CN117866071A - Preparation method of protein iron succinate - Google Patents
Preparation method of protein iron succinate Download PDFInfo
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- CN117866071A CN117866071A CN202311616145.XA CN202311616145A CN117866071A CN 117866071 A CN117866071 A CN 117866071A CN 202311616145 A CN202311616145 A CN 202311616145A CN 117866071 A CN117866071 A CN 117866071A
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- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 57
- 102000004169 proteins and genes Human genes 0.000 title claims abstract description 57
- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000001914 filtration Methods 0.000 claims abstract description 27
- 239000000243 solution Substances 0.000 claims description 200
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 114
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical class NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims description 98
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 235000018102 proteins Nutrition 0.000 claims description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 36
- -1 monomethyl succinate acyl chloride Chemical class 0.000 claims description 30
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 29
- 239000000463 material Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000005018 casein Substances 0.000 claims description 24
- 235000021240 caseins Nutrition 0.000 claims description 24
- 230000001276 controlling effect Effects 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 23
- 239000008213 purified water Substances 0.000 claims description 23
- 239000003513 alkali Substances 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 230000001376 precipitating effect Effects 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 18
- JDRMYOQETPMYQX-UHFFFAOYSA-N butanedioic acid monomethyl ester Natural products COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 16
- 238000004090 dissolution Methods 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- LOLKAJARZKDJTD-UHFFFAOYSA-N butanedioic acid monoethyl ester Natural products CCOC(=O)CCC(O)=O LOLKAJARZKDJTD-UHFFFAOYSA-N 0.000 claims description 14
- 238000004364 calculation method Methods 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 11
- 239000002244 precipitate Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 230000004580 weight loss Effects 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 238000007664 blowing Methods 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- XFKCVVFQGHCLIP-UHFFFAOYSA-N 2-ethylbutanedioyl dichloride Chemical class CCC(C(Cl)=O)CC(Cl)=O XFKCVVFQGHCLIP-UHFFFAOYSA-N 0.000 claims 1
- 239000012670 alkaline solution Substances 0.000 claims 1
- 244000005700 microbiome Species 0.000 abstract description 5
- 239000003755 preservative agent Substances 0.000 abstract description 2
- 230000002335 preservative effect Effects 0.000 abstract description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 44
- 229910052742 iron Inorganic materials 0.000 description 22
- 238000005917 acylation reaction Methods 0.000 description 14
- 230000010933 acylation Effects 0.000 description 11
- 239000004743 Polypropylene Substances 0.000 description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 241000607142 Salmonella Species 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000003916 acid precipitation Methods 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- VAMMNAAZSNNEDJ-UHFFFAOYSA-N butanedioic acid;iron Chemical compound [Fe].OC(=O)CCC(O)=O VAMMNAAZSNNEDJ-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 235000019750 Crude protein Nutrition 0.000 description 1
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 108010084684 iron protein succinylate Proteins 0.000 description 1
- 229940074442 iron protein succinylate Drugs 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4732—Casein
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to the technical field of pharmacy, in particular to a preparation method of protein iron succinate. The preparation method solves the problem of difficult filtration, and the obtained protein iron succinate solution has good quality and high clarity, and solves the problem of microorganism control of protein iron succinate, and the product can be stably stored for a long time without adding preservative in the preparation process.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of protein iron succinate.
Background
A nano polypeptide protein iron supplementing medicine for treating the iron succinate (Iron proteinsuccinylate, ISP) is prepared from casein through acylation of succinic anhydride, complexing with ferric trichloride, and features no dissociation of iron in solution, high pH value (pH 7.5-8.0) and high pH value (pH 4-7.5). In addition, the preparation is not digested by pepsin and is hydrolyzed by trypsin at neutral pH. Because of these properties, the iron contained in the protein iron succinate is protected by the protein film from reacting with gastric acid and pepsin in gastric juice, and thus it does not cause gastric mucosal damage. The iron in the product starts to release in the duodenum, especially in the jejunum, because the pH rise re-solubilizes the compound while the protein membrane is digested by trypsin. The iron is very favorable for physiological absorption of the organism, but does not form too high absorption peaks, presents a constant absorption trend, and gradually reaches the optimal state of absorption and storage at all parts of the organism. Thus, the protein iron succinate generally does not create gastrointestinal tolerability problems. Based on the above characteristics, the protein iron succinate is suitable for various symptoms, such as recessive or dominant iron deficiency anemia, gestational and lactation anemia, etc. caused by iron intake deficiency or malabsorption, acute or chronic blood loss and infection of patients of various ages.
