WO2021233125A1

WO2021233125A1 - Method for removing elemental impurities and pigments from sugammadex sodium refined products

Info

Publication number: WO2021233125A1
Application number: PCT/CN2021/091899
Authority: WO
Inventors: 潘攀; 郭辉; 吴友灵
Original assignee: 合肥博思科创医药科技有限公司
Priority date: 2020-05-22
Filing date: 2021-05-06
Publication date: 2021-11-25
Also published as: CN111518229B; CN111518229A

Abstract

Disclosed is a method for removing elemental impurities and pigments from a sugammadex sodium refined product, comprising: dissolving a sugammadex sodium refined product in an aqueous solution; adding dropwise a certain amount of a poor solvent such that a small part of sugammadex sodium and a large part of an elemental impurity and pigment are precipitated from the solution; after the analyte of said portion is separated, collecting sugammadex sodium contained in an upper layer mother liquor; and by means of direct concentration or solvent crystallization, obtaining a product that has had most elemental impurities removed. The color of the obtained product becomes lighter and the elemental impurity content is significantly reduced, satisfying the requirements of the ICH regarding elemental impurity limit; in addition, the method is simple and safe to operate, has good economic performance, and is suitable for industrialized production.

Description

Method for removing elemental impurities and pigments in Sodium Gluconate refined products

Technical field

The present invention relates to the technical field of medicine production and purification, in particular to a method for removing elemental impurities and pigments in refined sodium gluconate products.

Background technique

The chemical name of Sodium Gluconate is 6A, 6B, 6C, 6D, 6E, 7F, 6G, 6H-octa-S-(2-carboxyethyl)-6A, 6B, 6C, 6D, 6E, 7F, 6G, 6H-octathio-γ-cyclodextrin octasodium salt, the structural formula is:

Sugam Gluconate is a new type of muscle relaxant reversal agent developed by the Dutch company Organon. It is used clinically to reverse the neuromuscular blockade of rocuronium or vecuronium. It has a good curative effect and extremely Good security. Since the EU approved its listing in July 2008, it has been listed in Japan, South Korea, the United States and other countries, and listed in China in 2018.

Sodium Gluconate is a structurally modified γ-cyclodextrin. Due to its hollow cavity structure, it is easy to wrap small molecule impurities in the cavity, and there are many exposed hydroxyl groups, carboxyl groups and other polar groups in its structure. , Has a strong chelating effect on metal elements. Therefore, if excessive elemental impurities are introduced in the production process due to factors such as equipment materials and raw materials, it is difficult to remove them by conventional means. This feature has brought great challenges to the formulation of the elemental impurity control strategy of Sodium Gluconate. Moreover, the presence of iron and other metal elements will largely lead to the darkening of the color of the preparation product Sodium Gluconate Injection, and some pigment substances such as humin are not easy to be chelated from the Sodium Gluconate molecule. Elimination of the product also brings challenges to the chromaticity control of the product.

The research and control of elemental impurities are currently the key focus areas for regulatory agencies to fully evaluate whether drug quality research is adequate, and they are also the focus of attention in the drug production process. At present, common methods for removing elemental impurities in pharmaceutical production, including the use of specific types of resin adsorption, silica gel adsorption, chelating agents, etc., have problems such as high cost, cumbersome treatment process, and solid waste; conventional simple recrystallization methods Due to the influence of the special molecular structure of Sodium Gluconate, it is difficult to remove the impurities that are encapsulated and chelated on the Sodium Gluconate molecule; the purified water washing method cannot be applied to Sodium Gluconate, which has better water solubility. Of the substance. There are many reports about the preparation process of Sodium Gluconate and the purification process of related substances at home and abroad, but the report on the removal of elemental impurities and pigments is very rare. Therefore, the development of a method that can efficiently and conveniently remove elemental impurities in sugammadex sodium has important application value.

