Synthesis And Properties Study Of Cocrystals On A Phosphodiesterase 4 Inhibitor Chlorbipram

Objective Chlorbipram(ChBP)is a novel PDE4 inhibitor.Pharmacological studies have shown that it has good antidepressant activity,but it is almost insoluble in water,resulting in low bioavailability.In this study,by introducing ligands with high water solubility,the drug cocrystals are formed in a non-covalent bond with ChBP in a certain stoichiometric ratio to improve the properties of ChBP solubility and bioavailability.Besides,law of phase transition and thermodynamic mechanism about the cocrystals could be discoverd.Methods Based on the principle of supramolecular chemistry,supramolecular synthons were selected and designed,and the slow evaporating method of solvent,solvent-assisted grinding method and fast solvent removal method were used to synthesize the eutectic with novel structure and better pharmaceutical properties.The discovery and confirmation of the new eutectic system used methods of X-ray diffraction(single crystal and powder),thermodynamics(differential scanning calorimetry and thermogravimetric analysis),nuclear magnetic resonance(liquid hydrogen spectrum/solid carbon spectrum)and infrared and solid-state fluorescence spectroscopy to perform a comprehensive solid-state chemical characterization.This thesis carried out in vivo(bioavailability)and external(solubility,inherent dissolution rate,moisture absorption,etc.)experiments on the discovered new eutectic system to evaluate the changes in its properties.Phase transformation law and thermodynamic mechanism of unstable eutectic hydrate were tested by ternary phase and dissolution behavior diagram.Results In this study,for the first time,four novel cocrystal hydrates had been discovered and characterized:chlorbipram-fumaric acid(ChBP-FA·2H2O,2:1),chlorbipram-salicylic acid(ChBP-SA·2H2O,1:1),chlorbipram-gentisic acid(ChBP-GA·2H2O,1:1)and chlorbipram-m-hydroxybenzoic acid(ChBP-MHA·H2O,1:1).The single crystal X-ray diffraction analysis showed that ChBP-FA·2H2O belongs to the triclinic system and P 1 space group(ChBP:FA:H2O=2:1:2;a=4.433,b=13.470,c=23.504;α=80.123°,β=88.657°,γ= 86.6490),ChBP-SA·2H2O and ChBP-MHA·H2O belong to the monoclinic system,P 21/n space group(ChBP:SA:H2O=1:1:2;a=4.214,b=53.900,c=13.876;β=94.471°;ChBP:MHA:H20=1:1:1;a=4.429,b=52.629,c=13.686;β=94.047°).The results of differential scanning calorimetry and thermogravimetric analysis showed that the lattice water content of the sample was consistent with the single crystal X-ray diffraction results.Compared with the solubility of ChBP in isopropyl alcohol:water=1:1 solvent(2561.3 ± 150.4 μg/mL),the solubility of ChBP-GA·2H2O and ChBP-SA·2H2O cocrystal were significantly improved,reaching 3724.4± 58.7 μg/mL and 2897.4 ±81.9 μg/mL respectively.On this basis,SD rats were used for further bioavailability studies.The experimental results showed that the maximum blood concentration of ChBP-GA·2H2O and ChBP-SA·2H2O(Cmax=156.8±50.9 ng/mL,105.3 ± 35.6 ng/mL)were 3.1 and 2.1 times of API(51.3± 15.1 ng/mL).The area under the blood concentration-time curve of ChBP-GA·2H2O and ChBP-SA·2H2O(AUC0-∞=549.7± 86.7 ng·h/mL,417.5 ± 87.2 ng· h/mL)were also significantly greater than that of ChBP(346.8 ±90.4 ng·h/mL),while ChBP-FA·2H2O has the longest plasma concentration half-life(t1/2=10.0±2.6 h).Thermal analysis results showed that the stability of ChBP-MHA·H2O was lower than that of ChBP.Phase transformation law and apparent solubility of cocrystal hydrate were obtained by ternary phase diagram and dissolution behavior diagram.Conclusion Four novel cocrystals including ChBP-FA·2H2O,ChBP-SA·2H2O,ChBP-GA·2H2O,and ChBP-MHA·H2O were discovered and prepared for the first time.The atomic distribution,molecular arrangement,and intra/inter-molecular hydrogen bonding relationship were carried out by X-ray diffraction and other methods accurately.The evaluation results of in vivo and in vitro properties show that the solubility and bioavailability of the ChBP-GA·2H2O and ChBP-SA·2H2O cocrystals were significantly improved,while ChBP-FA-2H2O significantly prolongs the drug absorption time,which provided new methods and ideas for the development and application of ChBP.The ternary phase diagram determined the stable existence conditions of ChBP-MHA·H2O cocrystal hydrate,and the dissolution behavior diagram further explained the mechanism of ChBP cocrystal hydrate to promote drug absorption,both of them providing data support and scientific basis for the thermodynamic study of cocrystal hydrate.