The preparation methods provided in the existing protein iron succinate patents (application publication No. CN102838667A and application publication No. CN 104402984A) all comprise the following steps: dissolving casein, acylating (acid precipitating, centrifuging, dissolving alkali), carrying iron (centrifuging, acid precipitating, centrifuging, dissolving alkali, centrifuging, finely filtering, acid precipitating, washing precipitate), and drying. The prior patent has the problems that the processes of acid precipitation, centrifugation and alkali dissolution occur for a plurality of times in the process of preparing protein iron succinate, the acid precipitation, centrifugation and alkali dissolution in the acylation step are used for removing byproduct succinic acid in the acylation step, and the acid precipitation, centrifugation and alkali dissolution in the iron loading step are used for removing free iron. The method comprises the steps of acid precipitation, centrifugation and alkali dissolution, so that the protein iron succinate is changed into a suspension from a solution state, precipitates are collected in a centrifugal mode, and then the precipitates are transferred and dissolved again, so that the process takes a long time and can occur for many times.
US4493829 discloses a method for preparing iron protein succinate. Taking milk powder as a raw material, carrying out acylation reaction on the milk powder and succinic anhydride under alkaline conditions (pH 7.5-8), centrifuging or filtering a reaction solution after the reaction is finished, adding hydrochloric acid into filtrate to acidify (pH 2.5-3) to precipitate, and centrifuging or filtering to obtain the succinyl protein. Dispersing succinyl protein in water, dissolving under alkaline condition (pH 7.5), adding ferric trichloride solution for carrying out iron reaction, and filtering after the reaction is finished to obtain crude protein succinic acid iron product. The crude product of protein succinic acid iron is dispersed in water, dissolved under alkaline condition (pH 7.5), and filtered to obtain solution. The protein iron succinate can be prepared by the following method: 1) Acidifying (pH 2.5), filtering, and vacuum drying. 2) The solution is dialyzed to remove sodium chloride and then freeze-dried or spray-dried. The product prepared by this method had a degree of acylation of 95%.
The prior art fails to solve the problem of difficult filtration of the protein iron succinate solution, the solution clarity is poorer than that of the original ground product, and the control of protein iron succinate microorganisms is not solved.
Based on the above-mentioned current situation, a new preparation method of protein iron succinate is needed to overcome the disadvantages of the prior art and to prepare high-quality protein iron succinate on a large scale.
Disclosure of Invention
The invention aims to provide a novel preparation method of protein iron succinate, which solves the problem of difficult filtration, and the obtained protein iron succinate solution has good quality and high clarity, and solves the problem of microorganism control of protein iron succinate, and the product can be stably stored for a long time without adding a preservative in the preparation process.
The invention provides a novel preparation method of protein iron succinate, which comprises the following specific preparation routes:
a preparation method of novel protein iron succinate specifically comprises the following steps:
step 1: preparation of acylated casein
(1) Adding purified water into a reaction kettle, adding casein under stirring, keeping the temperature at 45-55 ℃, and dropwise adding an alkali solution until the pH value of the reaction solution is=7.5-8.5;
(2) The pH value is reduced in the dissolving process, and the alkali solution is continuously added dropwise to keep the pH value of the reaction solution to be 7.5-8.5, so that casein is dissolved into milky white to light yellow solution;
(3) Controlling the temperature to be 45-55 ℃, dropwise adding monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride, simultaneously dropwise adding an alkali solution to adjust the pH value of a reaction solution to be 7.5-8.5, continuously dropwise adding the alkali solution to keep the pH value of the reaction solution to be 7.5-8.5 after the dropwise adding of the monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride is finished, stirring for 2 hours, then cooling to 20-30 ℃, dropwise adding a hydrochloric acid solution to adjust the pH value to be 2.0-3.0, precipitating and precipitating, keeping the temperature to be 20-30 ℃, stirring for 0.5-1 hour, centrifuging, and finishing the filter cake by using a swinging granulator;
(4) Adding purified water into a reaction kettle, adding an acylated casein wet product under stirring, controlling the temperature to be 20-30 ℃, dropwise adding an alkali solution until the pH value is 7.5-8.5, dissolving the acylated casein into a milky white to pale yellow solution, filtering the solution through a filter, collecting filtrate into the reaction kettle to obtain an acylated casein solution, and calculating the weight of the acylated casein;
step 2: preparation of protein iron succinate
(1) Taking the acylated casein solution, controlling the temperature to be 20-30 ℃, slowly adding the prepared ferric trichloride solution while stirring, simultaneously dropwise adding an alkali solution to control the pH value to be 6.0-8.0, continuously dropwise adding the alkali solution to keep the pH value to be 6.0-8.0 after the ferric trichloride solution is added, maintaining for 3-4 hours, heating the feed liquid to 75 ℃, maintaining for 30 seconds, cooling to 50-55 ℃, maintaining the temperature to 50-55 ℃, filtering the feed liquid to a clean area reaction kettle through a filter, cooling to 20-30 ℃, regulating the pH value to be 2.0-3.0 by using a hydrochloric acid solution, and centrifuging;
(2) Washing the filter cake with purified water, collecting the filter cake, and finishing the filter cake by using a 20-mesh swing finishing machine; drying the materials in a boiling dryer, wherein the drying weight loss of the dried materials is less than 2%, crushing the materials by a crusher, and sieving by an oscillating screen to obtain the protein iron succinate.
