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

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 (H(2)FA), 2-hydroxybenzoic acid (2-HBA) and 4-hydroxybenzoic acid (4-HBA). Since DF is susceptible to co-crystallization with acids, the present work focuses on the solubilization of the synthesized molecular adducts from diverse structures and energies. All the new 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 revealed that DF presents uniform mono-protonation and forms charge-assisted hydrogen bonds to coformers, and the hydrogen bonding preference of the coformers governs the supramolecular architectures of the solid adducts; i.e., the complexes containing H(2)FA and 4-HBA, which prefer to form intermolecular hydrogen bonds, were extended to high dimensional 1-D chains and 2-D meso-helical layers, whereas the 2-HBA introduced salt showed a discrete structure by virtue of its common intramolecular connectivity. Solubility determinations suggest that 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 the CRYSTAL14 software at the DFT (B3LYP) level based on the single crystal structures. The correlation of supramolecular structures, lattice energies and solubilities are discussed in detail.