CN109232574B - Effective folic acid purification method - Google Patents
Effective folic acid purification method Download PDFInfo
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- CN109232574B CN109232574B CN201710560074.4A CN201710560074A CN109232574B CN 109232574 B CN109232574 B CN 109232574B CN 201710560074 A CN201710560074 A CN 201710560074A CN 109232574 B CN109232574 B CN 109232574B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Abstract
The invention belongs to the field of compound preparation, and discloses a method for purifying folic acid. The purification method of folic acid of the invention can greatly improve the purity of folic acid finished products by carrying out primary acid refining after obtaining alkali refined products. Experiments show that compared with the traditional folic acid purification method, the folic acid purification method effectively reduces the contents of the impurity A and the impurity D, and the yield is not obviously reduced.
Description
Technical Field
The invention belongs to the field of compound preparation, particularly relates to an effective folic acid purification method, and particularly relates to a purification method for reducing the content of folic acid impurity A (N- (4-aminobenzoyl) -L-glutamic acid).
Background
Folic acid is a basic variety of vitamin, is a substance essential for the growth and reproduction of body cells, and plays an important role in the division growth of cells and the synthesis of nucleic acid, amino acid and protein. The lack of folic acid in a human body can cause the abnormality of red blood cells, the increase of immature cells, anemia and the reduction of white blood cells; the lack of folic acid in pregnant women may cause low body weight, cleft lip and palate, heart defect, etc. in the fetus at birth.
There are many foods containing folic acid, but natural folic acid is extremely unstable, is easily oxidized by ultraviolet rays, high temperature and the like, and the bioavailability of folic acid is low, so that folic acid which can be really obtained from foods by a human body is not much. Human demand for folic acid depends on industrial synthesis of folic acid. The folic acid synthesized industrially can be kept stable within months or years, and is easy to absorb, and the human availability is about twice as high as that of the natural product. With the rapid development of the fields of medicine, food and the like, the demand of folic acid is rapidly increased, and the rapid development of folic acid synthesis technology is promoted.
However, the purity of the chemically synthesized folic acid crude product is not high, and further purification is needed to obtain a qualified folic acid finished product. At present, the folic acid is purified by a method combining acid refining and alkali refining. Firstly, carrying out an acid dissolution process, dissolving a crude product by using an acid solution, and carrying out elutriation and filter pressing on the dissolved crude product to obtain an acid extract; then carrying out an alkali dissolution process, adding water to the acid extract in an alkali dissolution reaction tank, stirring, adjusting the pH value to 9.0-9.5 at 90-100 ℃ by using an alkali solution, and carrying out filter pressing to obtain an alkali dissolution filtrate; and refining the alkali-soluble filtrate by acid regulation, crystallization, drying and the like to obtain a finished product. The folic acid purification method disclosed in the Chinese patent with the publication number of CN 102432610A comprises the following steps: dissolving the crude folic acid product with 25-35% dilute sulfuric acid, elutriating the dissolved crude folic acid product, and performing pressure filtration to obtain an acid extract; carrying out alkali dissolution on the acid extract by using alkali liquor, heating to 90-102 ℃, adjusting the pH value to 9.0-9.5 by using the alkali liquor, preserving the heat for 1 hour, adding activated carbon for decolorization, and carrying out filter pressing to obtain an alkali-dissolved filtrate; and then, salifying and refining the alkali liquor by using dilute acid to obtain a finished folic acid product. The method for purifying folic acid disclosed in the national patent publication No. CN 103102351B comprises: dissolving a folic acid crude product by using 15% -25% hydrochloric acid, adding water into the dissolved folic acid crude product solution, discharging, centrifuging, and directly drying by spin-drying to obtain an acid extract; in an alkali dissolution reaction vessel, mixing an acid extract with a solvent, adding an organic alkali solution to adjust the pH to 9.0-10.0, heating to 65-90 ℃, adding an adsorbent, keeping the temperature at 65-90 ℃ for 0.5-2 hours, carrying out filter pressing to obtain an alkali dissolution filtrate, adding the clarified alkali dissolution filtrate into a crystallization reaction vessel, heating to 80-90 ℃, adjusting the pH to 3.0-3.5 by using dilute hydrochloric acid, cooling to 55-60 ℃, and centrifuging to obtain a folic acid finished product.
