| 1.Objective of this thesisMethyl gallate is an intermediate of Bifendate independently developed by my country for the treatment of hepatitis.In addition,methyl gallate itself has great potential for drug development.Propyl gallate is widely used in patients with ischemic cerebrovascular disease,coronary heart disease,angina pectoris and so on.It is a promising drug.In 1996,the FDA requested the drug production department to provide detailed data on the solubility,particle size,and crystal form of new drugs.However,the solubility data of methyl gallate and propyl gallate in various solvents have not been recorded at home and abroad,and the crystallization process has not been involved.Therefore,the research on solid-liquid phase equilibrium and crystallization process optimization is very valuable to promote the development and utilization of methyl gallate and propyl gallate in medicine.In this paper,the solid-liquid phase equilibrium of methyl gallate and propyl gallate and the crystallization process optimization of methyl gallate were mainly studied.2.Experimental methods(1)Taking methyl gallate and propyl gallate as the objects of experimental research,the molecular structure of these two target substances before and after dissolution was characterized by X-ray diffraction.Differential scanning calorimetry was used to obtain the melting point value and melting enthalpy value of the two target substances.(2)The solubility of p-coumaric acid in ethanol solvent at different temperatures was determined.The reliability of the device and method used in the solid-liquid phase equilibrium experiment was judged by comparing the solubility values of p-coumaric acid measured in this experiment and the solubility values of p-coumaric acid published in the literature.(3)The solubility of methyl gallate and propyl gallate in 9 organic pure solvents and 9 mixed solvents with different concentration ratios was determined by gravimetric method.(4)The dissolution entropy,dissolution enthalpy,relative entropy contribution and relative enthalpy contribution of methyl gallate and propyl gallate were calculated by the Van't Hoff equation for dissolution thermodynamic analysis of these two target substances.(5)Five kinds of mathematical models including Apelblat equation,Van't Hoff equation,?h equation,NRTL model and Wilson model were used to correlate the experimental values of the molar solubility of methyl gallate and propyl gallate.The best correlation and solubility prediction model of methyl gallate and propyl gallate were evaluated based on the average relative deviation between the experimental value and the fitted value of the molar solubility.(6)On the basis of solid-liquid phase equilibrium research,the cooling crystallization process optimization of methyl gallate was further studied by controlling the single variable method.the effects of cooling rate,stirring rate,supersaturation,the final temperature and crystal growing time on the crystallization of methyl gallate were investigated.3.Experimental results(1)In the characterization experiment of the target substances,the XRD patterns of methyl gallate and propyl gallate showed that their peak positions before and after dissolution were consistent,and it can be judged that their molecular structures before and after dissolution were not changed.The melting points of methyl gallate and propyl gallate are 477.10 K and 421.94 K,respectively,and the enthalpy of fusion is 35828.22 J/mol and 22355.27 J/mol,respectively.The values of melting point and melting enthalpy can be used in the correlation study of the mathematical models of solubility.(2)The RD results between the measured values of the solubility of p-coumaric acid in this experiment and the solubility values of p-coumaric acid published in the literature showed that the RD values were all within 1.5%,and most were below 1%,indicating that the device and method used in the experiment of solid-liquid equilibrium determination were reliable.