J.Med.Chem.2002,45,1806-1816PP proposed that in the N,N-dimethylformamide system, under the catalysis of triphenylphosphorus, bromine reacted with γ-cyclodextrin to obtain 6-deoxy-6- Perbromo-γ-cyclodextrin. The product is reacted with methyl 3-mercaptopropionate under the catalysis of anhydrous cesium carbonate to obtain the product sugammadex methyl ester, which is then hydrolyzed by sodium hydroxide to obtain sugammadex sodium. The yield is 60%. According to this method, the crude product of Sodium Gluconate is obtained, and the purity is low. There is no report on further purification and purification and removal of elemental impurities and pigments.

Chem.Asian J.2011,6,2390–2399 First iodo γ-cyclodextrin to obtain crude 6-deoxy-6-periodo-γ-cyclodextrin, which is reacted with acetic anhydride to form an ester, which is passed through silica gel Purified by column chromatography, and then hydrolyzed with sodium methoxide to obtain 6-deoxy-6-periodo-γ-cyclodextrin product with higher purity. Finally, an ether is formed from 3-mercaptopropionic acid to obtain the target product. The reaction intermediate has high purity and few impurities, and the post-treatment and purification of the product is relatively simple. However, the risk of introducing elemental impurities brought by the strongly alkaline reaction system has not been considered.

WO0140316PP uses iodine as a halogenating reagent to react with γ-cyclodextrin under the catalysis of triphenylphosphorus to produce 6-deoxy-6-periodo-γ-cyclodextrin. This intermediate is then combined with 3-mercaptopropionic acid to form a thioether, which is purified by membrane dialysis to obtain the target product. The method has a simple and reliable route and high reaction activity, but the purification of the product only uses membrane dialysis purification, and it is difficult to obtain high-purity sodium gluconate. There is no report on further purification and purification and removal of elemental impurities and pigments.

CN105348412 discloses a purification method for crude Sodium Gluconate. The crude Sodium Sodium Gluconate is hydrolyzed under acidic conditions to obtain free acid solids. The free acid solids are beaten and purified with water, and then the free acids are reacted with organic amines. Prepare ammonium glucosamine salt, and the obtained ammonium salt is recrystallized and purified; then free acid is freed under acidic conditions, the free acid solid water is beaten, washed and purified, and the obtained free acid is reacted with sodium hydroxide to prepare sodium gluconate. Pure. This method does not use column chromatography, dialysis and other methods, but the steps are complicated and require multiple conversions between free acid and salt, which is inconvenient to operate. In addition, the risk of introducing more elemental impurities in industrial production of mineral-derived iodine and strong alkaline reaction systems has not been considered.

Summary of the invention

The purpose of the present invention is to solve the shortcomings in the prior art, and proposes a method for removing elemental impurities and pigments in Sodium Gluconate refined products.

In order to achieve the above objective, the present invention adopts the following two basically similar technical solutions:

Option One:

A method for removing elemental impurities and pigments in Sodium Gluconate refined products, including the following steps:

Step 1: Dissolve the Sodium Gluconate refined product in water to form a clear solution, add a certain amount of poor solvent A at room temperature, the solution becomes slightly turbid; transfer the slightly turbid solution to a separatory funnel, After standing for stratification, a small amount of oily matter sinks to the bottom; the lower oily matter B and the supernatant liquid C are separated;

Step 2: Transfer the supernatant liquid C to a flask, and concentrate it under reduced pressure to dryness to obtain the finished product E of sodium gluconate with the removal of elemental impurities and pigments.

Preferably, the poor solvent A is specifically any one of acetone, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, DMF and DMSO.

Preferably, the mass ratio of Sodium Gluconate refined product to water in step 1 is 1:0.5 to 1:50, and the mass ratio of water to bad solvent A is 1:0.1 to 1:50.

Further, in step 1, the mass ratio of Sodium Gluconate refined product to water is 1:1 to 1:10, and the mass ratio of water to poor solvent A is 1:1 to 1:10.

More preferably, the mass ratio of Sodium Gluconate refined product to water in step 1 is 1:3 to 1:4, and the mass ratio of water to poor solvent A is 1:0.5 to 1:1.

Option II:

Step 2: Transfer the supernatant liquid C to the flask, stir at room temperature, add a certain amount of poor solvent D while stirring, and a white solid precipitates out, filter it with suction and dry it to obtain a comfortable solution that removes elemental impurities and pigments Sodium gluconate finished product E.