The main impurities and the difficult-to-remove impurities in the folic acid purification process are impurity D (pteroic acid) and impurity A (N- (4-aminobenzoyl) -L-glutamic acid). The quality of the folic acid finished product in European pharmacopoeia requires that the content of impurity D is less than or equal to 0.6 percent, and the content of impurity A is less than or equal to 0.5 percent. In the traditional folic acid purification method, after an acid treatment product is subjected to an alkali refining step, the content of impurity A is increased, and the improvement of the purity of a finished folic acid product is limited. .
Disclosure of Invention
In view of the above, the present invention aims to provide a method for purifying folic acid against the defects of the prior art. According to the purification method of folic acid, after the refined product of alkali is obtained, the folic acid is refined again, so that the purity of the finished product of folic acid is improved, but the yield is not obviously reduced.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme.
A method for purifying folic acid comprises the steps of refining folic acid crude product with a first acid, refining with an alkali, adding an acid solution, refining with a second acid, and drying to obtain a folic acid finished product.
Wherein the first acid refining is specifically to dissolve the folic acid crude product by using an acid solution, heat the solution to be clear, add an adsorbent, stir, filter, add water into the filtrate, stir, stand, and filter to obtain an acid-treated wet product.
The acid solution in the first acid refining step may be at least one of sulfuric acid and hydrochloric acid.
The adsorbent in the first acid refining step may be activated carbon, diatomaceous earth or silica gel.
Further, the first acid refining is specifically to dissolve a folic acid crude product by using an acid solution, heat the solution to 35-45 ℃ to dissolve the folic acid crude product until the solution is clear, add an adsorbent, stir the solution for 25-35 min, filter the solution, add water to the filtrate, stir the solution for 25-35 min, stand the solution for 40-80 min, and filter the solution to obtain an acid-treated wet product.
Further, the first acid refining is preferably to add an acid solution into the folic acid crude product, dropwise add the acid solution while stirring, heat up to 38-42 ℃ to dissolve until the folic acid is clear, add an adsorbent, stir for 28-32min, filter, add water into the filtrate, stir for 28-32min, stand for 50-70 min, filter, and obtain an acid-treated wet product.
Preferably, the mass-to-volume ratio of the folic acid crude product to the acid solution is (2-4): 4; the mass ratio of the adsorbent to the folic acid crude product is (0.5-1.5): 45; and (4) the mass volume ratio of the folic acid crude product to the water added into the filtrate (4-8) is 100 in g/ml.
Further, the volume ratio of the acid solution added to the crude folic acid in the first acid purification step to the acid solution added dropwise with stirring is preferably 1: 1.
Further, the acid solution in the first acid purification step is preferably 45% to 55% sulfuric acid or 18% to 36% hydrochloric acid. In some embodiments the acid solution is 50% sulfuric acid; in other embodiments, the acid solution is 45% sulfuric acid; in other embodiments, the acid solution is 55% sulfuric acid; in other embodiments, the acid solution is 25% hydrochloric acid; in other embodiments, the acid solution is 18% hydrochloric acid; in other embodiments, the acid solution is 36% hydrochloric acid.
The purification method of folic acid provided by the invention is characterized in that after a folic acid crude product is refined by a first acid, alkali refining is carried out. And the alkali refining is specifically to add water to the acid-treated wet product, stir, heat, adjust the pH to 8.0-10.0 by using an alkali solution, add an adsorbent, stir and filter to obtain an alkali refining filtrate, and adjust the acid of the filtrate to crystallize to obtain the alkali refining wet product.
Wherein, the alkali solution in the alkali refining process can be at least one of sodium carbonate, potassium carbonate, ammonia water, sodium hydroxide and potassium hydroxide.
The adsorbent in the alkali refining process is preferably at least one of activated carbon, diatomite and silica gel.