Preferably, the weight ratio of the casein to the purified water in the step 1 is 1:10, and the weight ratio of the monomethyl succinate acyl chloride and/or the monoethyl succinate acyl chloride to the casein is 0.3-0.5:1.
Preferably, the weight ratio of the monomethyl succinate acyl chloride and/or the monoethyl succinate acyl chloride to the casein in the step 1 is 0.4:1.
Preferably, the alkali solution in the step 1 and the step 2 is a 10% lithium hydroxide solution, and the concentration of the hydrochloric acid solution is 5%.
Preferably, the concentration of the ferric trichloride solution in the step 2 is 2%.
Preferably, the method for calculating the weight of the acylated casein in the step 1 is as follows:
(1) Weighing about 200.0g of the acylated casein solution, namely D, regulating the pH value to 2.0-3.0 by using 9% hydrochloric acid solution, precipitating, filtering, and drying the obtained precipitate to constant weight by blowing at 60-70 ℃ and the weight is denoted as B;
(2) The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
Preferably, the amount of ferric trichloride and acylated casein in step 2 is 0.25:1.
Preferably, the air inlet temperature of the dryer in the step 2 is 70-80 ℃, and the air outlet temperature is 50-60 ℃.
Preferably, the filter in the step 1 is a 1 mu mPP microporous filter, and the filter in the step 2 is a 1 mu m titanium rod microporous filter and/or a 0.22 mu mPP microporous filter.
Further, the preparation method of the protein iron succinate provided by the invention comprises the following steps:
step 1: preparation of acylated casein
600.0kg of purified water is added into a 2000L reaction kettle, 60.0kg of casein is added under stirring to keep the temperature at 45-55 ℃, and 10% lithium hydroxide solution is added dropwise until the pH value of the reaction solution is 7.5-8.5. In the dissolving process, the pH value is reduced, and a 10% lithium hydroxide solution is continuously added dropwise to keep the pH value of the reaction solution to be 7.5-8.5, so that casein is dissolved into a milky white to light yellow solution. Controlling the temperature to be 45-55 ℃, dropwise adding 24.0kg of monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride, simultaneously dropwise adding 10% lithium hydroxide solution to adjust the pH value of a reaction solution to be 7.5-8.5, continuously dropwise adding 10% lithium hydroxide solution to keep the pH value of the reaction solution to be 7.5-8.5 after the dropwise adding of the monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride is finished, stirring for 2h, then cooling to 20-30 ℃, dropwise adding 5% hydrochloric acid solution to adjust the pH value to be 2.0-3.0, precipitating and precipitating, keeping the temperature to be 20-30 ℃, stirring for 0.5-1 h, centrifuging, and finishing granules (20 meshes) of filter cakes by using a swinging granulation machine.
600.0kg of purified water is added into a 3000L reaction kettle, an acylated casein wet product is added under stirring, the temperature is controlled to be 20-30 ℃, 10% lithium hydroxide solution is dripped until the pH value is 7.5-8.5, acylated casein is dissolved into milky white to light yellow solution, a solution microporous filter (1 mu mPP) is used for filtering, the filtrate is collected into the 3000L reaction kettle, the acylated casein solution is obtained, the weight A of the acylated casein solution is accurately weighed, and the acylation rate is detected.
Acylated casein weight calculation
About 200.0g of the above-mentioned acylated casein solution was weighed as D, the pH was adjusted to 2.0 to 3.0 with 9% hydrochloric acid solution, precipitated, filtered, and the resulting precipitate was air-dried at 60 to 70℃to constant weight, and the weight was designated as B. The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
Step 2: preparation of protein iron succinate
Taking the acylated casein solution, controlling the temperature to be 20-30 ℃, slowly adding the prepared 2% ferric trichloride (the dosage of ferric trichloride and acylated casein is 0.25:1.0) solution under stirring, simultaneously dropwise adding 10% lithium hydroxide solution to control the pH value to be 6.0-8.0, continuously dropwise adding 10% lithium hydroxide solution to keep the pH value to be 6.0-8.0 after the ferric trichloride solution is added, keeping the temperature for 3-4 h, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, quickly cooling to 50-55 ℃, keeping the temperature at 50-55 ℃, filtering the feed liquid to a clean area 2000L reaction kettle through a microporous filter (1 mu m titanium rod) and a microporous filter (0.22 mu m PP), cooling the feed liquid to 20-30 ℃, adjusting the pH value to be 2.0-3.0 by using 5% hydrochloric acid solution, and centrifuging. The filter cake was washed with purified water and collected and granulated (20 mesh) using a swing granulator. Drying the materials in a boiling dryer, wherein the air inlet temperature is 70-80 ℃, the air outlet temperature is 50-60 ℃, the drying weight loss of the dried materials is less than 2%, crushing the materials by a crusher, and sieving the crushed materials by a 100-mesh oscillating screen to obtain the protein iron succinate.