Preferably, the poor solvent A is specifically any one of acetone, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, DMF, and DMSO, and the poor solvent D is specifically acetone, methanol, ethanol, and isopropyl alcohol. Any of propanol, acetonitrile, 1,4-dioxane, DMF and DMSO.

Preferably, the mass ratio of Sodium Gluconate refined product to water in step one is 1:0.5 to 1:50, and the mass ratio of water to poor solvent A is 1:0.1 to 1:50; the supernatant in step two The mass ratio of C to poor solvent D is 1:0.5 to 1:50.

Further, the mass ratio of Sodium Gluconate refined product to water in step one is 1:1 to 1:10, and the mass ratio of water to poor solvent A is 1:1 to 1:10; the supernatant in step two The mass ratio of C to poor solvent D is 1:1 to 1:10.

More preferably, the mass ratio of Sodium Gluconate refined product to water in step one is 1:3 to 1:4, and the mass ratio of water to poor solvent A is 1:0.5 to 1:1; the middle and upper layer of step two The mass ratio of the clear liquid C to the poor solvent D is 1:2 to 1:4.

Obviously, the difference between Scheme 1 and Scheme 2 lies in the processing method of Step 2. Scheme 1 adopts the direct concentration method of supernatant C, and scheme 2 adopts the crystallization method with poor solvent D. The advantage of scheme 1 is that it saves organic solvents. The advantage of the second scheme is that the processing speed is fast and the batch is large; the two schemes have smaller differences in the removal rate of element impurities and pigments.

Compared with the prior art, the beneficial effects of the present invention are:

1. In the present invention, a poor solvent is added to the aqueous solution of sugammadex sodium, and it utilizes the capture and chelation between the sugammadex molecule itself, which has a large cavity structure and multi-site hydroxyl and carboxyl groups, and metal element impurities and pigments. The product can be obtained by adding a poor solvent to make a small amount of Sodium Gluconate and most of the element impurities and pigments separated from the solution first, and then adding the poor solvent to the mother liquor from which the element impurities and pigments are removed, or the mother liquor is directly concentrated and dried to obtain the product. Reduce the content of elemental impurities in Sodium Gluconate refined products and make the product lighter.

2. Using the method of the present invention to process the Sodium Gluconate refined product can effectively reduce the content of elemental impurities in the refined Sodium Gluconate product. Among them, the content of iron element can reach ≤10ppm, the level 1 metal element impurities and the level 2A metal element impurities can reach ≤1ppm. The product quality meets the quality requirements of injection raw materials, and also meets the relevant technical requirements of the European Union Quality Research Technical Guidance Principle ICH. The production of Shugeng Sodium Gluconate Injection provides high-quality raw materials.

3. The method for removing elemental impurities and pigments of the present invention has simple process, low cost, easy operation, good economy, and is more suitable for industrial production; the preparation made from the raw material has low elemental impurities and almost no product solution. Color, good safety, avoid the influence of iron on the color of the preparation to the greatest extent, and reduce the risk of toxicity caused by elemental impurities, and bring the greatest benefit to patients.

Description of the drawings

Figure 1 The HPLC diagram of the raw material used before the treatment of the present invention-the refined sodium gluconate product;

Figure 2 ICP-MS report of the raw material used before the treatment of the present invention—Sugeng Sodium Gluconate refined product;

Figure 3 is the HPLC chart of Sodium Gluconate after water/acetone treatment;

Figure 4 is the ICP-MS report of the Sodium Gluconate product after water/acetone treatment;

Figure 5 shows the ICP-MS report of the oil obtained after water/acetone treatment;

Figure 6 is the HPLC chart of the Sodium Suglucose product after water/DMF treatment;

Figure 7 is the ICP-MS report of the Sodium Gluconate product after water/DMF treatment;

Figure 8 is the HPLC chart of the Sodium Gluconate product after water/acetonitrile/ethanol treatment;

Figure 9 is the ICP-MS report of the Sodium Gluconate product after water/acetonitrile/ethanol treatment;

Figure 10 is the HPLC chart of the Sodium Gluconate product after water/ethanol/methanol treatment;

Figure 11 is the ICP-MS report of the Sodium Gluconate product after water/ethanol/methanol treatment;

Figure 12 is the HPLC chart of the sugammadex sodium product treated with water/1,4-dioxane;

Figure 13 is the ICP-MS report of the Sodium Sulfate Gluconate product after water/1,4-dioxane treatment;

Figure 14 is the HPLC chart of the Sodium sugammadex product after water/DMF/DMSO treatment;

Figure 15 is the ICP-MS report of the Sodium Gluconate product after water/DMF/DMSO treatment.