Further, the alkali refining is specifically to add water to the acid-treated wet product and stir, heat the acid-treated wet product to 75-85 ℃, adjust the pH to 8.0-10.0 with an alkali solution, add an adsorbent, stir for 25-35 min, filter the mixture to obtain an alkali refined filtrate, heat the alkali refined filtrate to 75-85 ℃, adjust the pH to 3.0-4.0 with an acid solution, cool the alkali refined filtrate to 65-75 ℃, stir for 25-35 min, centrifuge and drip wash the alkali refined wet product to obtain the alkali refined wet product.
Further, the alkali refining is preferably carried out by adding water into the wet product subjected to acid treatment, stirring and heating to 78-82 ℃, adjusting the pH to 8.0-10.0 by using an alkali solution, adding an adsorbent, stirring for 28-32min, filtering to obtain an alkali refining filtrate, heating the alkali refining filtrate to 78-82 ℃, adjusting the pH to 3.3-3.7 by using an acid solution, cooling to 68-72 ℃, centrifuging, and leaching by using deionized water at 35-40 ℃ to obtain an alkali refining wet product.
Wherein the mass volume ratio of the acid-treated wet product to water is (35-50): 72 in g/ml; the mass ratio of the adsorbent to the acid-treated wet product is 1 (14-20).
Further, the alkali solution is preferably 5-15% sodium carbonate solution, 5-15% potassium carbonate solution, 5-15% ammonia water, 5-15% sodium hydroxide solution or 5-15% potassium hydroxide solution.
In some embodiments the alkali solution is a 10% sodium carbonate solution. In some embodiments the base solution is a 10% aqueous ammonia solution. In some embodiments the base solution is a 10% potassium carbonate solution. In some embodiments the base solution is a 10% sodium hydroxide solution. In some embodiments the alkali solution is a 10% potassium hydroxide solution.
Further, the acid solution in the alkali refining step is 3-8% dilute sulfuric acid, 7-15% hydrochloric acid or 30-40% acetic acid solution; in some embodiments the acid solution is 5% dilute sulfuric acid; in some embodiments the acid solution is 10% hydrochloric acid; in some embodiments the acid solution is a 35% acetic acid solution.
The purification method of folic acid of the invention carries out secondary acid refining after alkali refining and drying to obtain folic acid finished products.
And the second acid refining is specifically to add an acid solution into an alkali refined wet product, heat up and dissolve the solution until the solution is clear, stir the solution, add water into the solution, stir the solution, stand the solution, filter the solution and dry the solution. Wherein the acid solution in the second acid purification step is preferably at least one of sulfuric acid and hydrochloric acid.
Further, the second acid refining is specifically to add an acid solution into the alkali refined wet product, heat the solution to 35-45 ℃ to dissolve the solution until the solution is clear, stir the solution for 25-35 min, add water, stir the solution for 25-35 min, stand the solution for 40-80 min, filter the solution and dry the solution.
Further, the second acid refining is preferably to add an acid solution into an alkali refined wet product, dropwise add the acid solution while stirring, heat up to 38-42 ℃ to dissolve until the solution is clear, stir for 28-32min, add water, stir for 28-32min, stand for 50-70 min, filter and dry.
The volume ratio of the acid solution added to the alkali-refined wet product in the second acid refining step to the acid solution added dropwise with stirring is preferably 1: 1.
Further, in the second acid refining step, the volume ratio of the alkali refined wet product to the acid solution is (35-50): 48; the volume ratio (7-10) of the alkali refined wet product to the added water is 120.
Further, the acid solution in the second acid refining step is 45-55% sulfuric acid or 18-36% hydrochloric acid. In some embodiments the acid solution is 50% sulfuric acid; in other embodiments, the acid solution is 45% sulfuric acid; in other embodiments, the acid solution is 55% sulfuric acid; in other embodiments, the acid solution is 25% hydrochloric acid; in other embodiments, the acid solution is 18% hydrochloric acid; in other embodiments, the acid solution is 36% hydrochloric acid.