The yield calculation formula: weight of protein iron succinate per casein 100%
Clarity: and compared with the turbidity standard solution No. 2, the total iron content is not more concentrated: 4.5 to 5.5 percent of succinic acid residue: less than 0.5%, free iron: less than 0.1%, loss on drying: less than 2.0%, aerobe: less than 103cfu, mold and yeast: not exceeding 102cfu, escherichia coli: no salmonella: no detection, staphylococcus aureus: pseudomonas aeruginosa, which is not detected: and cannot be detected.
The novel preparation method of the protein iron succinate has the following technical advantages:
1. the alkali used for preparing the acylated casein is determined as lithium hydroxide, and the aqueous solution with the concentration of 10 percent is favorable for improving the efficiency of the acylation reaction, and the acylation rate is more than 99.5 percent.
2. The acylated casein is prepared, the acylating reagent is monomethyl succinate acyl chloride or monoethyl succinate acyl chloride, the dosage ratio of the acylating reagent to the casein is 0.3-0.5:1.0, the efficiency of the acylation reaction is improved, and the acylation rate is more than 99.5%.
3. The acidylation reagent, namely the monomethyl succinate acyl chloride or the monoethyl succinate acyl chloride, has high acyl chloride activity, is added dropwise while reacting, can hydrolyze methyl ester and ethyl ester in the reaction process under the weak alkaline condition, and finally obtains the acylated casein with high acidylation rate by regulating the pH value to precipitate.
4. Preparing protein iron succinate, preparing the iron trichloride into 2% aqueous solution with the dosage ratio of the iron trichloride to the acylated casein being 0.25:1.0, controlling the pH of a reaction solution to be 6.0-8.0 while dripping, after finishing adding the iron trichloride solution, controlling the pH of the reaction solution to be 6.0-8.0, stirring for 3-4 hours, fully dissolving the protein iron succinate, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, sterilizing the feed liquid, then controlling the temperature of the feed liquid to be 50-55 ℃, filtering a 1 mu m titanium rod and 0.22 mu m PP to a clean area, ensuring that the feed liquid has better fluidity at 50-55 ℃, rapidly finishing filtering, thoroughly removing insoluble substances by the 1 mu m titanium rod, and filtering and removing microorganisms by 0.22 mu m PP to ensure that the clarity and microorganisms of a finished product meet the requirements.
5. And the protein iron succinate is prepared, and the moisture of the product is controlled to be less than 2% by drying, so that the product can be kept for a long time.
The novel preparation method of the protein iron succinate can be used for continuously and stably preparing high-quality protein iron succinate in a large scale.
Interpretation of key terms and technical abbreviations:
1 mu mPP refers to a filter element made of polypropylene with a pore diameter of 1 mu m
1 mu m titanium rod refers to a filter element made of titanium with the aperture of 1 mu m
0.22 mu mPP refers to a filter element made of polypropylene with a pore diameter of 0.22 mu m
Ferric trichloride refers to ferric trichloride hexahydrate
Drawings
FIG. 1 is an XRD pattern of iron succinate protein obtained in example 1 of the present invention.
FIG. 2 is an infrared spectrum of iron succinate protein obtained in example 1 of the present invention
Detailed Description
Example 1
Step 1: preparation of acylated casein
600.0kg of purified water was added to a 2000L reaction vessel, 60.0kg of casein was added under stirring to maintain the temperature at 50 ℃, and 10% lithium hydroxide solution was added dropwise to the reaction solution until ph=8.0. The pH value was reduced during the dissolution, and the reaction solution ph=8.0 was kept by continuously dropping a 10% lithium hydroxide solution, and casein was dissolved into a milky to pale yellow solution. Controlling the temperature to 50 ℃, dropwise adding 24.0kg of monomethyl succinate acyl chloride, simultaneously dropwise adding 10% lithium hydroxide solution to adjust the pH value of a reaction solution to be 8.0, continuously dropwise adding 10% lithium hydroxide solution after the dropwise adding of monomethyl succinate acyl chloride is finished to keep the pH value of the reaction solution to be 8.0, stirring for 2 hours, then cooling to 20 ℃, dropwise adding 5% hydrochloric acid solution to adjust the pH value to be 2.0, precipitating and precipitating, keeping the temperature to 20 ℃, stirring for 0.5 hours, centrifuging, and granulating a filter cake by using a swinging granulator (20 meshes).
