CN110251470B - Vitamin B12Method for preparing folic acid tablets - Google Patents

Vitamin B12Method for preparing folic acid tablets Download PDF

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CN110251470B
CN110251470B CN201910526980.1A CN201910526980A CN110251470B CN 110251470 B CN110251470 B CN 110251470B CN 201910526980 A CN201910526980 A CN 201910526980A CN 110251470 B CN110251470 B CN 110251470B
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folic acid
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corn starch
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CN110251470A (en
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李红艳
邓文峰
刘海琼
李思睿
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Shanghai Children Nutrition Center Hainan Co Ltd
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    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/42—Cobalamins, i.e. vitamin B12, LLD factor

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Abstract

The invention relates to vitamin B12The method for preparing the folic acid tablets comprises the following steps: step Sa: weighing folic acid and vitamin B in formula amount12Powder, lactose, edible corn starch and magnesium stearate for later use; and Sb: adding appropriate amount of edible corn starch into appropriate amount of purified water, stirring to obtain suspension, adding into boiling purified water, stirring to obtain paste, and cooling; step Sc: adding the weighed folic acid and vitamin B into the pasty product obtained in the step Sb12Uniformly stirring the powder for later use; step Sd: putting the rest edible corn starch and lactose into a high-efficiency wet mixing granulator, adding the adhesive prepared in the step Sb and the step Sc to prepare a soft material, and then granulating on a swinging granulator by using a nylon screen; step Se: drying the prepared wet granules by using an oven until the weight loss of the granules meets the requirement, adding the magnesium stearate with the formula amount and the granules obtained after drying into a mixer, and uniformly mixing; step Sf: tabletting to obtain the finished product.

Description

Vitamin B12Method for preparing folic acid tablets
Technical Field
The invention relates to the technical field of production and processing of vitamin tablets, in particular to vitamin B12A method for producing folic acid tablets.
Background
Folic acid, belonging to the water-soluble vitamin B group, is a generic name of a class of compounds having a molecule structure of discoylglutamic acid, also called as discoylglutamic acid, vitamin Bc, vitamin M, vitamin B11。
The important physiological function of folic acid is to participate in metabolism as a carrier of a carbon compound, and the derivative tetrahydrofolic acid is a carrier of a carbon unit in the form of coenzyme and plays an important role in methyl transfer and utilization of formate and formaldehyde.
Since folic acid in the human body is almost completely dependent on food intake, folic acid deficiency occurs in the human body when the amount of folic acid intake is insufficient or the utilization rate is reduced. Research shows that the folic acid deficiency of human body can cause the diseases of nuclear megaloblastic anemia of infants, megaloblastic anemia of pregnant women, nervous system abnormality of newborn, senile dementia and the like, so that the folic acid has very important medicinal value and development prospect.
Vitamin B12Also known as cobalamin or cyanocobalamin, vitamin B12The vitamin B is the latest one of the vitamins in the B family, is easy to dissolve in water and ethanol, is most stable under the condition of weak acid with the pH value of 4.5-5.0, can be damaged to a certain extent by decomposition and preheating in strong acid or alkaline solution, but has small high-temperature disinfection loss in short time and is easy to damage when meeting strong light or ultraviolet rays.
Vitamin B12The main functions of the device are as follows: 1. promoting the development and maturation of erythrocytes, keeping the hematopoietic function of the body in a normal state, preventing pernicious anemia, and maintaining the health of the nervous system; 2. the coenzyme exists in a coenzyme form, so that the utilization rate of folic acid can be increased, and the metabolism of carbohydrate, fat and protein is promoted; 3. has the functions of activating amino acid, promoting nucleic acid biosynthesis, promoting protein synthesis and playing an important role in the growth and development of infants; 4. metabolizing fatty acids to allow fats, carbohydrates, and proteins to be properly utilized by the body; 5. eliminating dysphoria, concentrating attention, and improving memory and balance; 6. is an indispensable vitamin for the functional perfection of the nervous system and participates in the formation of lipoprotein in nervous tissues.
Thus, vitamin B12Can be taken together with folic acid to provide a better nutriment for pregnant women.