According to the technical scheme, the invention provides a purification method of folic acid, which comprises the steps of refining folic acid crude product with a first acid, refining with an alkali, adding an acid solution, refining with a second acid, and drying to obtain a finished product of folic acid. The purification method of folic acid of the invention can greatly improve the purity of folic acid finished products by carrying out primary acid refining after obtaining alkali refined products. Experiments show that compared with the traditional folic acid purification method, the folic acid purification method effectively reduces the contents of the impurity A and the impurity D, and the yield is not obviously reduced.
Detailed Description
The invention discloses a method for purifying folic acid. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Comparative example 1
Acid refining: dissolving 100g of crude folic acid (the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%) by using 500ml of 18% hydrochloric acid, adding water into the dissolved crude folic acid solution, discharging, centrifuging, and spin-drying to obtain the acid extract.
Alkali refining: adding 3000ml deionized water into the acid extract, adding ammonia water dropwise to adjust pH9, heating to 85 deg.C, repeatedly measuring pH value, adding 20g activated carbon after pH is stable, maintaining at 85-90 deg.C for 1 hr, cooling to 55 deg.C, and press filtering.
Acid adjusting and crystallizing: the filtrate was heated to 80 ℃ and 10% hydrochloric acid was added dropwise to adjust the pH to 3.5. Heating to 83.5 deg.C, measuring pH at 3-3.5, and cooling to 57 deg.C. Discharging to a centrifugal machine for direct centrifugation, leaching twice with 300ml of deionized water with the temperature of 35-40 ℃, and drying at the temperature of 80 ℃ to obtain a refined folic acid product. Yield 81%, HPLC purity 99.2%, impurity a 0.41%, impurity D0.10%.
Example 1
First acid refining: adding 240mL of 18% hydrochloric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 18% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of activated carbon, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 456g of acid-treated wet product.
Alkali refining: 456g of the acid-treated wet product was added with 7.2L of distilled water, stirred and heated to 80 ℃, adjusted to pH 9.0 with 10% ammonia solution, added with 25g of activated carbon, stirred for 30min, and filtered. Heating the filtrate to 80 deg.C, adding 5% sulfuric acid to adjust pH to 3.5, and cooling to 70 deg.C. Discharging to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 442g of alkali refined wet product.
Second acid refining: adding 240mL of 18% hydrochloric acid into 442g of alkali refined wet product, dropwise adding 240mL of 18% hydrochloric acid while stirring, heating to 40 ℃ to dissolve until the solution is clear, stirring for 30min, then adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain the finished folic acid product. The yield is 80%, the folic acid purity is 99.6% by HPLC, the impurity A is not detected, and the impurity D is 0.07%.
Comparative example 2
Acid refining: adding 240mL of 50% sulfuric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%), continuing to dropwise add about 240mL of 50% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of active carbon, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 10.0 with 10% sodium hydroxide solution, adding 25g active carbon, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 79 percent, the folic acid purity is 98.7 percent by HPLC detection, the impurity A is 0.71 percent, and the impurity D is 0.35 percent.
Example 2
First acid refining: adding 240mL of 50% sulfuric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%), continuing to dropwise add about 240mL of 50% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of active carbon, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 453g of acid-treated wet product.
Alkali refining: 453g of the acid-treated wet product was added with 7.2L of distilled water, stirred and heated to 80 ℃, adjusted to pH10 with 10% sodium hydroxide solution, added with 25g of activated carbon, stirred for 30min, and filtered. Heating the filtrate to 80 deg.C, adding 10% hydrochloric acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 441g of alkali refined wet product.
Second acid refining: adding 240mL of 50% sulfuric acid into 441g of alkali refined wet product, dropwise adding 240mL of 50% sulfuric acid while stirring, heating to 40 ℃ to dissolve until the solution is clear, stirring for 30min, then adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain the finished product of folic acid. The yield is 78%, the folic acid purity is 99.5% by HPLC detection, the impurity A is 0.01%, and the impurity D is 0.29%.
Comparative example 3
Acid refining: adding 240mL of 45% sulfuric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 45% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of silica gel, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 9 with 10% sodium hydroxide solution, adding silica gel 25g, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 80%, the folic acid purity is 98.7% by HPLC detection, the impurity A is 0.66%, and the impurity D is 0.25%.
