CN104402984A - Preparation method of iron-protein succinylate with high iron content - Google Patents
Preparation method of iron-protein succinylate with high iron content Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine, and relates to a preparation method of iron-protein succinylate with a high iron content. The preparation method comprises the following steps: (1) acylation: adding succinic anhydride into a casein solution to carry out reactions, continuously adding a sodium hydroxide solution into the reaction system to keep the pH value in a range of 6 to 9, after the reaction, adding acid into the reaction liquid to adjust the pH value to a range of 1 to 4, and filtering to obtain precipitate; (2) iron loading: dispersing the obtained precipitate into water, adding a proper amount of sodium hydroxide solution, stirring to dissolve the precipitate, then adding a ferric trichloride solution containing sodium bicarbonate into the obtained protein succinylate solution, adding a sodium hydroxide solution simultaneously to maintain the pH value of the reaction liquid in a range of 6 to 9, after the reaction filtering to remove the insoluble substances so as to obtain a iron-protein succinylate solution; refining the solution to remove the insoluble substance, adding acid to generate precipitate, filtering to obtain the precipitate, washing the precipitate by water, and finally drying the precipitate. In the recent literature, the reported iron content of iron-protein succinylate is in a range of 4.5 to 10%, while the iron content of iron-protein succinylate prepared by the provided method is as high as 15%. Moreover, the provided preparation method has the advantages of simple technology, good product solubility, and stable product quality.
Description
Technical field
The present invention relates to medical art, be specifically related to the preparation method of the iron protein succinylate of a kind of high year iron.
Background technology
Iron is the trace element of needed by human, has important physiological action to human body.The trace element that can detect in human body about more than 70 is planted, and adds up and accounts for 0.05% of human elementary total amount, and the micro elements needed by human of generally acknowledging in the world at present has 13 kinds, iron, copper, chromium, fluorine, manganese, selenium, silicon, tin, vanadium and zinc etc.Wherein iron accounts for first place.Iron is the important composition composition of oxyphorase in blood of human body, myohaemoglobin and multiple enzyme.Oxyphorase has by O_2 transport to each tissue and organ, takes the carbonic acid gas that metabolism produces to lung again and gets rid of external function.As lacked ferro element in meals, or ferro element absorbs bad, hemoglobin concentration will be caused greatly to decline, thus cause hypoferric anemia.Visible human body whether anaemia, ferro element abundance is most important.Iron is that human body requirements amount is maximum, and the trace element of metabolic disturbance the most easily occurs.By China 1,300,000,000 population, about there are nearly 400,000,000 hypoferric anemia patients in the whole nation, group of people at high risk comprises pregnant woman, baby, children, women, old man and sportsmen, just there are 66.3% needs to take in annual 2000 ten thousand pregnant woman and mend iron medicine, be 75% ~ 82.5% at 6 months to 2 years old baby's sideropenia sickness rate, within 6 to 12 years old, be 21.6%, women's sickness rate is 43.3%.Therapeutic hypoferric anemia medicine has huge potential market demand.During iron deficiency, there is obstacle in protoheme synthesis, red blood cell life span is short, and iron content enzyme reduces or active reduction, and lower immune function, many metabolic processes get muddled, and children's more can cause intelligence and psychological abnormality.Chalybeate is the specifics for the treatment of iron deficiency, is secure unique, the effective and economic method for the treatment of hypoferric anemia.Can alleviate Anemia very soon after patient takes, general medication about 2 months, oxyphorase can return to normal level.
At present, domestic and international clinical conventional chalybeate is mainly oral, is divided into three types: inorganic salts: ferrous sulfate, iron protochloride etc.; Small molecule partner class: Ferrox, ferrous succinate, Ferric Ammonium Citrate, Ferrous Fumarate etc.; Macromolecule complex class: Iron Dextran, iron protein succinylate etc.
Normal oral chalybeate is because iron ion is to the stimulation of mucous membrane, and gastrointestinal side-effect is larger.Ferrous iron comparatively ferric iron absorbs well, but ferrous iron exists unstable feature.The particularly ferrous sulfate tablet of clinical first-selection for a long time, poor stability, is very easily oxidized to trivalent iron salt and is not easily absorbed by body, and has obvious GI irritation effect, as taken rear gastrointestinal upset, feel sick, stomachache and diarrhoea etc., not easily accepted by children.Gastrointestinal side effect incidence is up to more than 50%, and some patients can not adhere to treatment.In addition, it is reported, ferrous iron easily produces endogenous free radical in vivo, causes Cell membrane lipids peroxidation to cause cell injury.