Disclosure of Invention
The invention provides vitamin B12The method for preparing the folic acid tablets comprises the following steps:
step Sa: weighing the formula amount of the leavesAcid and vitamin B12Powder, lactose, edible corn starch and magnesium stearate for later use;
and Sb: adding appropriate amount of edible corn starch into appropriate amount of purified water, stirring to obtain suspension, adding into boiling purified water, stirring to obtain paste, and cooling;
step Sc: adding the weighed folic acid and vitamin B into the pasty product obtained in the step Sb12Uniformly stirring the powder for later use;
step Sd: putting the rest edible corn starch and lactose into a high-efficiency wet mixing granulator, adding the adhesive prepared in the step Sb and the step Sc to prepare a soft material, and then granulating on a swinging granulator by using a nylon screen;
step Se: drying the prepared wet granules by using an oven until the weight loss of the granules meets the requirement, adding the magnesium stearate with the formula amount and the granules obtained after drying into a mixer, and uniformly mixing;
step Sf: tabletting to obtain a finished product;
wherein vitamin B is added in the step Sc12The powder comprises vitamin B12And D-mannitol, vitamin B12The manufacturing method comprises the following steps:
step S1: inoculating denitrifying pseudomonas into a fermentation medium, and obtaining vitamin B after a rapid growth period and a stable growth period12Fermentation liquor;
step S2: to vitamin B12Adding cellulase and pectinase with certain concentration into the fermentation liquid, and magnetically stirring for a predetermined time to make vitamin B in cells12Breaking the wall of the components, dissolving out, and filtering with an ultrafiltration membrane to obtain supernatant;
step S3: adding iron cyanide complex and defoaming agent into the supernatant, and magnetically stirring for a predetermined time to obtain vitamin B-containing extract12The solution of (1);
step S4: will contain vitamin B12The solution is filtered by a nanofiltration system to obtain concentrated solution and dialysate;
step S5: the dialyzate passes through a continuous ion exchange system to be subjected to multiple adsorption exchanges to obtain the final vitamin B12Eluting, vacuum freezingDrying the eluent to obtain vitamin B12。
In step S1, the fermentation medium includes the following components by mass: 80-90g/L of sucrose, 50-65 g/L of corn steep liquor, 0.5-1.0 g/L of ammonium sulfate, 0.05-0.1 g/L of dimethyl benzimidazole, 0.05-0.1 g/L of arginine, 100-110 g/L of yeast extract, 0.5-2.0 g/L of zinc sulfate, 0.03-0.08 g/L of urea and 0.5-0.8 g/L of diamine hydrogen phosphate, 0.1-1.5 g/L of calcium carbonate, 0.1-1.0 g/L of glycerophosphoric acid, 0.5-1.3 g/L of monopotassium phosphate, 0.5-1.3 g/L of dipotassium phosphate, 0.5-0.8 g/L of magnesium oxide, 0.05-0.08 g/L of cobalt chloride, 20-35 g/L of betaine and 0.01-0.03g/L of thiamine.
Wherein, in the step S1, the pH value of the fermentation medium is controlled to be between 6.5 and 7.5 by sucrose and urea.
Wherein, in the step S1, the fermentation period of the rapid growth phase is between 65 and 75 hours, and the fermentation period of the stable growth phase is between 75 and 165 hours; in the rapid growth period, the stirring speed of the fermentation medium is controlled to be 300-350rpm, the aeration rate is controlled to be 1.5-1.8LPM, and the medium is intermittently irradiated by a stable light source for 6-10 hours every day; in the stable growth period, the stirring speed of the fermentation medium is controlled to be between 100 and 150rpm, the aeration rate is controlled to be between 0.5 and 0.8LPM, and the medium is intermittently irradiated by a stable light source for 3 to 6 hours every day.
In the step S2, the adding concentrations of the cellulase and the pectinase are both between 8 and 10g/L, the magnetic stirring temperature is between 0 and 4 ℃, and the stirring time is between 2 and 4 hours; when the ultrafiltration membrane is used for filtration, the filtration pressure is between 1.2 and 1.5 MPa.
