| In the pharmaceutical industry,industrial crystallization is one of the most critical unit operations,which has a decisive impact on the production and application of crystal form products,and directly affects many important indicators such as crystal form,crystal habit,purity,particle size,particle size distribution.Therefore,the development of industrial crystallization technology is the core technology that drives the development of China’s pharmaceutical industry towards high-quality and high-end directions,and meets major national needs.However,industrial crystallization,with its multi-objective,non-linear and strongly coupled characteristics,is still at the"half-science,half-art"stage and is internationally recognized as one of the most difficult chemical unit operations to design.In the crystallization process,the dissolution equilibrium data of multi-component,namely solubility,is particularly important as the thermodynamic basis.It is necessary to expand the solvent range and systematically determine the multicomponent dissolution equilibrium data of N-benzyloxycarbonyl amino acid derivatives at different temperatures.This thesis uses the static weighing method to determine three N-benzyloxycarbonyl amino acid derivatives(N-benzyloxycarbonyl-L-2-phenylglycine,N-benzyloxycarbonyl-L asparagine,N-benzyloxycarbonyl-L-tryptophan)in fifteen pure solvents within the temperature range(283.15-323.15 K)dissolution equilibrium data in the system of n-pentanol,isobutanol,n-butanol,isopropanol,n-propanol,ethanol,methanol,water,methyl acetate,ethyl acetate,acetonitrile,dichloromethane,1,4-dioxane,acetone,and2-butanone,as well as binary mixed solvents(ethanol+water).The phenomenon of crystal transformation in equilibrium solid phase was analyzed using powder X-ray diffraction as a characterization method.The results showed that the three N-benzyloxycarbonyl amino acid derivatives did not undergo crystal transformation in all systems.In a pure solvent system,the solubility of three N-benzyloxycarbonyl amino acid derivatives monotonically increases with the increase of absolute temperature,and the solubility of the three solutes in different solvents also varies with the rate of temperature change.The solvent effects of three N-benzyloxycarbonyl amino acid derivatives in different solvents on their dissolution behavior were discussed.In binary mixed solvent system,the solvent composition is constant,and the solubility increases with increasing temperature.The solubility of N-benzyloxycarbonyl-_L-2-phenylglycine first increases and then decreases with the increase of ethanol molar fraction.When the ethanol molar fraction is 0.900,the solubility peaks,indicating a synergistic solvent effect.The dissolution behavior of N-benzyloxycarbonyl-_L-asparagine was analyzed using Hansen solubility parameters.This thesis uses a thermodynamic model to fit solubility data and evaluates its fitting results.The results showed that in the pure solvent system,the calculated values of the Yaws model and the modified Apelblat model fitted well with the experimental values of solubility data.Based on the AIC values and Akaike weight parameters of the two thermodynamic models,the results showed that the modified Apelblat model had a slightly better fitting effect.For the binary solvent system with a certain temperature,the Apelblat-Jouyban-Acree model can show a good fitting effect. |