600.0kg of purified water is added into a 3000L reaction kettle, an acylated casein wet product is added under stirring, the temperature is controlled to be 20 ℃, 10% lithium hydroxide solution is dripped until the pH value is 8.0, acylated casein is dissolved into milky white to light yellow solution, a solution microporous filter (1 mu mPP) is used for filtering, the filtrate is collected into the 3000L reaction kettle, the acylated casein solution is obtained, the weight A (810.0 kg) of the acylated casein solution is accurately weighed, and the detected acylation rate is 99.8%.
Acylated casein weight calculation
About 200.0g of the above-mentioned acylated casein solution was weighed as D, the pH was adjusted to 2.5-3.0 with 9% hydrochloric acid solution, precipitated, filtered, and the resulting precipitate was air-dried at 60-70℃to constant weight, and the weight was denoted as B. The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
The amount of solids of the acylated casein solution was 56.7kg.
Step 2: preparation of protein iron succinate
Taking the acylated casein solution, controlling the temperature to 20 ℃, slowly adding the prepared 2% ferric trichloride (the dosage of the ferric trichloride is 14.18 kg) solution under stirring, starting to dropwise add the 10% lithium hydroxide solution at the same time after the pH value is reduced to 6.0, controlling the pH value to be 6.0, continuously dropwise adding the 10% lithium hydroxide solution after the addition of the ferric trichloride solution is finished, keeping the pH value to be 6.0, keeping for 3 hours, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, quickly reducing the temperature to 50 ℃, keeping the temperature at 50 ℃, filtering the feed liquid to a clean area 2000L reaction kettle through a microporous filter (1 mu m titanium rod) and a microporous filter (0.22 mu m PP), reducing the temperature of the feed liquid to 20 ℃, adjusting the pH value to be 2.0 by using a 5% hydrochloric acid solution, and centrifuging. The filter cake was washed with purified water and collected and granulated (20 mesh) using a swing granulator. Drying the materials in a boiling dryer, wherein the temperature of an air inlet is 70 ℃, the temperature of an air outlet is 50 ℃, the drying weight loss of the dried materials is 1.51%, crushing the materials by a crusher (the aperture of a screen is 120 meshes), and sieving the crushed materials by a 100-mesh oscillating screen to obtain 51.0kg of protein iron succinate. Yield: 85.0%.
The iron succinate-XRD pattern of the protein prepared in this example is shown in FIG. 1, the infrared pattern is shown in FIG. 2, and the circular dichroism data is shown in Table 1.
TABLE 1 round two chromatography (secondary structure) of the protein iron succinate prepared in example 1 of the present invention
Clarity: clear solution, total iron content: 5.0% of succinic acid residue: 0.04%, free iron: 0.001%, loss on drying: 1.51%, aerobe: undetected; mould and yeast: undetected; escherichia coli: undetected; salmonella: undetected; staphylococcus aureus: undetected; pseudomonas aeruginosa: not detected.
Example 2
Step 1: preparation of acylated casein
600.0kg of purified water was added to a 2000L reaction vessel, 60.0kg of casein was added under stirring to maintain the temperature at 45 ℃, and 10% lithium hydroxide solution was added dropwise to the reaction solution until ph=7.5. The pH value was reduced during the dissolution, and the reaction solution ph=7.5 was kept by continuously dropping a 10% lithium hydroxide solution, and casein was dissolved into a milky to pale yellow solution. Controlling the temperature to 45 ℃, dropwise adding 18.0kg of monomethyl succinate acyl chloride, simultaneously dropwise adding 10% lithium hydroxide solution to adjust the pH=7.5 of the reaction solution, continuously dropwise adding 10% lithium hydroxide solution to keep the pH=7.5 of the reaction solution after the dropwise adding of the monomethyl succinate acyl chloride is finished, stirring for 2 hours, then cooling to 20 ℃, dropwise adding 5% hydrochloric acid solution to adjust the pH=2.0, precipitating and precipitating, keeping the temperature to 20 ℃, stirring for 0.5 hours, centrifuging, and granulating a filter cake by using a swinging granulator (20 meshes).
600.0kg of purified water is added into a 3000L reaction kettle, an acylated casein wet product is added under stirring, the temperature is controlled to be 20 ℃, 10% lithium hydroxide solution is dripped until the pH value is 7.5, acylated casein is dissolved into milky white to light yellow solution, a solution microporous filter (1 mu mPP) is used for filtering, the filtrate is collected into the 3000L reaction kettle, the acylated casein solution is obtained, the weight A (810.0 kg) of the acylated casein solution is accurately weighed, and the detected acylation rate is 99.7%.
