Lattice water provides hydrogen atom donor to form hydrate: A case study of chlorbipram: m-hydroxybenzoic acid (1:1) cocrystal

Abstract

Cocrystal hydrate accounts for a small percentage of cocrystals of poorly water-soluble drugs, and still lack the explanation on its cause of formation. In this study, a cocrystal hydrate with a novel phosphodiesterase-4 (PDE-4) inhibitor, chlorbipram, is prepared and characterized using multi-techniques. The dissolution behavior, ternary phase diagram and theoretical calculations are further performed and discussed. Chlorbipram: m-Hydroxybenzoic acid (ChBP-MHBA, 1: 1) cocrystal hydrate presents approximate equivalent dissolution (1.61 mg/mL) in comparison with ChBP (1.90 mg/mL) in isopropanol/water (1: 1, v/v) solution. Ternary phase diagram plotted in ethyl acetate solvent suggests that ChBP-MHBA cocrystal hydrate has an optimum mass percentage range from (2.91%: 2.64%: 94.45%) to (3.20%: 10.74%: 86.06%) among ChBP, MHBA and ethyl acetate. There are two lattice waters in each unit cell of ChBP-MHBA cocrystal hydrate, accounting for 4.5% proportion of the cell volume using contact surface calculations. Molecular Electrostatic Potential Surface (MEPS) investigations indicate that the strong hydrogen bonds are formed within the cocrystal lattice, which are between the global minimum values of ChBP/MHBA and the global maximum values of lattice water. In summary, lattice water plays an important role in the formation of cocrystal hydrate, providing hydrogen atom donor and forming hydrogen bonds to support its three-dimensional crystal structure.