Due to the aspect such as security and curative effect, early stage inorganic salt and small molecule partner iron supplementary just gradually by Polyferose, protein-iron class macromolecule complex substitute, iron protein succinylate is wherein representative kind.Ferplex in the existing iron supplementary in market (iron protein succinylate, iron content is 5%) curative effect is better, and untoward reaction is little; Niferex (Nu-Iron, iron content is 46%) curative effect is better, and untoward reaction is less; Dextran iron plate (Iron Dextran, iron content is 25%) curative effect is better, and untoward reaction is general; Iron lactate (iron content is 19%) curative effect is general, untoward reaction is high, although import preparation Ferplex curative effect is better in iron supplementary, untoward reaction is also little, but compared with other iron supplementary, iron content is lower, dose is compared greatly, if can improve its iron content further, its curative effect should also can improve greatly.
Iron protein succinylate is the product that casein obtains with iron trichloride complexing after succinic anhydride acylation; it is a kind of organoiron compound; iron does not wherein dissociate in the solution; it is complex status; solution is precipitated form when pH value is less than 4, and when pH value is higher, (pH7.5 ~ 8.0) become soluble substance again.In addition, said preparation, can by trypsin hydrolyzing when pH neutral not by gastric pepsin digestion.Due to these character, the iron contained by iron protein succinylate does not react with hydrochloric acid in gastric juice in gastric juice and stomach en-by the protection of protein film.Therefore, gastric mucosa injury can not be caused.In this product, iron starts release at duodenum, and especially in jejunum release, because the rising of pH value makes compound again become solvable, protein film is by tryptic digestion simultaneously.Iron is wherein very beneficial for the physiological absorption of body, but can not form too high absorption peak, presents a kind of constant absorption trend, reaches the optimum regime absorbed with storage at each position of body gradually.Therefore, iron protein succinylate generally can not produce the problem of resistance of stomach and intestine.
The preparation method of EP0939083A2 to iron protein succinylate has been described in detail.Acidylate: add Succinic anhydried reaction in casein solution, keep reacting liquid pH value 6 ~ 9 by constantly adding sodium hydroxide solution, after having reacted, acid adding makes precipitation, makes pH value 1 ~ 4, crosses leaching precipitation.Carry iron: precipitation be dispersed in water, strong stirring, and hydro-oxidation sodium solution is stirred to dissolve, in the succsinic acid protein solution of dissolving gained, add ferric chloride aqueous solutions start reaction, reacting solution pH value slowly drops to 2 ~ 3 from 6 ~ 9, stopped reaction, filters, get precipitation, be iron protein succinylate crude product.The iron level of the preparation-obtained iron protein succinylate of this technical scheme is 5.4% (weight ratio).
Publication (application number: 201210358524.9) also the preparation method of iron protein succinylate has been described in detail: acidylate: add Succinic anhydried in casein solution; reacting liquid pH value 9.0 ~ 10.0 is kept by constantly adding sodium hydroxide solution; centrifuging; filtrate acid adding makes precipitation; make pH value 1 ~ 4, cross leaching precipitation.Carry iron: precipitation adds water-dispersion, hydro-oxidation sodium solution stirs and makes solution, in succsinic acid protein solution, add ferric chloride aqueous solutions, drips sodium hydroxide solution simultaneously and makes reaction solution keep pH value 9.0 ~ 10.0.The iron level of the iron protein succinylate that this technical scheme obtains is 8% ~ 9.5%.
Publication (application number: 200680045712.9) provide a kind of novel method preparing ferri-succinylcasein, feature is one kettle way, carrying in iron step is the ferric chloride aqueous solutions directly added in not separated succsinic acid albumen test liquid, reacting liquid pH value slowly drops to 2 ~ 3 from 6 ~ 9, stopped reaction.The iron level of the iron protein succinylate that this technical scheme obtains is 5.1% ~ 5.4%.