Acylated casein weight calculation
About 200.0g of the above-mentioned acylated casein solution was weighed as D, the pH was adjusted to 2.5-3.0 with 9% hydrochloric acid solution, precipitated, filtered, and the resulting precipitate was air-dried at 60-70℃to constant weight, and the weight was denoted as B. The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
The amount of solids of the acylated casein solution was 56.5kg.
Step 2: preparation of protein iron succinate
Taking the acylated casein solution, controlling the temperature to 20 ℃, slowly adding the prepared 2% ferric trichloride (the dosage of the ferric trichloride is 14.13 kg) solution under stirring, starting to dropwise add the 10% lithium hydroxide solution at the same time when the pH value is reduced to 7.0, controlling the pH value to 7.0, continuously dropwise adding the 10% lithium hydroxide solution after the addition of the ferric trichloride solution is finished, keeping the pH value=7.0, keeping for 3 hours, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, quickly reducing the temperature to 50 ℃, keeping the temperature at 50 ℃, filtering the feed liquid to a clean area 2000L reaction kettle through a microporous filter (1 mu m titanium rod) and a microporous filter (0.22 mu m PP), reducing the temperature of the feed liquid to 20 ℃, adjusting the pH value to 2.0 by using a 5% hydrochloric acid solution, and centrifuging. The filter cake was washed with purified water and collected and granulated (20 mesh) using a swing granulator. Drying the materials in a boiling dryer, wherein the air inlet temperature is 70 ℃, the air outlet temperature is 50 ℃, the drying weight loss of the dried materials is 1.52%, the materials are crushed by a crusher (the aperture of a screen is 120 meshes), and the crushed materials are screened by a 100-mesh oscillating screen, so that 50.9kg of protein iron succinate is obtained. Yield: 84.8%.
Clarity: clear solution, total iron content: 5.0% of succinic acid residue: 0.05%, free iron: 0.002%, loss on drying: 1.52%, aerobe: undetected; mould and yeast: undetected; escherichia coli: undetected; salmonella: undetected; staphylococcus aureus: undetected; pseudomonas aeruginosa: not detected.
Example 3
Step 1: preparation of acylated casein
600.0kg of purified water was added to a 2000L reaction vessel, 60.0kg of casein was added under stirring to maintain the temperature at 55 ℃, and 10% lithium hydroxide solution was added dropwise to the reaction solution until ph=8.5. The pH value was reduced during the dissolution, and the reaction solution ph=8.5 was kept by continuously dropping a 10% lithium hydroxide solution, and casein was dissolved into a milky to pale yellow solution. Controlling the temperature to 55 ℃, dropwise adding 30.0kg of monomethyl succinate acyl chloride, simultaneously dropwise adding 10% lithium hydroxide solution to adjust the pH value of a reaction solution to be 8.5, continuously dropwise adding 10% lithium hydroxide solution to keep the pH value of the reaction solution to be 8.5 after the dropwise adding of the monomethyl succinate acyl chloride is finished, stirring for 2 hours, then cooling to 20 ℃, dropwise adding 5% hydrochloric acid solution to adjust the pH value to be 2.0, precipitating and precipitating, keeping the temperature to 20 ℃, stirring for 0.5 hours, centrifuging, and granulating a filter cake by using a swinging granulator (20 meshes).
600.0kg of purified water is added into a 3000L reaction kettle, an acylated casein wet product is added under stirring, the temperature is controlled to be 20 ℃, 10% lithium hydroxide solution is dripped until the pH value is 8.5, acylated casein is dissolved into milky white to light yellow solution, a solution microporous filter (1 mu mPP) is used for filtering, the filtrate is collected into the 3000L reaction kettle, the acylated casein solution is obtained, the weight A (810.0 kg) of the acylated casein solution is accurately weighed, and the detected acylation rate is 99.8%.
Acylated casein weight calculation
About 200.0g of the above-mentioned acylated casein solution was weighed as D, the pH was adjusted to 2.5-3.0 with 9% hydrochloric acid solution, precipitated, filtered, and the resulting precipitate was air-dried at 60-70℃to constant weight, and the weight was denoted as B. The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
The solids content of the acylated casein solution was 56.8kg.
