Solubility Behavior And Solvation Effects Of L-Proline And Its Derivatives

In recent years,enterprises have higher and higher requirements for the quality of fine chemical products,especially pharmaceutical products.However,the impurities and by-products introduced in the process of drug synthesis could not only have a great negative impact on the pharmacological effects and clinical applications,but also pollute the ecological environment by the by-products produced in the process of downstream production.Crystallization,the traditional operation of chemical separation unit,which can act as a crucial means to improve the purity and yield of target products.The quality of upstream products can be effectively improved through crystallization separation.In the crystallization process,multicomponent solid-liquid equilibrium data,that is,solubility,is particularly important as the basic thermodynamic data.A large and accurate solubility database can not only be used to effectively guide the selection of crystallization solvents,the selection of crystallization methods,and the regulation and optimization of crystallization process,but also help to understand the mechanism of intermolecular interactions between solute and solvent in the solid-liquid phase equilibrium system.L-Proline and its derivatives can be used as important intermediates in drug synthesis.However,there is no systematic report and research on their solubility behavior in solvent systems in the research field of small molecule solid-liquid equilibrium at home and abroad.For this purpose,this paper carries out the research in the following five aspects:(1)The reliability and applicability of the solubility determination method were verified,and the dissolution equilibrium time was determined.The results of the verification experiment show that the relative deviations(RDs)and average relative deviations(ARDs)between the experimental values and literature values are within a reasonable range,indicating that the solubility determination method used in this paper can be used to accurately determine the solubility of L-proline and its five derivatives in the solvent systems.The experimental results for dissolution equilibrium time show that the time to achieve solid-liquid phase equilibrium is 1 h for each system.(2)The solid state in the solid-liquid equilibrium systems was characterized by powder X-ray diffraction and TG-DSC.The X-ray diffraction patterns show that except for the system of N-acetyl-L-proline+acetonitrile,the positions of the X-ray diffraction characteristic peaks of the equilibrium solids are the same as that of the corresponding raw materials,which indicates that except for the solid phase transformation of N-acetyl-L-proline in the dissolution process of pure acetonitrile,the solid phases in other dissolution equilibrium systems did not undergo polymorphism transformation,formation of solvates and crystalline-amorphous transition.In addition,the TG-DSC curves show that the solid state of solute did not change during the process of solubility determination,such as thermal decomposition,melting and melting recrystallization.(3)The solubility of L-proline and its five derivatives in different solvent systems were systematically determined by improved static gravimetric method.The experimental results showed that in the pure solvents,although the solubility of L-proline and its five derivatives showed a monotonic increasing tendency with the increase of the absolute temperature of the system,the solubility of the same solute in different solvents showed different dependence on the temperature.For the binary solvent systems,when the temperature is constant,the solubility of solutes in most systems increases monotonously with the increase of positive solvent content in binary solvents,while there are synergistic solvation effects in the solubility curves of L-proline+ethanol+acetone,L-proline+ethanol+acetonitrile and Ethyl L-thiazolidine-4-carboxylate hydrochloride+ethanol+methyl acetate;when the solvent composition is constant,the solubility in all systems is positively correlated with temperature.(4)The solvation effects of L-proline and its five derivatives were discussed.For the solubility behavior of the same solute in different solvent systems,it can be seen from the relationship between solubility and solvent polarity that solvent polarity dominates the solvation effects of L-proline and its derivatives except for L-hydroxyproline and L-thioproline.It can be concluded by the analysis of the relationship between solubility and other properties of solvents that the relatively strong hydrogen bond interaction,as well as similar groups between solute and solvent molecules could promote the solvation process of solute to a certain extent,which means that they can enhance the solubility,while the relatively large cohesive energy density,steric hindrance and viscosity of solvent may inhibit the solvation process of solute,resulting in the lower solubility of solute in some solvents with stronger polarities.In addition,there are special solubility behaviors in several solvent systems,including the intersection of solubility curves and synergistic solvation effect.The reasons can be attributed to the competitive relationship between solvent-solute and solvent-solvent interactions in affecting the solubility.For the solubility behavior of different solutes in the same solvent,by analyzing the solvation effect determined by the structure-activity relationship of solutes,it can be concluded that the differences in the size of solute molecules,the structure(groups)similar to solvent molecules and the number and size of hydrophobic groups could all result in the different solubility behaviors.(5)The semi-empirical thermodynamic models were used to fit the solubility data,and the fitting effect was evaluated.The fitting and calculation results reveal that the calculated values of solubility data via all models are in good agreement with the experimental values.For the pure solvent systems,the correlation results of the modified Apelblat model are similar to the Yaws model,and the fitting effect is slightly better than the Yaws model in most cases;for the fitting effect of the solubility in binary solvent systems at a certain temperature,the correlation results of Jouyban-Acree model are better than the Machatha model;for the three-dimensional model fitting of the solubility in binary solvent systems,Apelblat-Jouyban-Acree model could provide a better fitting effect than Apelblat-Machatha model.