Impurity removal method of fructose sodium diphosphate

Abstract

The invention provides an impurity removal method of fructose sodium diphosphate. The impurity removal method comprises the following steps: mixing a decolorizing solution containing fructose sodium diphosphate with ethanol, controlling the mass content of the ethanol in a mixed system to be 40-48%, and standing for layering after complete mixing, so as to obtain impurity-removed syrup at the lower layer. According to the method, ethyl alcohol is adopted for cleaning the decolorizing solution containing fructose diphosphate sodium, the impurity content of the product is reduced, the impurity removal effect is further improved by controlling the content of ethyl alcohol in a mixed system to be 40-48%, meanwhile, the product is basically not separated out in the washing process, and the product yield is higher.

Description

Technical Field

[0001] The present invention relates to a method for removing impurities from sodium fructose diphosphate. Background Art

[0002] Fructose diphosphate (FDP) is an important intermediate metabolite in the process of glucose glycolysis in the body. It exists in human and all other higher animal and plant cells, and has the activity of regulating several enzymes in sugar metabolism and restoring and improving cell metabolism at the molecular level. Exogenous fructose diphosphate can act on the cell membrane, increase the concentration of high-energy phosphate bonds and adenosine triphosphate in the cell by activating phosphofructokinase on the cell membrane, thereby promoting the influx of potassium ions, restoring the cell resting state, increasing the content of diphosphoglyceric acid in red blood cells, inhibiting the release of oxygen free radicals and histamine, and being beneficial to cell energy metabolism and the utilization of glucose in states such as shock, ischemia, hypoxia, tissue injury, extracorporeal circulation, blood transfusion, etc., playing a role in promoting repair and improving cell function.

[0003] In previous studies, we developed a production process for sodium fructose diphosphate, which specifically includes the steps of enzyme reaction - filtration - cation exchange - anion exchange - impurity removal - elution - concentration - decolorization - crystallization - drying - packaging. See Patent CN102839201B. With in-depth research, it is found that due to the limited purity of raw materials, solvents, and the limitations of containers and tools used in the operation process, unnecessary metal ions are often introduced into the product. The product obtained by the above method contains more impurities (including heavy metals such as sodium chloride, lead, barium, and iron), and the yield of the product is not high. The purity and yield of the product need to be further improved. Therefore, we need to develop a method for removing impurities from sodium fructose diphosphate to improve the yield and purity of the product. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for removing impurities from sodium fructose diphosphate.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for removing impurities from sodium fructose diphosphate, the impurity removal method includes mixing the decolorized solution containing sodium fructose diphosphate with ethanol, controlling the mass content of ethanol in the mixed system to be 40 - 48%, standing and separating after complete mixing to obtain the syrup after impurity removal located in the lower layer.

[0007] In our previous research, although ethanol was also used for impurity removal before crystallization, it was difficult to achieve both high yield and high purity. The applicant found that if the ethanol concentration in the mixed system was too low (below 40%), the impurity removal would be incomplete, while if the concentration was too high (above 48%), some of the product would crystallize out, affecting the product yield. By controlling the ethanol content in the mixed system to be 40 - 48%, while ensuring the impurity removal effect, the product would basically not crystallize out during the washing process, thus further improving the product yield and purity.

[0008] Preferably, the mass content of ethanol in the mixed system is controlled to be 43 - 47%.

[0009] Preferably, the mass concentration of the ethanol is 93 - 98%.

[0010] Preferably, the mass content of sodium chloride in the syrup is less than or equal to 0.1%, the iron salt content is lower than 10 ppm, and the content of other heavy metals and / or their salts except iron is lower than 1 ppm.

[0011] Preferably, the decolorized liquid is obtained by subjecting phosphoric acid or its salt and glucose to enzymatic reaction, filtration, cation exchange, anion exchange, impurity removal, elution, concentration, and decolorization.

[0012] More preferably, the preparation method of the decolorized liquid specifically refers to Patent CN102839201B.

[0013] Preferably, the impurity removal method specifically includes putting the decolorized liquid into a washing syrup tank, starting stirring, adding ethanol, stirring, and then standing for 1 - 1.5 h for stratification.

[0014] Preferably, the impurity removal method further includes collecting the syrup, diluting it with water to a solution relative density of 1.2 - 1.6 g / cm 3 , filtering, crystallizing, and drying to obtain the finished product.

[0015] In some embodiments, the steps of collecting the syrup and diluting it with water to a solution relative density of 1.2 - 1.6 g / cm 3 include: putting part of the water into a collecting tank, stirring, putting the impurity-removed syrup located in the lower layer into the collecting tank, and then adding the remaining water.

[0016] In some embodiments, the crystallization includes putting the filtered solution into a crystallization tank, adding ethanol to the crystallization tank, and controlling the ethanol concentration in the crystallization system to be 70 - 75%.