Wherein, in the step S3, the added antifoaming agent is selected from soybean oil or corn oil.
In the step S5, the dialysate is adsorbed by polyacrylate type macroporous adsorption resin and divinylbenzene polymeric macroporous adsorption resin, and eluted by edible ethanol, with a feeding volume of 100L and a feeding flow rate of 60-70 mL/min.
In step S1, when the strain is in the fast growth phase, the following nutrients are added to the fermentation medium at predetermined time intervals: 15-20g/L of betaine, 30-40g/L of sophorose, 10-15g/L of cellobiose, 0.01-0.03g/L of sodium bicarbonate, 0.15-0.45g/L of geniposide, 0.1-0.5g/L of nicotinamide mononucleotide, 15-20g/L of glycine and 15-20g/L of threonine.
Wherein vitamin B is produced12In the folic acid tablet, the mass ratio of each component is as follows: 0.06-0.10 parts of folic acid and vitamin B120.01-0.03 part of powder, 75-80 parts of lactose, 18-20 parts of edible corn starch and 0.6-1.0 part of magnesium stearate.
The vitamin B provided by the invention12The production method of folic acid tablets has the advantages of simple process, low cost, high yield and high safety performance in the production process.
Drawings
FIG. 1: the invention provides vitamin B12A production process flow chart of folic acid tablets.
Detailed Description
In order to further understand the technical scheme and the advantages of the present invention, the following detailed description of the technical scheme and the advantages thereof is provided in conjunction with the accompanying drawings.
FIG. 1 shows a vitamin B provided by the present invention12The production process flow chart of folic acid tablets is shown in figure 1, and the vitamin B provided by the invention12A complete production process flow of the folic acid tablets is approximately as follows:
1. examination of
All the raw and auxiliary materials and the inner packaging material can be led into a workshop for use after being inspected to be qualified.
2. Pretreatment before production
Pretreating raw materials and auxiliary materials: the materials are conveyed to a clean workshop for standby after being cleaned and disinfected.
3. Weighing machine
Weighing folic acid and vitamin B according to the required dosage of batch production12The powder (cyanocobalamine, D-mannitol), lactose, edible corn starch and magnesium stearate are filled in a clean container or a material bag, sealed and stuck with a material label at a position with obvious outer layer of the container or the material bag for standby.
4. Granulating
(1) Preparation of adhesive (8% starch slurry): weighing appropriate amount of edible corn starch, adding appropriate amount of purified water, stirring to obtain suspension, adding into boiling purified water, stirring to obtain paste, cooling, adding folic acid and vitamin B12And (3) uniformly stirring the powder (cyanocobalamine and D-mannitol) for later use to obtain the adhesive.
(2) The remaining starch and formula amount of lactose were poured into a high efficiency wet mix granulator, added with binder to make a soft mass, and then granulated on a rocking granulator with a (24 mesh) nylon screen.
5. Drying
Drying the prepared wet granules by using an oven (55 +/-5 ℃) until the drying weight loss of the granules meets the requirement, and finishing the dry granules by using a 24-mesh screen.
6. Total mixing
Weighing magnesium stearate and qualified granules according to the formula ratio, adding into a mixer, and uniformly mixing.
7. Tabletting
Tabletting was carried out at the indicated weight of 0.3 g/tablet, and the appearance and weight of the tablets were checked at regular times.
8. Inner package
And (4) performing inner packaging according to the operation rules of the equipment, and clearing the yard according to the SOP requirement after the production is finished.
9. External packing
And (5) packing and boxing the small boxes.
The invention has the core invention point that the vitamin B is obtained by the autonomous fermentation and extraction process12The detailed preparation method comprises the following steps:
first, fermentation stage
Inoculating denitrifying pseudomonas into a fermentation medium, and obtaining vitamin B after a rapid growth period and a stable growth period12And (3) fermenting the liquid.
