Powder grinding preparation of co-amorphous β-azelnidipine and maleic acid combination: Molecular interactions and physicochemical properties

• Powder co-grinding method was used to prepare novel co-amorphous of β-azelnidipine.
• The co-amorphous was formed through N–H ⋯ O and C–H ⋯ O hydrogen bonds.
• Two heterogeneous dimers and one trimer were obtained using simulated calculation.
• The solubility and dissolution rate of co-amorphous in vitro were improved.

The formation of co-amorphous combination of drug-excipient has proved to be a powerful approach to increase the dissolution of poorly water-soluble drugs. In the present study, four novel co-amorphous combinations of β-azelnidipine (β-AZE) and maleic acid (MAL) with the molar ratio of 1:1 and 1:2 were prepared by neat powder grinding (NG) and solvent-assisted grinding (SG) procedures, respectively. The obtained co-amorphous combinations were characterized by powder X-ray diffraction (PXRD), cryo-field emission scanning electric microscope (SEM), differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR), solid-state nuclear magnetic resonance (ssNMR) and terahertz (THz) spectroscopy. The PXRD technique confirmed the amorphous feature of these resultant combinations, and DSC technique was employed to access the glass transition temperature (Tg). The IR and ssNMR spectroscopy suggested the existence of hydrogen bonds of N–H ⋯ O (N–H in β-AZE ⋯ OC in MAL) and C–H ⋯ O (C–H in β-AZE ⋯ OC in MAL) in co-amorphous. Meanwhile, two heterogeneous dimers and one trimer were obtained using simulated calculation, in which existence of another type of hydrogen bond of O–H ⋯ O (O–H in MAL ⋯ ON in β-AZE). Interestingly, simulation suggests that two configurations may exist in one β-AZE/MAL 1:1 dimer. The THz spectrum revealed that four β-AZE/MAL combinations showed different vibration mode compared with the starting components and own the same type of intermolecular interactions. The solubility in different media and the dissolution rate in 0.1 mol/L HCl for four co-amorphous were determined; the dramatically improved dissolution rate of the β-AZE/MAL 1:2 (SG) combination in vitro showed potential to improve the physicochemical properties of β-AZE by co-amorphous.

This work demonstrates molecular interactions and physicochemical properties of β-azelnidipine/maleic acid co-amorphous combination prepared by powder co-grinding method, which include two heterogeneous dimers and one trimer and exhibit dramatically improved dissolution rate in vitro.Figure optionsDownload as PowerPoint slide