[0017] Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0018] The present invention uses ethanol to wash the decolorized solution containing fructose diphosphate, reducing the impurity content of the product. By controlling the ethanol content in the mixed system to be 40-48%, while further improving the impurity removal effect, the product is basically not precipitated during the washing process, and the product yield is higher. Detailed implementation mode

[0019] In previous research, we developed a production process flow of fructose diphosphate. For details, refer to Patent CN102839201B. Although this method uses ethanol to wash the decolorized solution before crystallization and removes impurities in the decolorized solution to a certain purity, with the in-depth research, we found that the product purity and yield need to be further improved. Based on this, we developed a method for removing impurities of fructose diphosphate on the basis of Patent CN102839201B. By controlling the ethanol feeding amount, the impurity content in the product, especially the contents of chloride ions and metal ions, is further reduced, and at the same time, the product yield is increased.

[0020] The present invention will be further described below in conjunction with embodiments. However, the present invention is not limited to the following embodiments. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are the conventional conditions in the industry. The technical features involved in each implementation mode of the present invention can be combined with each other as long as they do not conflict with each other.

[0021] Unless otherwise specified, the raw materials involved in the following examples and comparative examples are commercially available products, and the preparation method of the decolorized solution involved refers to Example 2 of Patent CN102839201B.

[0022] Unless otherwise specified, the following examples and comparative examples are carried out at room temperature (25±5°C).

[0023] Example 1

[0024] A method for removing impurities of fructose diphosphate, which includes pumping the decolorized solution into a washing syrup tank, starting stirring, adding 95% ethanol to make the final ethanol mass concentration 45%, stirring for about 10 min after adding, and then standing for about 1-1.5 h to completely separate the syrup into layers. Then, the syrup at the bottom is put into a syrup collection tank (about 300 L of water is pre-put into the collection tank and stirring is started), and then an appropriate amount of water is added to dilute it to a certain amount to obtain an intermediate solution, and the relative density of the intermediate solution is 1.4 g / cm 3 ; Drain the upper waste ethanol completely into the waste liquid treatment system.

[0025] Take 150 L of the intermediate solution, filter it, pump it into a crystallization tank, slowly add 95% ethanol to make the final ethanol mass concentration in the tank 72%, stir for crystallization to precipitate, and perform vacuum drying after complete crystallization to obtain a finished product with a final mass of 38 kg.

[0026] Comparative Example 1

[0027] A method for removing impurities from sodium fructose diphosphate, which includes pumping the decolorized liquid into the washing syrup tank, starting stirring, adding 95% ethanol to make the final ethanol mass concentration 15%, stirring for about 10 min after adding, then standing for about 1 - 1.5 h to completely separate the syrup into layers, and then putting the syrup at the bottom into the syrup collection tank (about 300 L of water has been pre - placed in the collection tank and stirring is started), adding an appropriate amount of water to dilute to a certain volume to obtain an intermediate liquid, and the relative density of the intermediate liquid is 1.4 g / cm 3 ; Drain the upper - layer waste ethanol completely into the waste liquid treatment system.

[0028] Take 150 L of the intermediate liquid, filter it, pump it into the crystallization tank, slowly add 95% ethanol to make the final ethanol mass concentration in the tank 72%, stir for crystallization to precipitate, and perform vacuum drying after complete crystallization to obtain the finished product, with a final mass of 32 kg.

[0029] Comparative Example 2

[0030] A method for removing impurities from sodium fructose diphosphate, which includes pumping the decolorized liquid into the washing syrup tank, starting stirring, adding 95% ethanol to make the final ethanol mass concentration 20%, stirring for about 10 min after adding, then standing for about 1 - 1.5 h to completely separate the syrup into layers, and then putting the syrup at the bottom into the syrup collection tank (about 300 L of water has been pre - placed in the collection tank and stirring is started), adding an appropriate amount of water to dilute to a certain volume to obtain an intermediate liquid, and the relative density of the intermediate liquid is 1.4 g / cm 3 ; Drain the upper - layer waste ethanol completely into the waste liquid treatment system.

[0031] Take 150 L of the intermediate liquid, filter it, pump it into the crystallization tank, slowly add 95% ethanol to make the final ethanol mass concentration in the tank 72%, stir for crystallization to precipitate, and perform vacuum drying after complete crystallization to obtain the finished product, with a final mass of 33 kg.

[0032] Comparative Example 3

[0033] A method for removing impurities from sodium fructose diphosphate, which includes pumping the decolorized liquid into the washing syrup tank, starting stirring, adding 95% ethanol to make the final ethanol mass concentration 35%, stirring for about 10 min after adding, then standing for about 1 - 1.5 h to completely separate the syrup into layers, and then putting the syrup at the bottom into the syrup collection tank (about 300 L of water has been pre - placed in the collection tank and stirring is started), adding an appropriate amount of water to dilute to a certain volume to obtain an intermediate liquid, and the relative density of the intermediate liquid is 1.4 g / cm 3 ; Drain the upper - layer waste ethanol completely into the waste liquid treatment system.