Detailed ways

The preferred embodiments of the method of the present invention are described in more detail below. It should be understood correctly that the method in the embodiments of the present invention is only used to further illustrate the present invention, not to limit the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are claimed by the present invention. Range.

Unless otherwise stated in the present invention, the reagents, instruments and equipment used are all commercially available products.

HPLC method to determine purity:

Take the product to be tested, put it in a 25ml volumetric flask, add a small amount of water and shake to dissolve it, then add a solvent to dilute to the mark, shake well, as the test solution; accurately measure 1ml of the solution and place it in a 100ml volumetric flask, add solvent Dilute to the mark, shake up, and use as a control solution; follow the chromatographic conditions under the content determination item (using octadecyl silane bonded silica as filler, phosphate buffer as mobile phase A, acetonitrile as mobile phase B, and linear Gradient elution, detection wavelength is 200nm), take 20μl of the control solution and inject into the liquid chromatograph, adjust the sensitivity of the detector so that the peak height of the main component chromatographic peak is 10-25% of the full scale, and then accurately measure the test solution 20μl each of the control solution and the control solution were injected into the liquid chromatograph, and the chromatogram was recorded to 3 times the retention time of the main component peak, 6-octa-(2-carboxyethyl)thio-γ-cyclodextrin sodium salt and 6- The sum of the peak area percentages of hepta-(2-carboxyethyl)thio-γ-cyclodextrin sodium salt is the purity of the sample to be tested.

ICP-MS method for determination of elemental impurities:

Mode: KED mode,

Timing: Sweeps/reading 20, Readings/replicate 1, Replicates 3, Helium Flow 3.5.

Processing: Detector, Dual; Process spectral peak, Average; QID, On; Isotope Ratio Mode, Off; Blank subtraction Blank), After Internal Std (after internal standard experiment); Process signal profile, Average; Measurement Unit, cps; Baseline Readings, 0; Apply Smoothing Factor (application smoothing factor) ,5. Sampling

To	Time(时间)Time	Speed(速度)(+/-rpm)Speed (+/-rpm)
Sample Flush(样品冲洗)Sample Flush	00	-42.0-42.0
Read Delay(读取延迟)Read Delay	5050	-35.0-35.0
Analysis(分析)Analysis	To	-35.0-35.0
Wash(冲洗)Wash	00	-42.0-42.0

The Shugeng sodium gluconate refined products used in the examples are all products of the same batch, and their HPLC purity is 99.80% (Figure 1), and the sample is light yellow. The content of Fe is 113ppm and the content of Ti is 6.3 as determined by ICP-MS. ppm, Cr content is 6.4ppm, Co is 1.1ppm (Figure 2).

Example 1:

Take 100g of Sodium Gluconate refined product, add 300g of water to dissolve until clear, stir and add 190g of acetone at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for layering, and an orange-yellow oily substance sank to the bottom. Oily matter separated out. The supernatant liquid was transferred to the flask, and 1300g acetone was added with stirring at room temperature. A white solid precipitated out. The white solid was filtered and dried to obtain 83g of Sodium Gluconate. The purity was 99.78% by HPLC (Figure 3). There was no significant change in product purity. The Fe content determined by ICP-MS was 4.1 ppm, and the remaining elemental impurities were less than 1 ppm (Figure 4). The orange-yellow oil was tested and its Fe content was 200 ppm (Figure 5).

