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.
Xiaoyue Yang,Christophe Blecker,Huan Liu,Dequan Zhang,Zhenyu Wang
To elucidate the regulation of different structures of polyphenolic compounds with m-hydroxy and o-hydroxy groups inhibiting the formation of different heterocyclic amines (HAs), the reactions between classified polyphenols (cover flavonoids , phenolic acids , stilbenes, coumarins, chalcones, and with different hydroxyl groups) and roasted lamb patties were studied, and then validated in model systems in vitro. The results indicated that the chalcone, coumarin, and stilbene compounds were more efficient to inhibit the HAs generation in roasted lamb patties in comparison with the flavonoids, while phenolic acid had the worst effect. Besides, polyphenols inhibit the formation of HAs through a synergistic action of scavenging free radicals and trapping active carbonyls. Polyphenols with m-hydroxyl structures have a stronger inhibition of PhIP 1 , Harman and Norharman by capturing the reaction intermediate carbonyl compounds . Polyphenols with the o-hydroxyl group had a stronger inhibitory effect on MeIQx by scavenging free radicals. It was concluded that the ability of polyphenols to inhibit different HAs can be predicted by their m-hydroxyl and o-hydroxyl groups.
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