Example 3
First acid refining: adding 240mL of 45% sulfuric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 45% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of silica gel, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 458g of acid-treated wet product.
Alkali refining: 458g of acid-treated wet product is added with 7.2L of distilled water, stirred and heated to 80 ℃, pH is adjusted to 9 by 10 percent sodium hydroxide solution, 25g of silica gel is added, stirred for 30min and filtered. Heating the filtrate to 80 deg.C, adding 35% acetic acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging the materials to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 439g of alkali refined wet product.
Second acid refining: adding 240mL of 45% sulfuric acid into 439g of alkali refined wet product, dropwise adding 240mL of 45% sulfuric acid while stirring, heating to 40 ℃ to dissolve until the solution is clear, stirring for 30min, then adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain the finished product of folic acid. The yield is 79%, the folic acid purity is 99.4% by HPLC, the impurity A is not detected, and the impurity D is 0.21%.
Comparative example 4
Acid refining: adding 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%) into 240mL of 55% sulfuric acid, continuously dropwise adding about 240mL of 55% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of diatomite, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 8.0 with 10% sodium carbonate solution, adding 25g diatomaceous earth, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 80%, the folic acid purity is 98.9% by HPLC detection, the impurity A is 0.67%, and the impurity D is 0.28%.
Example 4
First acid refining: adding 240mL of 55% sulfuric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%), continuing to dropwise add about 240mL of 55% sulfuric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of diatomite, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 459g of acid-treated wet product.
Alkali refining: 459g of the acid-treated wet product was added with 7.2L of distilled water, stirred and heated to 80 ℃, adjusted to pH 8.0 with 10% sodium carbonate solution, added with 25g of diatomaceous earth, stirred for 30min and filtered. Heating the filtrate to 80 deg.C, adding 10% hydrochloric acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 441g of alkali refined wet product.
Second acid refining: adding 240mL of 55% sulfuric acid into 441g of alkali refined wet product, dropwise adding 240mL of 55% sulfuric acid while stirring, heating to 40 ℃ to dissolve until the solution is clear, stirring for 30min, then adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain a finished product of folic acid. The yield is 79%, the folic acid purity is 99.5% by HPLC detection, the impurity A is 0.03%, and the impurity D is 0.25%.
Comparative example 5
Acid refining: adding 240mL of 25% hydrochloric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 25% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of activated carbon, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 10.0 with 10% potassium hydroxide solution, adding 25g active carbon, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 80%, the folic acid purity detected by HPLC is 98.7.1%, the impurity A is 0.61%, and the impurity D is 0.31%.
Example 5
First acid refining: adding 240mL of 25% hydrochloric acid into 360g of a folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 25% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of activated carbon, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 457g of an acid-treated wet product.
Alkali refining: 457g of acid-treated wet product is added with 7.2L of distilled water, stirred and heated to 80 ℃, the pH value is adjusted to 10.0 by 10 percent potassium hydroxide solution, 25g of active carbon is added, stirred for 30min and filtered. Heating the filtrate to 80 deg.C, adding 10% hydrochloric acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging the materials to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 443g of alkali refined wet product.
Second acid refining: adding 240mL of 25% hydrochloric acid into 443g of alkali refined wet product, dropwise adding 240mL of 25% hydrochloric acid while stirring, heating to 40 ℃ for dissolving, stirring for 30min, adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain the finished product of folic acid. The yield is 79%, the folic acid purity is 99.5% by HPLC, the impurity A is not detected, and the impurity D is 0.26%.
Comparative example 6
Acid refining: adding 240mL of 18% hydrochloric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 18% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of silica gel, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 9.0 with 10% potassium hydroxide solution, adding silica gel 25g, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 81%, the folic acid purity detected by HPLC is 98.6.1%, the impurity A is 0.67%, and the impurity D is 0.33%.