Summary of the invention
We are when developing iron protein succinylate, synthesize with reference to patent EP0939083A2, this method is carried in iron step, liquor ferri trichloridi acidity is comparatively strong, and locally generate precipitation when adding liquor ferri trichloridi, succsinic acid albumen also can precipitate, form suspension, when dropping to 2 ~ 3 etc. pH value, precipitate completely, there is the problem that succsinic acid albumen test is insufficient and year iron is limited.The iron level of the iron protein succinylate prepared is 5.1%.Concrete outcome is in table 1.
With reference to publication (application number: 201210358524.9) synthesize, drip sodium hydroxide solution when reacting unlike year iron with patent EP0939083A2 simultaneously and maintain reacting liquid pH value 9.0 ~ 10.0, carry iron time reaction solution be suspension state, the iron level of the iron protein succinylate prepared is 8%.This method is carried in iron step, because sodium hydroxide solution maintains the scope of pH value 9.0 ~ 10.0, be conducive to succsinic acid albumen not precipitated, sustainable participation reaction, improve to a certain extent and carry iron, but liquor ferri trichloridi being easily partially formed ferric hydroxide colloid precipitation when contacting sodium hydroxide, reducing iron ion reactive behavior and making the insufficient year iron that causes of iron reaction limited.Concrete outcome is in table 1.
(application number: 200680045712.9) similar with year iron step of patent EP0939083A2, does not try publication again.
At present there are no iron-holder higher than 10% the document of iron protein succinylate synthesis technique and patent report.Technical problem to be solved by this invention is the preparation method of the iron protein succinylate providing a kind of high year iron.
The limited problem of year iron is all there is based on aforementioned, we study unexpected discovery and add a certain amount of sodium hydrogen carbonate solution when preparing liquor ferri trichloridi, and by dripping sodium hydroxide solution maintenance pH value 6 ~ 9 when year iron reacts, year iron efficiency improves greatly, significantly improve and carry iron, reach about 15wt%.
Particularly, to prepare the method concrete steps of iron protein succinylate as follows in the present invention:
(1) acidylate: add Succinic anhydried reaction in casein solution, keep reacting liquid pH value 6 ~ 9 by constantly adding sodium hydroxide solution, after having reacted, acid adding makes reacting liquid pH value 1 ~ 4, filters to obtain precipitation;
(2) iron is carried: the precipitation that step (1) obtains be dispersed in water, add appropriate sodium hydroxide solution to be stirred to dissolve, to dissolving in gained succsinic acid protein solution the liquor ferri trichloridi dripped containing sodium bicarbonate, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution simultaneously, reacted rear filtration, removing insolubles obtains iron protein succinylate solution;
(3) refining: iron protein succinylate solution refining step (2) obtained, removing insolubles, then adds Acid precipitation, filters out precipitation, dry after washing.
In step (1), take casein as raw material, add the water of 15 times of weight and appropriate sodium hydroxide solution stirring and dissolving, dissolve rear pH value 6 ~ 9, added Succinic anhydried reaction, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution, add in three hours, and continue to stir half an hour, then making pH value 1 ~ 4 by adding appropriate hydrochloric acid solution, filtering to obtain precipitation.
In step (2), drip the liquor ferri trichloridi containing sodium bicarbonate in succsinic acid protein solution, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution, liquor ferri trichloridi added in 2 ~ 3 hours simultaneously, and continued to stir half an hour.
In step (3), the iron protein succinylate solution weight that step (2) obtains is added with Acid precipitation, sedimentation and filtration, adds alkali dissolution, crosses the operation filtering insolubles, then filtrate obtains iron protein succinylate solution through the filter of millipore filtration essence.
More specifically, in step (3), in the iron protein succinylate solution that step (2) obtains, add appropriate hydrochloric acid solution makes pH value 1 ~ 4 make precipitation, filter to obtain precipitation, precipitation is dispersed in water, strong stirring, adds appropriate sodium hydroxide solution and make dissolving, the pH value of last solution, 6 ~ 9, filters to obtain solution; Then adding hydrochloric acid soln makes pH value 1 ~ 4 make precipitation, filters to obtain precipitation, precipitation is dispersed in water, strong stirring, adds appropriate sodium hydroxide solution and make dissolving, and the pH value of last solution is 6 ~ 9, and filter, filtrate filters to obtain iron protein succinylate solution through millipore filtration essence.
In order to realize the object of the invention better, in steps in pH value 6 ~ 9, preferably pH value 7.0 ~ 8.5; PH value 1 ~ 4, preferably pH value 2.5 ~ 3.
