Study On The Phase Diagram And Transformation Thermodynamics Of Omeprazole Sodium Solvates

Solvates are an important form of drugs,which have a major influence on the physical and chemical properties,production processes,preparations,storage processes,and clinical applications.Therefore,it is of great significance to study the formation of solvates,the transformation regular patterns between solvates,and the thermodynamic stability of solvates.Omeprazole sodium（OMS）is a kind of API which is short of hydrogen bond donors.Therefore it is easy to form a variety of solvates.In this paper,OMS is as a model drug to study the ternary phase diagram and transformation thermodynamics of solvate.Combining the characteristics of OMS,a two-step method combined static method with dynamic method for determination of OMS-S₁-S₂ ternary phase diagram was proposed.The two-step method was used to determine the ternary phase diagrams for OMS-Water-Acetonitrile,OMS-Methanol-Water,OMS-Ethanol-Water,and OMS-Methanol-Ethanol at temperature 278.15 K～313.15 K.Based on the OMS-Water-Acetonitrile ternary phase diagram,the dissolution-precipitation equilibrium was studied.Solubility product constants of OMS solvate were calculated,which can be used to decide the direction of the dissolution-precipitation reaction of OMS solvate.The standard equilibrium constant for the transformation between OMS solvates were calculated by two methods.According to the van’t Hoff equation,the solubility product is correlated with the temperature,and the thermodynamic functions of the dissolution-precipitation equilibrium reaction of OMS solvate are calculated,including dissolution enthalpy and dissolution entropy which provide thermodynamics data to calculate the solubility product and predict solubility at any temperature within the experimental temperature range.The thermodynamic stability of OMS solvate was explained from the standpoint of dissolution-precipitation equilibrium combining with the phase diagram.Based on the ternary phase diagrams of OMS-Methanol-Water,OMS-Ethanol-Water,and OMS-Methanol-Ethanol,the chemical equilibrium of OMS solvates transformation was studied.The standard equilibrium constants were calculated and related to temperature to calculate the thermodynamic functions for the transformation of OMS solvate,including the standard molar reaction Gibbs free energy change,the standard molar reaction enthalpy change,and the standard molar reaction entropy change,which can be used to decide the direction of solvate phase transformation and calculate the standard equilibrium constants and transformation point at any temperature within the experimental temperature range.The thermodynamic stability of OMS solvate was explained from the standpoint of chemical equilibrium combining with the phase diagram.The above contents have not been reported in the relevant literature.