Example 6
First acid refining: adding 240mL of 18% hydrochloric acid into 360g of a folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the content of the impurity A is 3.5%, and the content of the impurity D is 6.4%), continuing to dropwise add about 240mL of 18% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of silica gel, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 457g of an acid-treated wet product.
Alkali refining: 454g of the acid-treated wet product was added with 7.2L of distilled water, stirred and heated to 80 ℃, adjusted to pH 9.0 with 10% potassium hydroxide solution, added with 25g of silica gel, stirred for 30min, and filtered. Heating the filtrate to 80 deg.C, adding 10% hydrochloric acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 441g of alkali refined wet product.
Second acid refining: adding 240mL of 18% hydrochloric acid into 441g of alkali refined wet product, dropwise adding 240mL of 18% hydrochloric acid while stirring, heating to 40 ℃ for dissolving, stirring for 30min, adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain a finished product of folic acid. The yield is 80%, the folic acid purity is 99.4% by HPLC, the impurity A is not detected, and the impurity D is 0.27%.
Comparative example 7
Acid refining: adding 240mL of 36% hydrochloric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%), continuing to dropwise add about 240mL of 36% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of diatomite, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain an acid-treated product.
Alkali refining: adding 7.2L distilled water into the acid treated product, stirring, heating to 80 deg.C, adjusting pH to 8.0 with 10% potassium carbonate solution, adding 25g diatomaceous earth, stirring for 30min, and filtering.
Acid adjusting and crystallizing: heating the filtrate to 80 deg.C, adjusting pH to 3.5 with 5% dilute sulfuric acid solution, stirring, cooling to 70 deg.C, filtering after about 30min, and oven drying at 50 deg.C to obtain folic acid product. The yield is 80%, the folic acid purity is 98.7% by HPLC detection, the impurity A is 0.60%, and the impurity D is 0.35%.
Example 7
First acid refining: adding 240mL of 36% hydrochloric acid into 360g of folic acid crude product (detected by a pharmacopoeia HPLC method, the folic acid purity is 85.86%, the impurity A content is 3.5%, and the impurity D content is 6.4%), continuing to dropwise add about 240mL of 36% hydrochloric acid under stirring, heating to 40 ℃ to dissolve until the solution is clear, adding 8g of diatomite, stirring for 30min, filtering, adding 6L of distilled water into the filtrate, stirring for 30min, standing for 1h, and filtering to obtain 458g of acid-treated wet product.
Alkali refining: 458g of acid-treated wet product was added with 7.2L of distilled water, stirred and heated to 80 ℃, adjusted to pH 8.0 with 10% potassium carbonate solution, added with 25g of diatomaceous earth, stirred for 30min and filtered. Heating the filtrate to 80 deg.C, adding 10% hydrochloric acid dropwise to adjust pH to 3.5, and cooling to 70 deg.C. Discharging to a centrifugal machine for direct centrifugation, and leaching twice by using 300ml of deionized water with the temperature of 35-40 ℃ to obtain 440g of alkali refined wet product.
Second acid refining: adding 240mL of 36% hydrochloric acid into 440g of alkali refined wet product, dropwise adding 240mL of 36% hydrochloric acid while stirring, heating to 40 ℃ for dissolving, stirring for 30min, adding about 6L of distilled water, stirring for 30min, standing for 1h, filtering, and drying at 50 ℃ to obtain the finished product of folic acid. The yield is 79%, the folic acid purity is 99.4% by HPLC, the impurity A is not detected, and the impurity D is 0.26%.
In conclusion, compared with the traditional folic acid purification methods (comparative examples 1 to 7), the folic acid purification method (examples 1 to 7) of the invention effectively reduces the contents of the impurities A and D and improves the purity of the folic acid finished product without obviously reducing the yield.