In order to realize the object of the invention better, in described step (1) is food grade caseins, and the mass ratio that itself and Succinic anhydried react is 4 ~ 2: 1.
In order to realize the object of the invention better, liquor ferri trichloridi iron trichloride, water and 0.2mol/L sodium hydrogen carbonate solution preparation in described step (2), the weight ratio of the sodium hydrogen carbonate solution of iron trichloride, water and 0.2mol/L is: 1:20:(25 ~ 35), that optimum is 1:20:30.
Synthetic method of the present invention is simple, not with an organic solvent, environmental protection, cost is lower, products obtained therefrom steady quality, and yield is high, is applicable to industry's enlarging production; The product biological activity that this legal system is standby in addition is significantly better than iron protein succinylate oral solution commercially available at present.
Table 1-carries iron reactions steps comparing result
Compared with prior art, Advantages found of the present invention is carrying in iron step, in present method, liquor ferri trichloridi and feed postition and pH value of reaction system are done improvement: containing a certain amount of sodium hydrogen carbonate solution in liquor ferri trichloridi, strong base-weak acid salt both may facilitate Fe to a certain extent
3+fe is protected again with the binding ability of succsinic acid albumen
3+not by strong OH
-in conjunction with and reduce active, drip sodium hydroxide solution makes pH value keep 6 ~ 9 simultaneously, makes reaction solution maintain solution state.Improve yield, and carry iron far away higher than 5% of present commercially available prod, reach about 15%, quality product stable homogeneous.
Accompanying drawing explanation
Fig. 1, the infrared spectrogram of embodiment 1 highly finished product.
Fig. 2, the 24K Mossbauer figure of embodiment 3 highly finished product.
Fig. 3, the 295K Mossbauer figure of embodiment 3 highly finished product.
Fig. 4, embodiment 5 highly finished product XRD figure.
Embodiment
Below for the preparation method of iron protein succinylate of the present invention is described better, the present invention is further described.
In example, the content of iron adopts measurement with the following method below:
Get testing sample and be about 1.25g, accurately weighed, add water 20ml, stirs, be about 25ml adjust ph 6.5 ~ 8.0, make to dissolve completely, add water and be settled to 50ml measuring bottle, as iron protein succinylate storing solution with 0.1mol/L sodium hydroxide solution.Precision pipettes 2ml, puts 25ml volumetric flask, is diluted with water to scale, shake up, as need testing solution.Precision pipettes reference substance solution and [takes ferric ammonium sulfate (FeNH respectively
4(SO
4)
212H
2o) 86.3mg, put in 100ml measuring bottle, after being dissolved in water, add sulfuric acid 0.25ml, add water to scale, shake up, obtain (every 1ml iron content 10 μ g)] and each 2ml of need testing solution, put in 50ml measuring bottle respectively, add hydrochloric acid 2ml, ultrasonic 5 minutes, add 10% hydroxylamine hydrochloride solution 3ml, shake up, then add 0.3% dipyridyl solution and (take 2, 2,-dipyridyl 0.15g puts in 50ml measuring bottle, add suitable quantity of water, add Glacial acetic acid 3ml, jolting is dissolved, then scale is added water to, shake up and get final product) 5ml, shake up, add 85wt% hydrazine hydrate solution 2ml, shake up that (after adding hydrazine hydrate solution, solution can generate heat, room temperature should be chilled to.All to shake up after often adding a kind of reagent.So 80wt% hydrazine hydrate solution, should 3ml be added), then add water to scale, shake up, place 30 minutes, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV A), measure absorbancy at 525nm wavelength place.Iron level is calculated by external standard method.
Calculation formula:
The structural identification of iron protein succinylate is as follows:
Illustrate: reference substance is originated: the iron protein succinylate oral solution (trade(brand)name that iron protein succinylate reference substance is produced by Italian ITALFARMACO, S.A. company
lot number: separation and purification and obtaining 110711).
Iron protein succinylate prepared by the inventive method taking casein as starting raw material, after carrying out succsinic acid modification, then makes with ferric chloride reaction complexing, and namely casein have passed through acidylate and carries iron two steps.On casein basis, carry out structural modification transformation in view of this product to be prepared from, belong to the semi-synthetic product of macromole class, belong to protein macromolecule mixture, the activeconstituents of this product is iron, protein part is equivalent to the effect of carrier, ensures the distinctive release of iron in gi tract, absorbs behavior.Therefore accurate Structural determination cannot be carried out as common single pure compound, ultimate analysis and nucleus magnetic resonance, Information in Mass Spectra cannot accurate Analysis product structure.