Specifically, the fermentation medium comprises the following components in parts by mass: 80-90g/L of sucrose, 50-65 g/L of corn steep liquor, 0.5-1.0 g/L of ammonium sulfate, 0.05-0.1 g/L of dimethyl benzimidazole, 0.05-0.1 g/L of arginine, 100-110 g/L of yeast extract, 0.5-2.0 g/L of zinc sulfate, 0.03-0.08 g/L of urea and 0.5-0.8 g/L of diamine hydrogen phosphate, 0.1-1.5 g/L of calcium carbonate, 0.1-1.0 g/L of glycerophosphoric acid, 0.5-1.3 g/L of monopotassium phosphate, 0.5-1.3 g/L of dipotassium phosphate, 0.5-0.8 g/L of magnesium oxide, 0.05-0.08 g/L of cobalt chloride, 20-35 g/L of betaine and 0.01-0.03g/L of thiamine. The environment of the fermentation culture medium is preferably neutral, the pH value is controlled by adding sucrose and urea, when the fermentation culture medium is alkaline, the sucrose is added, and when the fermentation culture medium is acidic, the urea is added.
In the invention, the normal intracellular osmotic pressure and cell membrane permeability of the fermentation strain can be ensured by adding the betaine, the stress resistance of the microorganism in a severe environment is improved, and the metabolism speed of nutrients, oxygen and wastes is improved. By adding dipotassium hydrogen phosphate and potassium dihydrogen phosphate, certain potassium ion concentration in the fermentation medium is ensured, and vitamin B in the fermentation product can be effectively improved12The yield of the strain is high, and the dipotassium hydrogen phosphate and the monopotassium dihydrogen phosphate can provide an excellent buffer environment for a fermentation culture medium, so that the acid-base balance can be maintained, and the strain can grow in a stable environment.
The invention provides enough dissolved oxygen and illumination to shorten the rapid growth period and improve the effect of the stable number of the pseudomonas denitrificans, preferably, the invention controls the stirring speed of the fermentation culture medium to be 300-350rpm and the aeration rate to be 1.5-1.8LPM in the rapid growth period, and intermittently irradiates the culture medium for 6-10 hours by adopting a stable light source every day.
In addition, in the rapid growth period, nutrients can be periodically supplemented into the fermentation medium so as to improve the strain number of the denitrogenated pseudomonas after the rapid growth period is finished, and the nutrient components and the mixture ratio added in the invention are as follows: 15-20g/L of betaine, 30-40g/L of sophorose, 10-15g/L of cellobiose, 0.01-0.03g/L of sodium bicarbonate, 0.15-0.45g/L of geniposide, 0.1-0.5g/L of nicotinamide mononucleotide, 15-20g/L of glycine and 15-20g/L of threonine. The frequency of addition was essentially 10 hours once, at a ratio between nutrient volume: fermentation medium volume = 1: 10-1: 5. experiments prove that the addition ratio is 1: in case 10, the number of bacterial colonies after the end of the flash growth phase increased by nearly 30% compared to the fermentation medium without added nutrients.
After the strain enters the stable growth period, the strain number is kept stable, and at the moment, the vitamin B is produced by fermenting the pseudomonas denitrificans12In order to prolong the time period of the stationary growth phase as much as possible, in order to increase the production of vitamin B by the strains12Compared with the rapid growth period, the invention properly reduces the dissolved oxygen amount of the fermentation medium and the lighting condition of the strain, and improves the vitamin B to the maximum extent under the condition of not influencing the normal growth of the pseudomonas denitrificans12The yield of (2). Preferably, the fermentation period in the stationary growth phase is between 75 and 165 hours; in the stable growth period, the stirring speed of the fermentation medium is controlled to be between 100 and 150rpm, the aeration rate is controlled to be between 0.5 and 0.8LPM, and the medium is intermittently irradiated by a stable light source for 3 to 6 hours every day.
Second, extraction stage
1. Breaking cell wall
The fermentation broth obtained after fermentation is mostly present in intracellular form, so the first step of working on the fermentation broth consists in the addition of vitamin B12Adding cellulase and pectinase with certain concentration into the fermentation liquid, and magnetically stirring for a predetermined time to make vitamin B in cells12Breaking cell wall, dissolving out, and filtering with ultrafiltration membrane to obtain supernatant.