Example 2:

Take 100g of Sodium Gluconate refined product, add 200g of water to dissolve until clear, stir and add 290g of DMF at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for stratification, and a small amount of oil settled on the bottom. The oily matter was separated, the supernatant liquid was transferred to the flask, and 310 g of DMF was added with stirring at room temperature. A white solid precipitated out. The white solid was filtered and dried to obtain 85 g of Sodium Gluconate. The purity of the white solid was 99.78 by HPLC. % (Figure 6), the Fe content determined by ICP-MS is 7.1ppm, and the other elemental impurities are less than 1ppm (Figure 7)

Example 3:

Take 100g of Sodium Gluconate refined product, add 400g of water to dissolve it until clear, stir and add 750g of acetonitrile at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for stratification, and a small amount of oil settled on the bottom. The oily substance was separated, the supernatant liquid was transferred to the flask, and 1600 g of ethanol was added under stirring at room temperature. A white solid was precipitated. The white solid was filtered and dried to obtain 73 g of Sodium Gluconate. The purity of the white solid was 99.78 as determined by HPLC. % (Figure 8), the Fe content determined by ICP-MS is 7.0ppm, and the other elemental impurities are less than 1ppm (Figure 9)

Example 4:

Take 100g of Sodium Gluconate refined product, add 300g of water to dissolve it until it is clear, stir and add 610g of ethanol at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for stratification, and a small amount of oil settled on the bottom. The oily substance was separated, the supernatant liquid was transferred to the flask, and 640g of methanol was added with stirring at room temperature. A white solid precipitated out. The white solid was filtered and dried to obtain 73g of Sodium Gluconate. The purity was 99.79 by HPLC. % (Figure 10), the Fe content determined by ICP-MS was 8.2ppm, and the remaining elemental impurities were less than 1ppm (Figure 11).

Example 5:

Take 100g of Sodium Gluconate refined product, add 300g of water to dissolve it until it is clear, stir and add 490g of 1,4-dioxane at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for stratification, and a small amount of oil settled on the bottom. The oily matter was separated, and the supernatant was transferred to a flask, and it was directly concentrated under reduced pressure to dryness. 79 g of Sodium Gluconate was obtained. The purity was 99.78% by HPLC (Figure 12). The Fe content was 7.4 by ICP-MS. ppm, the other element impurities are less than 1ppm (Figure 13).

Example 6:

Take 100 g of Sodium Gluconate refined product, add 200 g of water to dissolve it until clear, stir and add 290 g of DMF/DMSO (M:M=1:1) at room temperature, after the addition, the solution becomes slightly turbid. The solution was transferred to a separatory funnel, left to stand for stratification, and a small amount of oil settled at the bottom. The oily substance was separated, the supernatant liquid was transferred to the flask, and 310g of DMF/DMSO (M:M=1:1) was added with stirring at room temperature. A white solid precipitated out. Filtered by suction and dried to obtain a white solid, namely sugammadex. 81 g of sugar sodium has a purity of 99.76% as determined by HPLC (Figure 14), the Fe content determined by ICP-MS is 8.5 ppm, and the remaining elemental impurities are less than 1 ppm (Figure 15).

The following is a brief description of the mechanism of the experimental part in the embodiments 1-6 of the present invention:

1) The present invention is a process used by the applicant in the research to process and remove the excess element impurities and pigments of Sodium Gluconate. In the production process, after being processed by ordinary and conventional methods, the Shugan Sodium Gluconate product may still contain a large amount of excess element impurities. For example, the raw material used in Examples 1-6 of the present invention-Shugan Sodium Gluconate refined product, Its properties are light yellow solid powder, determined by ICP-MS, the content of Fe is 113ppm, the content of Ti is 6.3ppm, the content of Cr is 6.4ppm, and the content of Co is 1.1ppm. After being dissolved in water, it forms a brownish-red or yellow-brown clear solution. This kind of solution adopts conventional treatment methods such as crystallization, activated carbon decolorization, ion exchange adsorption, etc., but the effect is poor, the treatment method is more complicated, and the cost is high.

2) Through a large number of experiments, the applicant, in view of the above situation, used the organic solvent that does not dissolve the sodium gluconate but is miscible with water added to the aqueous solution of the sodium gluconate, and the sodium gluconate in the mixed solution system The solubility will gradually decrease with the increase of the ratio of poor solvents until the characteristic of precipitation.