[0034] Take 150 L of the intermediate liquid, filter it, pump it into the crystallization tank, slowly add 95% ethanol, so that the final ethanol mass concentration in the tank is 72%, stir to crystallize and precipitate. After crystallization is complete, carry out vacuum drying to obtain the finished product, with a final mass of 35 kg.

[0035] Comparative Example 4

[0036] An impurity removal method for sodium fructose diphosphate, which includes pumping the decolorized liquid into the washing syrup tank, starting stirring, adding 95% ethanol, so that the final ethanol mass concentration is 70%. After adding, stir for about 10 min, and then let it stand for about 1 - 1.5 h to completely separate the syrup into layers. Then put the syrup at the bottom into the syrup collection tank (about 300 L of water is pre - placed in the collection tank and stirring is started), and add an appropriate amount of water to dilute to obtain the intermediate liquid, and the relative density of the intermediate liquid is 1.4 g / cm 3 ; Drain the upper - layer waste ethanol completely into the waste liquid treatment system.

[0037] Take 150 L of the intermediate liquid, filter it, pump it into the crystallization tank, slowly add 95% ethanol, so that the final ethanol mass concentration in the tank is 72%, stir to crystallize and precipitate. After crystallization is complete, carry out vacuum drying to obtain the finished product, with a final mass of 26 kg.

[0038] The test results of impurities in the intermediate liquid are shown in Table 1 and Table 2 below. Among them, the determination of sodium chloride refers to the sodium chloride determination method in General Chapter 3107 of the Third Edition of the Chinese Pharmacopoeia in 2015, the determination of iron salts refers to the thiocyanate method in the Pharmacopoeia of the People's Republic of China (2015), and heavy metals are detected by ultraviolet - visible spectrophotometry.

[0039] Table 1

[0040]

[0041]

[0042] Table 2

[0043]

[0044] By comparing Comparative Examples 1 - 4 and Example 1, it is found that by adding ethanol for washing to the decolorized liquid, the impurity content of the product can be reduced and the product quality can be improved. As the ethanol concentration in the washing system increases, the removal effects on sodium chloride, iron salts and heavy metals are better and the product yield shows an upward trend. However, as the ethanol concentration is further increased, the impurity removal effect decreases, and some products crystallize out during the impurity removal process, resulting in a decrease in the product yield. Preferably, the ethanol concentration in the system is 45%. In addition, the applicant also found that if the ethanol concentration is too low (less than 40%), it will also affect the product yield. The applicant guesses that the high impurity content in the syrup will affect crystallization, thus resulting in a low yield.

[0045] The above has made a detailed description of the present invention, aiming to enable those skilled in the art to understand the content of the present invention and implement it. However, it should not be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A method for removing impurities from sodium fructose diphosphate, characterized in that: The impurity removal method includes mixing the decolorized liquid containing sodium fructose diphosphate with ethanol, controlling the mass content of ethanol in the mixed system to be 40-48%, standing and separating layers after complete mixing to obtain the syrup after impurity removal located in the lower layer.

2. The method for removing impurities from sodium fructose diphosphate according to claim 1, characterized in that: Control the mass content of ethanol in the mixed system to be 45-46%.

3. The method for removing impurities from sodium fructose diphosphate according to claim 1 or 2, characterized in that: The mass concentration of the ethanol is 93-98%.

4. The method for removing impurities from sodium fructose diphosphate according to claim 1, characterized in that: The mass content of sodium chloride in the syrup is less than or equal to 0.1%, the iron salt content is lower than 10 ppm, and the content of other heavy metals and / or their salts except iron is lower than 1 ppm.

5. The method for removing impurities from sodium fructose diphosphate according to claim 1, characterized in that: The decolorized liquid is obtained by subjecting phosphoric acid or its salt and glucose to an enzymatic reaction, filtration, cation exchange, anion exchange, impurity removal, elution, concentration and decolorization.

6. The method for removing impurities from sodium fructose diphosphate according to claim 1, characterized in that: The impurity removal method specifically includes putting the decolorized liquid into a syrup washing tank, starting stirring, adding ethanol, stirring, and then standing for 1-1.5 h to separate layers.

7. The method for removing impurities from sodium fructose diphosphate according to claim 1, characterized in that: The impurity removal method further includes the steps of collecting the syrup, diluting it with water to a relative density of the solution of 1.2 to 1.6 g / cm 3 , filtering, crystallizing, and drying to obtain the finished product.

8. The method for removing impurities from sodium fructose diphosphate according to claim 7, characterized in that: The step of collecting the syrup and diluting it with water to a solution relative density of 1.2 to 1.6 g / cm 3 includes: putting a part of water into the collection tank, stirring, putting the syrup after impurity removal in the lower layer into the collection tank, and then adding the remaining water.

9. The method for removing impurities from sodium fructose diphosphate according to claim 7, characterized in that: The crystallization includes putting the filtered solution into a crystallization tank, adding ethanol to the crystallization tank, and controlling the concentration of ethanol in the crystallization system to be 70-75%.

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