The cellulase and pectinase have the effect of decomposing cellulose and pectin, which are main components of cell wall, to make vitamin B12Dissolving natural stable components out of cells, wherein the adding concentrations of cellulase and pectinase are both between 8 and 10g/L, the temperature of magnetic stirring is between 0 and 4 ℃, and the stirring time is between 2 and 4 hours; extracting vitamin B by breaking cell wall of cellulase and pectinase12The existing steps of enzymolysis, flocculation and the like can be omitted, and the vitamin B extracted by wall breaking can be obtained without heating and wall breaking12And is originally present in vitamin B12Vitamin B in fermentation broth12All can be filtered by an ultrafiltration membraneSeparated into the supernatant obtained after filtration. The extraction step of wall breaking and enzymolysis avoids the addition of chemical components such as flocculating agent, enzymolysis agent and the like, and ensures the vitamin B extracted subsequently12The purity and the safety of the cellulase and the pectinase are high, the cellulase and the pectinase can be completely intercepted on the ultrafiltration membrane when being filtered by the ultrafiltration membrane, impurities cannot be brought to subsequent processes, the cost of the cellulase and the pectinase is low, the safety is high, and side effects cannot be caused.
In the present invention, the filtration pressure is preferably 1.2 to 1.5MPa in the case of ultrafiltration with an ultrafiltration membrane.
2. Cyanide conversion
Vitamin B extracted by cell wall breaking and ultrafiltration membrane filtration12Is a cyano vitamin B12Most of them exist in the form of adenosine coenzyme, and vitamin B is a conventional form of adenosine coenzyme12Conversion to cyano group B12The method adopts the highly toxic sodium cyanide, undoubtedly brings potential safety hazards to workshop workers, and the iron cyanide complex is adopted to replace the sodium cyanide, so that the conversion rate can be improved and the potential safety hazards can be reduced on the premise of not influencing the conversion efficiency.
One preferred conversion reaction is as follows: adding iron cyanide complex and defoaming agent into the supernatant, and magnetically stirring for a predetermined time to obtain vitamin B-containing extract12The solution of (1); the added antifoaming agent is selected from soybean oil or corn oil, and is an edible antifoaming agent, so that potential safety hazard is avoided.
3. Filtration and dialysis
(1) Will contain vitamin B12The solution is filtered by a nanofiltration system to obtain concentrated solution and dialysate;
(2) the dialyzate passes through a continuous ion exchange system to be subjected to multiple adsorption exchanges to obtain the final vitamin B12Vacuum freeze drying the eluent to obtain vitamin B12。
The invention preferably selects and respectively adsorbs the dialyzate by polyacrylate type macroporous adsorption resin and divinylbenzene polymerization macroporous adsorption resin, and the polyacrylate type macroporous adsorption resin mainly has the function of removing most impurities to ensure that most impurities are removedThe purity of the final product, namely the function of the divinylbenzene polymeric macroporous adsorption resin, is to further remove the remaining impurities so as to further improve the purity of the final product, and on the other hand, the inventor finds that the divinylbenzene polymeric macroporous adsorption resin can adsorb and elute vitamin B12In this case, it has strong adsorption effect on the eluent, but does not affect vitamin B12The elution effect of the method is that after the eluent is adsorbed by the divinylbenzene polymeric macroporous resin, about 80% of the eluent can be absorbed, the concentration of the finally obtained finished product solution is high, the cost of the subsequent freeze drying process can be greatly reduced, and the efficiency of the whole process production process is improved.
In the invention, in two times of adsorption elution, edible ethanol is used for eluting the adsorption elution, the feeding volume is 100L, and the feeding flow is between 60 and 70 mL/min. The ethanol has strong volatility, the edible ethanol is safe, and the final product cannot be caused by side effect, and the selection of the edible ethanol eluent is the most suitable eluent selected by the inventor on the premise of considering the recoverability of the polyacrylate type macroporous adsorption resin and the divinylbenzene polymerization macroporous adsorption resin.