Claims (8)
1. A purification method of folic acid is characterized in that folic acid crude products are refined by first acid and alkali, and then acid solution is added for second acid refining and drying to obtain folic acid finished products;
adding an acid solution into an alkali refined wet product, dropwise adding the acid solution while stirring, heating to 35-45 ℃, dissolving until the solution is clear, stirring for 25-35 min, adding water, stirring for 25-35 min, standing for 40-80 min, filtering and drying;
in the second acid refining step, the volume ratio of the alkali refined wet product to the acid solution is (35-50): 48; the volume ratio (7-10) of the alkali refined wet product to the added water is 120;
the acid solution in the second acid refining step is 45-55% sulfuric acid or 18-36% hydrochloric acid.
2. The purification method according to claim 1, wherein the first acid refining is specifically to dissolve the crude folic acid with an acid solution, raise the temperature to dissolve the crude folic acid until the crude folic acid is clear, add an adsorbent, stir, filter, add water to the filtrate, stir, stand, filter, and obtain an acid-treated wet product; wherein the acid solution is at least one of sulfuric acid and hydrochloric acid; the adsorbent is at least one of active carbon, diatomite and silica gel.
3. The purification method according to claim 2, wherein the first acid refining is specifically to add an acid solution to the folic acid crude product, dropwise add the acid solution while stirring, heat up to 35-45 ℃ to dissolve until clarification, add an adsorbent, stir for 25-35 min, filter, add water to the filtrate, stir for 25-35 min, stand for 40-80 min, filter, obtain an acid-treated wet product; wherein the mass-volume ratio of the folic acid crude product to the acid solution is (2-4) to 4 in g/ml; the mass ratio of the adsorbent to the folic acid crude product is (0.5-1.5): 45; according to g/ml, the mass-volume ratio (4-8) of the folic acid crude product to the water added into the filtrate is 100; the acid solution is 45-55% sulfuric acid or 18-36% hydrochloric acid.
4. The purification method according to claim 1, wherein the alkali refining is specifically that the acid-treated wet product is added with water and stirred, heated, adjusted to pH 8.0-10.0 with an alkali solution, added with an adsorbent, stirred and filtered to obtain an alkali refining filtrate, and the filtrate is subjected to acid adjustment and crystallization to obtain an alkali refining wet product; wherein the alkali solution is at least one of sodium carbonate, potassium carbonate, ammonia water, sodium hydroxide and potassium hydroxide; the adsorbent is at least one of active carbon, diatomite and silica gel.
5. The purification method according to claim 4, wherein the alkali refining is specifically that water is added into the wet product after acid treatment, the temperature is raised to 75-85 ℃ through stirring, the pH is adjusted to 8.0-10.0 through an alkali solution, an adsorbent is added, the mixture is stirred for 25-35 min and filtered to obtain an alkali refined filtrate, the filtrate is heated to 75-85 ℃, the pH is adjusted to 3.0-4.0 through an acid solution, the temperature is lowered to 65-75 ℃, centrifugation and leaching are carried out to obtain an alkali refined wet product; wherein the mass volume ratio of the acid-treated wet product to water is (35-50): 72 in g/ml; the mass ratio of the adsorbent to the acid-treated wet product is 1 (14-20); the alkali solution is 5-15% sodium carbonate solution, 5-15% potassium carbonate solution, 5-15% ammonia water, 5-15% sodium hydroxide solution or 5-15% potassium hydroxide solution; the acid solution is 3-8% dilute sulfuric acid, 7-15% hydrochloric acid or 30-40% acetic acid solution.
6. The purification method according to claim 1, wherein the acid solution in the second acid refining step is 50% sulfuric acid, 45% sulfuric acid, 55% sulfuric acid, 25% hydrochloric acid, 18% hydrochloric acid, or 36% hydrochloric acid.
7. The purification method according to claim 3, wherein in the first acid purification, the acid solution is 45% sulfuric acid, 50% sulfuric acid, 55% sulfuric acid, 18% hydrochloric acid, 25% hydrochloric acid, or 36% hydrochloric acid.
8. The purification method according to claim 5, wherein in the alkali refining, the alkali solution is a 10% sodium carbonate solution, a 10% potassium carbonate solution, 10% ammonia water, a 10% sodium hydroxide solution, or a 10% potassium hydroxide solution; the acid solution is 5% dilute sulfuric acid, 10% hydrochloric acid or 35% acetic acid solution.
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