Study On The Dissolution Rule Of Hydrochlorothiazide Cocrystal

In recent years,with the changes in people's diet and the aging of the population,high blood pressure has become an important factor that endangers human life because of its vulnerability to cardiovascular and cerebrovascular diseases.Hydrochlorothiazide is a first-line drug for the treatment of such diseases,and is essentially a diuretic.However,the solubility of hydrochlorothiazide is poor,which affects the dissolution and bioavailability,so that it cannot achieve sufficient efficacy.In this paper,the thermodynamic properties and dissolution of hydrochlorothiazide synthetic drugs were investigated.The laser dynamic method was used to measure hydrochlorothiazide in ten pure solvents(methanol,ethanol,n-propanol,isopropanol,acetonitrile,ethyl acetate,water,2-butyl alcohol,1-pentanol,isobutyl alcohol)and two mixed solvents(methanol+water,acetonitrile+n-propanol)at a normal pressure and a temperature in the range of 10 to 50?.The solubility of hydrochlorothiazide in the ten pure solvents determined in this paper increases as the temperature rises.The solubility is ranked as methanol>acetonitrile>ethanol>ethyl acetate>n-propanol(isopropanol)>2-butyl alcohol(isobutyl alcohol)>1-pentanol>water.In methanol+ water mixed solvent,the solubility of hydrochlorothiazide increases with the increasing initial mole fraction of methanol;but in acetonitrile+n-propanol mixed solvent,hydrochlorothiazide had the maximum solubility when the initial mole fraction of acetonitrile was roughly 0.6.The experimental results were fitted using the Apelblat equation,the ?h equation and the NRTL equation and the fitting effect is all good.According to the solubility data,the thermodynamic parameters of hydrochlorothiazide dissolution process were calculated,and the dissolution process of hydrochlorothiazide was explored.The cocrystals of hydrochlorothiazide with nicotinic acid,4',4-bipyridine,pyrazinamide and Nicotinic acid N-oxide were prepared by evaporation crystallization and liquid assisted grinding.Diffraction of four products was observed by X-ray diffraction(XRD)and there were new peaks and the disappearance of the original peaks,so it was preliminarily determined that cocrystals were formed.According to differential scanning calorimetry(DSC),it is found that all four products have new endothermic peaks,that is,the products have new melting points.Further,it was confirmed that cocrystals were formed.The morphology of the crystal surface was analyzed by optical microscopy,and it was found that the products were different from the morphology of the two components.Three qualitative analysis methods were combined to determine that four cocrystals were formed.Ultraviolet spectrophotometer was used to explore the relationship between the concentration and the absorbance of hydrochlorothiazide in water,simulated gastric fluid,simulated duodenal fluid,simulated intestinal fluid,that is,the standard curve.The relationship between the dissolution of hydrochlorothiazide and hydrochlorothiazide-nicotinic acid N-oxide acid cocrystal in four dissolution media and time,that is,the dissolution curve.The dissolution of hydrochlorothiazide and hydrochlorothiazide-nicotinic acid N-oxide acid in the four dissolution media increased with time,and the dissolution of cocrystal was significantly higher than that of hydrochlorothiazide,indicating that the cocrystal can increase the dissolution of the drug.The dissolution of hydrochlorothiazide-nicotinic acid N-oxide acid cocrystal increased firstly and then decreased in the four dissolution media,which was consistent with the " Spring-Parachute " model.In this paper,the dissolution of the drug is increased by the method of synthesizing the hydrochlorothiazide cocrystal,which increases the data of the previous study to further increase the bioavailability of the drug.