, Accepted Manuscript
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    Structural and computational insights into the enhanced solubility of dipfluzine by complexation: salt and salt-cocrystal

    W. Guo, S. Du, Y. Lin, B. Lu, C. Yang, J. Wang and Y. Zeng, New J. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C8NJ01576G

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