The invention has the following beneficial effects:
1. by controlling different dissolved oxygen amounts and illumination conditions in the rapid growth period and the stable growth period and combining the addition of nutrients, the strain number is ensured to reach the optimal value after the rapid growth period is finished, and the vitamin B produced by the strain in the stable growth period through fermentation is improved12The efficiency of (c).
2. Extracting vitamin B by breaking cell wall of pectinase and cellulase12And the step of ultrafiltration membrane filtration, avoids the addition of chemical components such as flocculating agent, enzymolysis agent and the like, and ensures the vitamin B extracted subsequently12Purity and safety of the product.
3. Vitamin B production by replacing sodium cyanide with iron cyanide complex12The conversion of the form can improve the conversion rate on the premise of not influencing the conversion efficiency and reduce the potential safety hazard of workshop staff.
4. Sequentially adsorbing vitamins by two different macroporous adsorption resinsElement B12The method improves the purity and concentration of the final product, greatly reduces the cost of the subsequent freeze drying process, and improves the efficiency of the whole process production process.
5. Through the selection of the edible ethanol eluent and the matching of the edible ethanol eluent and two different macroporous adsorption resins, the recoverability of the corresponding macroporous adsorption resin is improved.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that the scope of the present invention is not limited thereto, and those skilled in the art will appreciate that various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims (9)

1. Vitamin B12The method for manufacturing the folic acid tablets is characterized by comprising the following steps:
step Sa: weighing folic acid and vitamin B in formula amount12Powder, lactose, edible corn starch and magnesium stearate for later use;
and Sb: adding appropriate amount of edible corn starch into appropriate amount of purified water, stirring to obtain suspension, adding into boiling purified water, stirring to obtain paste, and cooling;
step Sc: adding the weighed folic acid and vitamin B into the pasty product obtained in the step Sb12Uniformly stirring the powder for later use;
step Sd: putting the rest edible corn starch and lactose into a high-efficiency wet mixing granulator, adding the adhesive prepared in the step Sb and the step Sc to prepare a soft material, and then granulating on a swinging granulator by using a nylon screen;
step Se: drying the prepared wet granules by using an oven until the weight loss of the granules meets the requirement, adding the magnesium stearate with the formula amount and the granules obtained after drying into a mixer, and uniformly mixing;
step Sf: tabletting to obtain a finished product;
wherein vitamin B is added in the step Sc12The powder comprises vitamin B12And D-mannitol, vitamin B12The manufacturing method comprises the following steps:
step S1: inoculating denitrifying pseudomonas into a fermentation medium, and obtaining vitamin B after a rapid growth period and a stable growth period12Fermentation liquor;
step S2: to vitamin B12Adding cellulase and pectinase with certain concentration into the fermentation liquid, and magnetically stirring for a predetermined time to make vitamin B in cells12Breaking the wall of the components, dissolving out, and filtering with an ultrafiltration membrane to obtain supernatant;
step S3: adding iron cyanide complex and defoaming agent into the supernatant, and magnetically stirring for a predetermined time to obtain vitamin B-containing extract12The solution of (1);
step S4: will contain vitamin B12The solution is filtered by a nanofiltration system to obtain concentrated solution and dialysate;
step S5: the dialyzate passes through a continuous ion exchange system to be subjected to multiple adsorption exchanges to obtain the final vitamin B12Vacuum freeze drying the eluent to obtain vitamin B12；
In the step S2, the adding concentration of the cellulase and the pectinase is between 8 and 10g/L, the magnetic stirring temperature is between 0 and 4 ℃, and the stirring time is between 2 and 4 hours.
2. Vitamin B as claimed in claim 112The method for preparing the folic acid tablets is characterized in that in the step S1, the fermentation medium comprises the following components in parts by mass: 80-90g/L of sucrose, 50-65 g/L of corn steep liquor, 0.5-1.0 g/L of ammonium sulfate, 0.05-0.1 g/L of dimethyl benzimidazole, 0.05-0.1 g/L of arginine, 100-110 g/L of yeast extract, 0.5-2.0 g/L of zinc sulfate, 0.03-0.08 g/L of urea and 0.5-0.8 g/L of diamine hydrogen phosphate, 0.1-1.5 g/L of calcium carbonate, 0.1-1.0 g/L of glycerophosphoric acid, 0.5-1.3 g/L of monopotassium phosphate, 0.5-1.3 g/L of dipotassium phosphate, 0.5-0.8 g/L of magnesium oxide, 0.05-0.08 g/L of cobalt chloride, 20-35 g/L of betaine and 0.01-0.03g/L of thiamine.