3) The technical route described in the previous embodiment is simply the reverse method of dripping a poor solvent. When the poor solvent is added dropwise to the critical point, Sodium Gluconate will be precipitated. Due to the molecular characteristics of Sodium Gluconate, it will pack and chelate element impurities and pigments together and precipitate out. Of course, a small amount of sugammadex sodium is precipitated at this time, and a large amount of product remains in the mother liquor. The remaining mother liquor continues to be dripped with poor solvents, which will cause the proportion of poor solvents in the mother liquor to continue to rise, and the Sodium Gluconate will continue to precipitate.

4) Therefore, in Step 1 of Scheme 1 or Scheme 2, the ratio range of Sodium Gluconate Refined Product, Water and Poor Solvent A is not a specific fixed ratio. According to the solubility characteristics, it can be summarized as the following four points:

①Sugeng Sodium Gluconate has better solubility in water. Therefore, the larger the amount of water, the more the amount of poor solvent A required for the solution to become turbid, but if the amount of water is too small, the subsequent layering of oily matter will be difficult, resulting in Sodium gluconate loss is too large, so the mass ratio of sodium gluconate refined product to water in step one is 1:0.5～1:50, preferably 1:1～1:10, more preferably 1: 3～1:4 ratio range;

②The amount of poor solvent A is not only related to the concentration of the sodium gluconate solution. At the beginning, there is more water to dissolve the sodium gluconate. The disguised increase in the total volume of water and the poor solvent during precipitation, so it also needs to be added dropwise. Many poor solvents; the dropping ratio of poor solvent A is also related to itself, so the final mass ratio of water to poor solvent A is selected to be 1:0.1 to 1:50, preferably 1:1 to 1:10, and more preferably The ratio range of 1:0.5～1:1 can be determined according to repeated experiments of each solvent;

③The oily substance stratification process has multiple critical points. At the initial concentration of the sodium sugammadex aqueous solution, the poor solvent A is gradually added. When the poor solvent A reaches a certain value, the solution begins to become turbid and separate after standing. A trace of oily matter precipitates out, this is the initial critical point; if you continue to add poor solvent A, there will still be oily matter that will continue to precipitate until the oily matter no longer increases, which is the termination critical point; if you continue to add poor solvent A to the oily matter The appearance of solids indicates that the Sodium Gluconate is beginning to crystallize at this time, which is undesirable;

④The amount of poor solvent A in the present invention is the actual amount located at the initial critical point-terminating critical point. The ratio of poor solvent A must be closer to the critical point when the oil is precipitated, so that a higher yield can be achieved and the separation of elements can be achieved. Purpose of impurities; based on this conclusion, the amount of poor solvent A closer to the termination critical point is used in Examples 1-6 of the present invention, and different solvents have different critical values;

⑤Since the experimental amount of the value-by-value experiment is too large, the present invention only proposes the more preferred examples 1-6 for simple demonstration, but it does not mean that the examples 1-6 are the best experimental plan, which corresponds to the poor solvent used. A. The content of water and poor solvent D is not necessarily the best technical solution; the present invention proposes the above examples only to prove that the so-called "poor solvent inverse method" is adopted, and the cavity structure of the sodium gluconate itself is used to have adsorption elements. The performance of impurities and pigments, the most of the element impurities and pigments are gathered into the layerable oil, which greatly reduces the content of excessive element impurities in the Sodium Gluconate, and the cost is lower. It is a popular detoxification In addition to the element ion impurity method.

5) Referring to Figures 1-15, according to the composition analysis of the Sodium Gluconate refined product and the oily substance obtained in Examples 1-6 and the Sodium Gluconate product, the oily substance is compared to the Sodium Gluconate refined product. The content of elemental impurities increased, the elemental impurities in the Sodium Gluconate products were greatly reduced, from 100ppm to ≤10ppm, and the color changed from light yellow Sodium Gluconate refined products to pure white Sodium Sodium Gluconate products. Solid powder, the effect is remarkable to prove that the scheme of the present invention is completely feasible. It is also possible to repeat the scheme of the present invention many times to obtain products with the lowest elemental impurities and pigments.

