Crystal engineering approach to produce complex of azelnidipine with maleic acid

A novel azelnidipine–maleic acid complex was prepared by the solvent-assisted co-grinding method. The obtained complex was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), infrared (IR), Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. The PXRD and DSC measurement identified new different crystal form of the obtained complex other than those of the single azelnidipine and maleic acid. It was revealed that the azelnidipine–maleic acid complex was formed at a molar ratio of 2 : 1. IR, Raman and ssNMR spectroscopy verified that a C–H⋯O hydrogen bond was formed between CO from maleic acid and methyl groups from azelnidipine. The distinctive THz spectrum showed that the vibrational mode of the complex was different from those of the starting materials, suggesting that THz spectroscopy is an ideal tool to evaluate complex formation. The solubilities of azelnidipine in maleic acid with different concentrations at different temperatures were investigated; the obtained values were used to calculate the formation constants and thermodynamic parameters. The improved dissolution rate in vitro of the complex showed potential to improve the physicochemical properties of azelnidipine API by a crystal engineering approach.