Step 2: preparation of protein iron succinate
Taking the acylated casein solution, controlling the temperature to 20 ℃, slowly adding the prepared 2% ferric trichloride (the dosage of the ferric trichloride is 14.20 kg) solution under stirring, starting to dropwise add the 10% lithium hydroxide solution at the same time after the pH value is reduced to 8.5, controlling the pH value to be 8.5, continuously dropwise adding the 10% lithium hydroxide solution after the addition of the ferric trichloride solution is finished, keeping the pH value to be 8.5, keeping for 3 hours, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, quickly reducing the temperature to 55 ℃, keeping the temperature at 55 ℃, filtering the feed liquid to a 2000L reaction kettle in a clean area through a microporous filter (1 mu m titanium rod) and a microporous filter (0.22 mu m PP), reducing the temperature of the feed liquid to 20 ℃, adjusting the pH value to 2.0 by using a 5% hydrochloric acid solution, and centrifuging. The filter cake was washed with purified water and collected and granulated (20 mesh) using a swing granulator. Drying the materials in a boiling dryer, wherein the air inlet temperature is 70 ℃, the air outlet temperature is 50 ℃, the drying weight loss of the dried materials is 1.50%, the materials are crushed by a crusher (the aperture of a screen is 120 meshes), and the crushed materials are screened by a 100-mesh oscillating screen, so that 51.1kg of protein iron succinate is obtained. Yield: 85.2%.
Clarity: clear solution, total iron content: 5.0% of succinic acid residue: 0.03%, free iron: 0.002%, loss on drying: 1.50%, aerobe: undetected; mould and yeast: undetected; escherichia coli: undetected; salmonella: undetected; staphylococcus aureus: undetected; pseudomonas aeruginosa: not detected.
Example 4
Step 1: preparation of acylated casein
600.0kg of purified water was added to a 2000L reaction vessel, 60.0kg of casein was added under stirring to maintain the temperature at 55 ℃, and 10% lithium hydroxide solution was added dropwise to the reaction solution until ph=8.5. The pH value was reduced during the dissolution, and the reaction solution ph=8.5 was kept by continuously dropping a 10% lithium hydroxide solution, and casein was dissolved into a milky to pale yellow solution. Controlling the temperature to 55 ℃, dropwise adding 24.0kg of succinic acid monoethyl ester acyl chloride, simultaneously dropwise adding 10% lithium hydroxide solution to adjust the pH value of a reaction solution to be 8.5, continuously dropwise adding 10% lithium hydroxide solution to keep the pH value of the reaction solution to be 8.5 after the dropwise adding of succinic acid monoethyl ester acyl chloride is finished, stirring for 2 hours, then cooling to 20 ℃, dropwise adding 5% hydrochloric acid solution to adjust the pH value to be 2.0, precipitating and precipitating, keeping the temperature to 20 ℃, stirring for 0.5 hours, centrifuging, and granulating a filter cake by using a swinging granulator (20 meshes).
600.0kg of purified water is added into a 3000L reaction kettle, an acylated casein wet product is added under stirring, the temperature is controlled to be 20 ℃, 10% lithium hydroxide solution is dripped until the pH value is 8.5, acylated casein is dissolved into milky white to light yellow solution, a solution microporous filter (1 mu mPP) is used for filtering, the filtrate is collected into the 3000L reaction kettle, the acylated casein solution is obtained, the weight A (810.0 kg) of the acylated casein solution is accurately weighed, and the detected acylation rate is 99.8%.
Acylated casein weight calculation
About 200.0g of the above-mentioned acylated casein solution was weighed as D, the pH was adjusted to 2.5-3.0 with 9% hydrochloric acid solution, precipitated, filtered, and the resulting precipitate was air-dried at 60-70℃to constant weight, and the weight was denoted as B. The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
The solids content of the acylated casein solution was 56.6kg.
Step 2: preparation of protein iron succinate
Taking the acylated casein solution, controlling the temperature to 20 ℃, slowly adding the prepared 2% ferric trichloride (the dosage of the ferric trichloride is 14.15 kg) solution under stirring, starting to dropwise add the 10% lithium hydroxide solution at the same time after the pH value is reduced to 7.0, controlling the pH value to be 7.0, continuously dropwise adding the 10% lithium hydroxide solution after the addition of the ferric trichloride solution is finished, keeping the pH value to be 8.0, keeping for 3 hours, heating the feed liquid to 75 ℃, keeping the temperature for 30 seconds, quickly reducing the temperature to 50 ℃, keeping the temperature at 50 ℃, filtering the feed liquid to a clean area 2000L reaction kettle through a microporous filter (1 mu m titanium rod) and a microporous filter (0.22 mu m PP), reducing the temperature of the feed liquid to 20 ℃, adjusting the pH value to be 2.0 by using a 5% hydrochloric acid solution, and centrifuging. The filter cake was washed with purified water and collected and granulated (20 mesh) using a swing granulator. Drying the materials in a boiling dryer, wherein the air inlet temperature is 70 ℃, the air outlet temperature is 50 ℃, the drying weight loss of the dried materials is 1.57%, the materials are crushed by a crusher (the aperture of a screen is 120 meshes), and the crushed materials are screened by a 100-mesh oscillating screen, so that 50.7kg of protein iron succinate is obtained. Yield: 84.5%.