6) As for the oily matter, its total volume is relatively small, and it still contains some sugammadex sodium. The oily matter that has accumulated multiple times can be processed intensively, and then continue to use the solution one or the second solution announced by the present invention to continue to collect Most of the oily substance is comfortable sodium gluconate to avoid waste.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modification, equivalent replacement, or improvement made by those skilled in the art based on this patent within the spirit and principle of the present invention (For example, by adjusting the acid-base to make the product free acid and then processing according to the patent method, or the intermediates, crude products, etc. of the production process of this product, first removing elemental impurities and pigments and then making the target product, etc.), all should be included in this Within the scope of protection of the invention.

Claims

A method for removing elemental impurities and pigments in Sodium Gluconate refined products, which is characterized in that it comprises the following steps:

Step 1: Dissolve Sodium Gluconate refined product in water to form a clear solution, add a certain amount of poor solvent A at room temperature, the solution becomes slightly turbid; transfer the slightly turbid solution to a separatory funnel, After standing for stratification, a small amount of oily matter sinks to the bottom; the lower oily matter B and the supernatant liquid C are separated;

Step 2: Transfer the supernatant liquid C to a flask, and concentrate it under reduced pressure to dryness to obtain the finished product E of sodium gluconate with the removal of elemental impurities and pigments.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 1, wherein the poor solvent A is specifically acetone, methanol, ethanol, isopropanol, acetonitrile, 1, A mixture of any one or more of 4-dioxane, DMF and DMSO.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 1, characterized in that the mass ratio of Sodium Gluconate refined products to water in the first step is 1:0.5 ～1:50, the mass ratio of water to poor solvent A is 1:0.1～1:50.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 3, characterized in that the mass ratio of Sodium Gluconate refined products to water in the first step is 1:1 ～1:10, the mass ratio of water to poor solvent A is 1:1～1:10.
A method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 3, characterized in that the mass ratio of Sodium Gluconate refined products to water in the first step is 1:3 ～1:4, the mass ratio of water to poor solvent A is 1:0.5～1:1.
A method for removing elemental impurities and pigments in Sodium Gluconate refined products, which is characterized in that it comprises the following steps:

Step 1: Dissolve Sodium Gluconate refined product in water to form a clear solution, add a certain amount of poor solvent A at room temperature, the solution becomes slightly turbid; transfer the slightly turbid solution to a separatory funnel, After standing for stratification, a small amount of oily matter sinks to the bottom; the lower oily matter B and the supernatant liquid C are separated;

Step 2: Transfer the supernatant liquid C to the flask, stir at room temperature, add a certain amount of poor solvent D while stirring, and a white solid precipitates out, filter it with suction and dry it to obtain a comfortable solution that removes elemental impurities and pigments Sodium gluconate finished product E.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 6, wherein the poor solvent A is specifically acetone, methanol, ethanol, isopropanol, acetonitrile, 1, A mixture of any one or more of 4-dioxane, DMF and DMSO, the poor solvent D is specifically acetone, methanol, ethanol, isopropanol, acetonitrile, 1,4-dioxane, Any one or a mixture of DMF and DMSO.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 6, characterized in that the mass ratio of Sodium Gluconate refined products to water in the first step is 1:0.5 ~1:50, the mass ratio of water to poor solvent A is 1:0.1 to 1:50; the mass ratio of supernatant C to poor solvent D in the second step is 1:0.5 to 1:50.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 8, wherein the mass ratio of Sodium Gluconate refined products to water in the first step is 1:1 ~1:10, the mass ratio of water to poor solvent A is 1:1 to 1:10; the mass ratio of supernatant C to poor solvent D in the second step is 1:1 to 1:10.
The method for removing elemental impurities and pigments in Sodium Gluconate refined products according to claim 8, characterized in that the mass ratio of Sodium Gluconate refined products to water in the first step is 1:3 ~1:4, the mass ratio of water to poor solvent A is 1:0.5 to 1:1; the mass ratio of supernatant C to poor solvent D in the second step is 1:2 to 1:4.