(3)The solubility of methyl gallate in pure solvents and ethanol+n-propanol mixed solvents increased with the increase of the experimental temperature.This result provided a theoretical basis for the selection of cooling crystallization method in the study of crystallization process optimization of methyl gallate.At the same temperature,the solubility order of methyl gallate in 9 pure solvents was:acetone>methanol>ethanol>isopropanol>n-propanol>n-butanol>methyl acetate>ethyl acetate>isobutanol.The solubility of methyl gallate in the ethanol+n-propanol mixed solvent increased with the increase of the mass fraction of ethanol.This result provided theoretical basis and data support for the selection of crystallization solvent and calculation of supersaturation in the study of crystallization process optimization of methyl gal late.The solubility of propyl gallate in pure solvents and ethanol+n-propanol mixed solvents increased with the increase of experimental temperature.At the same temperature,the solubility order of propyl gallate in 9 pure solvents was roughly:acetone>n-propanol>isopropanol>methyl acetate>n-butanol>methanol>ethyl acetate>isobutanol>ethanol The solubility of propyl gallate in the ethanol+n-propanol mixed solvent decreased with the increase of the mass fraction of ethanol(4)Whether methyl gallate and propyl gallate were dissolved in 9 different organic pure solvents or in mixed solvents of ethanol and n-propanol with different ratios,the relative enthalpy contribution value was always greater than the relative entropy contribution Value,indicating that both dissolution processes were enthalpy-driven processes.In addition,the enthalpy of dissolution and the entropy of dissolution in the dissolution process were both positive,indicating that the process was endothermic process and the entropy was increasing during the process(5)In the methyl gallate-pure solvent system,the RAD values of the five mathematical models are almost all within 1%.It shows that these five mathematical models have good correlation effects on the experimental values of the molar solubility of methyl gallate in pure solvents.The average RAD of Apelblat equation,Van't Hoff equation,?h equation,NRTL model and Wilson model are 0.35%,0.59%,0.43%,0.55%and 0.58%,respectively.The correlation effects of Apelblat equation,?h equation,NRTL model,Wilson model,Van't Hoff equation are successively decreasing.In the methyl gallate-mixed solvent system,the RAD values of the five mathematical models are all within 3%,and most are within 2%,indicating that these five mathematical models have good correlation effects on the experimental values of the molar solubility of methyl gallate in mixed solvents.The average RAD of Apelblat equation,Van't Hoff equation,?h equation,NRTL model and Wilson model are 0.09%,1.11%,0.86%,1.48%and 2.03%,respectively.The correlation effects of Apelblat equation,?h equation,Van't Hoff equation,NRTL model,Wilson model are successively decreasing.In the propyl gallate-pure solvent system,the RAD values of the five mathematical models are almost all within 1%.indicating that these five mathematical models have good correlation effects on the experimental values of the molar solubility of propyl gallate in pure solvents.The average RAD of Apelblat equation,Van't Hoff equation,?h equation,NRTL model and Wilson model are 0.14%,0.34%,0.35%,0.66%and 0.62%respectively.The correlation effects of Apelblat equation,Van't Hoff equation,?h equation,Wilson model,NRTL model are successively decreasing.In the propyl gallate-mixed solvent system,the RAD values of the five mathematical models are all within 1%,indicating that these five mathematical models have good correlation effects on the experimental values of the molar solubility of propyl gallate in mixed solvents.The average RAD of Apelblat equation,Van't Hoff equation,?h equation,NRTL model,and Wilson model are 0.17%,0.25%,0.27%,0.57%.and 0.52%,respectively.The correlation effects of Apelblat equation,Van't Hoff equation,?h equation,Wilson model,NRTL model are successively decreasing.(6)In the study of the cooling crystallization process optimization of methyl gallate,according to the shape of the crystals obtained and the size distribution of the crystals,the final crystallization process optimization conditions were determined as follows:the cooling rate was 0.4?/min;the stirring rate was 130 rpm/min;the supersaturation was S=1.08;the final temperature was 10?;and the crystal growing time was 90 min4.Conclusion of this thesis(1)The solubility of methyl gallate and propyl gallate in pure solvents and ethanol+n-propanol mixed solvents increase with the increase of temperature.Their dissolution processes are both enthalpy-driven and endothermic processes,and the entropy was increasing during the process(2)Apelblat equation,Van't Hoff equation,?h equation,NRTL model,and Wilson model have good correlation effects on the solubility of methyl gallate and propyl gallate in solvents.However,the Apelblat equation is the best correlation and solubility prediction model for methyl gallate and propyl gallate.(3)The preferred crystallization process optimization conditions are:the cooling rate is 0.4?/min;the stirring rate is 130 rpm/min;the supersaturation is S=1.08;the final temperature is 10?;and the crystal growing time is 90 min. |
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