Study On Crystallization Thermodynamics And New Crystallization Technology Of Fosfomycin Phenylethylamine Calt

As an important chiral intermediate,Fosfomycin Phenylethylamine Calt is widely used in the preparation of calcium fosfomycin,sodium fosfomycin and other drugs,and the market demand is increasing.The purification of Fosfomycin Phenylethylamine Calt is traditionally carried out in ethanol as a solvent with cooling crystallization at a low temperature.It is particularly important to improve the traditional crystallization process because of its disadvantages of low effective equipment utilization,high solvent loss,poor operating environment,and high energy consumption and the lack of necessary thermodynamic data.In this paper,a large number of thermodynamic data of the cooling crystallization process of Fosfomycin Phenylethylamine Calt was perfected,and based on this,a new cooling-dissolving coupled crystallization process was developed,which greatly reduced the cooling temperature and solvent consumption of the crystallization process.The specific research content is as follows:The solubility of Fosfomycin Phenylethylamine Calt in pure water and absolute ethanol in the range of 278.65 K-347.85 K were measured by the laser dynamic method.In the experimental temperature measurement range,solubility and temperature have a nonlinear relationship,so the operation method using cooling crystallization is more appropriate.At the same temperature,the solubility of Fosfomycin Phenylethylamine Calt in water is greater than that in ethanol.If the same product yield is considered,the required amount of ethanol is twice that of water,and the ethanol cooling termination temperature is about 14° C higher than that of water.Apelblat model was used to correlate the measuredsolubility data with good results and the root mean square deviations of solubility data for water and ethanol were 0.0248% and 0.0527%,respectively.The densities of Fosfomycin Phenylethylamine Calt solution and Fosfomycin Phenylethylamine Calt ethanol solution of various mass fractions in the range of278.15K-343.15 K were determined by a vibrating tube densimeter method.The viscosity of Fosfomycin Phenylethylamine Calt solution and the viscosity of Fosfomycin Phenylethylamine Calt ethanol solution with different mass fractions in the range of302.85K-338.33 K were determined by the capillary method.Density and viscosity decrease with the increase of temperature,and increase with the increase of the content of Fosfomycin Phenylethylamine Calt.Using the least squares method,the density of the research system was correlated with temperature and concentration by two-parameter semi-empirical equation with standard deviations of 0.039% and 0.047%,respectively.The viscosity of the research system changed with temperature and concentration was correlated using the VTF equation and the standard deviations were 1.2% and 0.7%,respectively.The dissolution heat of Fosfomycin Phenylethylamine Calt in water and ethanol was determined by microcalorimetry at atmospheric pressure and 30°C,respectively,and which in water is 16.359 kJ/mol,18.498 kJ/mol in ethanol.That the differential dissolution heat of Fosfomycin Phenylethylamine Calt is 16.194 kJ/mol in water and 17.980 kJ/mol in ethanol are obtained through drawing.At the same time,the energy consumed using water as a solvent is 10% more than that ethanol as a solvent when the same amount of Fosfomycin Phenylethylamine Calt is obtained by calculating.A new process of cooling-dissolving coupled crystallization of Fosfomycin Phenylethylamine Calt was developed,and the optimal operating conditions for the newprocess were determined experimentally.The average yield of Fosfomycin Phenylethylamine Calt under the new crystallization process is 70.9%,which is equivalent to the yield of the current crystallization process with water as a solvent in the factory.However,the new process is simple,with low energy consumption and less emission and can be performed at room temperature without the need of deep-cooling crystallization,and whose solvent acetone and water can be recovered and recycled.