3. Vitamin B as claimed in claim 112Method for producing folic acid tabletsCharacterized in that in the step S1, the pH value of the fermentation medium is controlled to be between 6.5 and 7.5 by sucrose and urea.
4. Vitamin B as claimed in claim 112The method for preparing folic acid tablets is characterized in that in the step S1, the fermentation period of the rapid growth period is 65-75 hours, and the fermentation period of the stable growth period is 75-165 hours; in the rapid growth period, the stirring speed of the fermentation medium is controlled to be 300-350rpm, the aeration rate is controlled to be 1.5-1.8LPM, and the medium is intermittently irradiated by a stable light source for 6-10 hours every day; in the stable growth period, the stirring speed of the fermentation medium is controlled to be between 100 and 150rpm, the aeration rate is controlled to be between 0.5 and 0.8LPM, and the medium is intermittently irradiated by a stable light source for 3 to 6 hours every day.
5. Vitamin B as claimed in claim 112The method for producing folic acid tablets is characterized in that in the step S2, when the ultrafiltration membrane is used for filtration, the filtration pressure is between 1.2 and 1.5 MPa.
6. Vitamin B as claimed in claim 112The method for making folic acid tablets is characterized in that in the step S3, the added antifoaming agent is selected from soybean oil or corn oil.
7. Vitamin B as claimed in claim 112The method for preparing folic acid tablets is characterized in that in the step S5, the dialysate is adsorbed by polyacrylate type macroporous adsorption resin and divinylbenzene polymerization macroporous adsorption resin respectively, the dialysate is eluted by edible ethanol, the feeding volume is 100L, and the feeding flow is 60-70 mL/min.
8. Vitamin B as claimed in claim 112The method for preparing the folic acid tablets is characterized in that in the step S1, when the strain is in a rapid growth phase, the following nutrients are added into a fermentation medium at intervals of preset time: betaine 15-20g/L, sophorose 30-40g/L, cellobiose 10-15g/L, sodium bicarbonate 0.01-0.03g/L, 0.15-0.45g/L geniposide, 0.1-0.5g/L nicotinamide mononucleotide, 15-20g/L of glycine and 15-20g/L of threonine.
9. Vitamin B as claimed in claim 112The method for preparing folic acid tablets is characterized in that the vitamin B is prepared12In the folic acid tablet, the mass ratio of each component is as follows: 0.06-0.10 parts of folic acid and vitamin B120.01-0.03 part of powder, 75-80 parts of lactose, 18-20 parts of edible corn starch and 0.6-1.0 part of magnesium stearate.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101176734A (en) * 2006-11-10 2008-05-14 江西省药物研究所 Nutrients replenisher for replenishing folic acid and vitamin B12 and preparation method thereof
WO2017011133A1 (en) * 2015-07-10 2017-01-19 Mjn U.S. Holdings Llc Nutritional compositions and methods for promoting cognitive development
CN108913738A (en) * 2018-07-28 2018-11-30 广济药业（孟州）有限公司 A kind of raising vitamin B based on Dissolved oxygen regulation12The method of yield

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101176734A (en) * 2006-11-10 2008-05-14 江西省药物研究所 Nutrients replenisher for replenishing folic acid and vitamin B12 and preparation method thereof
WO2017011133A1 (en) * 2015-07-10 2017-01-19 Mjn U.S. Holdings Llc Nutritional compositions and methods for promoting cognitive development
CN108913738A (en) * 2018-07-28 2018-11-30 广济药业（孟州）有限公司 A kind of raising vitamin B based on Dissolved oxygen regulation12The method of yield

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
大孔吸附树脂LX-20从发酵液中分离纯化维生素B12;张智聪等;《离子交换与吸附》;20110731;第27卷(第4期);第368-374页 *

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