Study On The Preparation And Dissolution Performance Of Pyrazinamide Cocrystal

At present,tuberculosis is still a world disease that threatens human life and health.Pyrazinamide(PZA)is the most effective drug for the treatment of this disease,but its low water solubility severely limits its oral absorption.Pharmaceutical cocrystal as a new type of solid form which can modulate the poor physicochemical properties,so as to improve its curative effect.Therefore,this paper selected PZA the research object,the cocrystal of PZA was systematically studied from the following aspects.In this paper,cinnamic acid,tartaric acid and maleic acid(MA)were selected as cocrystal formers(CCF),the reaction crystallization method was used to screen the cocrystal.The products were qualitatively analyzed by powder X-ray diffraction,differential scanning calorimetry,infrared spectroscopy,scanning electron microscopy;the PZA-MA cocrystal was quantitatively analyzed by powder X-ray diffraction and high performance liquid chromatography,it is finally determined that PZA and MA are combined with the stoichiometric ratio of 1:2.The solubility of PZA and PZA-MA cocrystal in five pure solvents(methanol,n-propanol,water,acetone,ethyl acetate)and binary mixed solvents(acetone+n-propanol)were measured by laser technique.It can be seen from the solubility data that the solubility of PZA-MA cocrystal is obviously higher than that of PZA in the selected solvent.Meanwhile,the measured data were correlated and calculated by using the different empirical models,the results show that the models selected in this paper can well predict the solubility data at a specific temperature.On the basis of the measured solubility data,the thermodynamic properties of the PZA and PZA-MA cocrystal dissolved in selected solvents were calculated.At the same time,the mechanism of enhanced solubility of the PZA-MA cocrystal was explained based on the theory of lattice energy and solvation energy.The[API concentration]versus[dissolution time]plots(dissolution rate)were determined of PZA and PZA-MA cocrystal in water,simulated gastric juice(hydrochloric acid buffer pH=1.2),simulated duodenal juice(acetic acid buffer pH=4.0)and simulated intestinal juice(phosphoric acid buffer pH=6.8)in this paper.At the same time,the dissolution performance of PZA-MA cocrystal was analyzed in combination with the "spring and parachute"concept for amorphous drug;on the basis of the related theory of inhibition of drug precipitation,the effect of MA on the precipitation process of PZA when PZA-MA cocrystal were dissolved was further speculated.The research content of this paper provides some theoretical basis and basic data for studying the solubility of insoluble drugs by cocrystal.