Clarity: clear solution, total iron content: 5.0% of succinic acid residue: 0.02%, free iron: 0.001%, loss on drying: 1.57%, aerobe: undetected; mould and yeast: undetected; escherichia coli: undetected; salmonella: undetected; staphylococcus aureus: undetected; pseudomonas aeruginosa: not detected.
Claims (10)
1. A novel preparation method of protein iron succinate is characterized by comprising the following steps:
2. the method for preparing protein iron succinate according to claim 1, wherein the method comprises the following steps:
step 1: preparation of acylated casein
(1) Adding purified water into a reaction kettle, adding casein under stirring, keeping the temperature at 45-55 ℃, and dropwise adding an alkali solution until the pH value of the reaction solution is=7.5-8.5;
(2) The pH value is reduced in the dissolving process, and the alkali solution is continuously added dropwise to keep the pH value of the reaction solution to be 7.5-8.5, so that casein is dissolved into milky white to light yellow solution;
(3) Controlling the temperature to be 45-55 ℃, dropwise adding monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride, simultaneously dropwise adding an alkali solution to adjust the pH value of a reaction solution to be 7.5-8.5, continuously dropwise adding the alkali solution to keep the pH value of the reaction solution to be 7.5-8.5 after the dropwise adding of the monomethyl succinate acyl chloride and/or monoethyl succinate acyl chloride is finished, stirring for 2 hours, then cooling to 20-30 ℃, dropwise adding a hydrochloric acid solution to adjust the pH value to be 2.0-3.0, precipitating and precipitating, keeping the temperature to be 20-30 ℃, stirring for 0.5-1 hour, centrifuging, and finishing the filter cake by using a swinging granulator;
(4) Adding purified water into a reaction kettle, adding an acylated casein wet product under stirring, controlling the temperature to be 20-30 ℃, dropwise adding an alkali solution until the pH value is 7.5-8.5, dissolving the acylated casein into a milky white to pale yellow solution, filtering the solution through a filter, collecting filtrate into the reaction kettle to obtain an acylated casein solution, and calculating the weight of the acylated casein;
step 2: preparation of protein iron succinate
(1) Taking the acylated casein solution, controlling the temperature to be 20-30 ℃, slowly adding the prepared ferric trichloride solution while stirring, simultaneously dropwise adding an alkali solution to control the pH value to be 6.0-8.0, continuously dropwise adding the alkali solution to keep the pH value to be 6.0-8.0 after the ferric trichloride solution is added, maintaining for 3-4 hours, heating the feed liquid to 75 ℃, maintaining for 30 seconds, cooling to 50-55 ℃, maintaining the temperature to 50-55 ℃, filtering the feed liquid to a clean area reaction kettle through a filter, cooling to 20-30 ℃, regulating the pH value to be 2.0-3.0 by using a hydrochloric acid solution, and centrifuging;
(2) Washing the filter cake with purified water, collecting, and granulating with a swing granulator; drying the materials in a boiling dryer, wherein the drying weight loss of the dried materials is less than 2%, crushing the materials by a crusher, and sieving by an oscillating screen to obtain the protein iron succinate.
3. The method according to claim 2, wherein the weight ratio of casein to purified water in step 1 is 1:10, and the weight ratio of monomethyl and/or monoethyl succinate acid chloride to casein is 0.3-0.5:1.
4. A process according to claim 3, wherein the weight ratio of monomethyl and/or monoethyl succinyl chlorides to casein in step 1 is 0.4:1.
5. The method according to claim 2, wherein the alkaline solution in step 1 and step 2 is a 10% lithium hydroxide solution, and the hydrochloric acid solution concentration is 5%.
6. The method of claim 2, wherein the ferric trichloride solution concentration in step 2 is 2%.
7. The method according to claim 2, wherein the acylated casein weight calculation method in step 1 is as follows:
(1) Weighing about 200.0g of the acylated casein solution, namely D, regulating the pH value to 2.0-3.0 by using 9% hydrochloric acid solution, precipitating, filtering, and drying the obtained precipitate to constant weight by blowing at 60-70 ℃ and the weight is denoted as B;
(2) The amount of solids X in the acylated casein solution was calculated from the weight A of the solution obtained by dissolution, and the calculation formula of the amount of solids X was X=B.times.D.times.A.
8. The method of claim 2, wherein the amount of ferric trichloride and acylated casein in step 2 is 0.25:1.
9. The method according to claim 2, wherein the inlet air temperature of the dryer in the step 2 is 70-80 ℃ and the outlet air temperature is 50-60 ℃.
10. The method of claim 2, wherein the filter in step 1 is a 1 μmpp microporous filter, and the filter in step 2 is a 1 μιτι titanium rod microporous filter and/or a 0.22 μmpp microporous filter.
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