We are respectively from protein portion, and succsinic acid acylating moiety and year iron construction part three levels confirm the constitutional features of this product.
(1) composition of protein portion and structural identification, contrast through the infrared spectra of this product and reference substance, UV spectrum, amino acid forms, Polyacrylamide Gel Electrophoresis, Matrix Assisted Laser Desorption time-of-flight mass spectrometry measure several means of different mensuration, this product and reference substance protein portion amino acid classes and content distribution basically identical, also meet caseic amino acid characteristics; Cataphoretic determination molecular weight and reference substance basically identical, be about 20,000; The result of flight mass spectrum shows simultaneously, may contain four kinds of protein ingredients, meet and the starting raw material of this product-caseic constitutional features, also form basically identical with reference substance protein molecular weight in this product.The infrared spectra information of this product, UV spectrum information are also basically identical with the structure of reference substance protein portion with display in addition, meet protein structure feature.All these information comprehensive, in conjunction with the synthetic route of this product, can judge that the protein portion structure of this product and reference substance is basically identical with composition;
(2) feature of succsinic acid acylating moiety, through the mensuration of our intermediate acylated degree, in conjunction with the information of infrared spectra, (charateristic avsorption band is 1650cm
-1, be acid amides I bands of a spectrum C=O stretching vibration), meet the constitutional features of this product after acylation reaction, consistent with reference substance;
(3) carry the confirmation of iron construction, we can confirm by the mensuration of carrying iron the quantity about 15% that this product carries iron; Measurement result simultaneously through Mo&4&ssbauer spectrum shows (Fig. 2 ~ Fig. 3): be symmetrical two spectral lines under 295K, 24K, show the coordination shell only having a type; Under 295k, the isomeric shift of highly finished product is 0.35mm/s, electricity level Four split values is 0.67mm/s, under 24K, isomeric shift is 0.45mm/s, electricity level Four split values is 0.68mm/s, all show the feature isomeric shift of Fe, in iron protein succinylate, Fe is trivalent high-spin, and only has the hapto of a type.Report consistent with pertinent literature; Simultaneously the g-factor highly finished product of electron paramagnetic resonance spectrum ESR and reference substance are 2.004, and result shows: the iron in this product is complex status, are the strong form of Fe-O-Fe, consistent with the combination of iron in reference substance, report consistent with pertinent literature.Comprehensive above-mentioned information, can illustrate iron complexing position in this product and reference substance, form and combination stability basically identical, there is identical keyed feature.
(4) other, X-ray diffraction result shows (Fig. 4), and the diffraction peak of highly finished product and diffraction angle meet the constitutional features of iron protein succinylate.
The above analysis test and sample preparation industrial analysis, this product meets iron protein succinylate pertinent literature report, can confirm as iron protein succinylate.Structural representation is as follows:
Comparative example 1
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 940ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value about 8, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 175g, in iron: succsinic acid albumen=0.18: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 150.5g, add water 3.1L, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 4.51L is added while stirring), liquor ferri trichloridi is added in succsinic acid protein solution, add sodium hydroxide solution makes reacting solution pH value remain on 9.0 ~ 10.0 simultaneously, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal, get filtrate.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 250ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 168g, for the homogeneous powder of brown color, yield is 84%, carry iron 11.5%.
Comparative example 2
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 940ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value about 8, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 175g, in iron: succsinic acid albumen=0.18: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 150.5g, add water 3.01L, stirring and dissolving, then 0.2mol/L sodium carbonate solution 4.51L is added while stirring), liquor ferri trichloridi is added in succsinic acid protein solution, add sodium hydroxide solution makes reacting solution pH value remain on 6 ~ 9 simultaneously, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal, get filtrate.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 250ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 166g, for the homogeneous powder of brown color, yield is 80%, carry iron 10.1%.
Documents 1
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 940ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value about 8, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 176.5g, in iron: succsinic acid albumen=0.18: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 151.8g, add water 3.01L, stirring and dissolving), liquor ferri trichloridi is added in succsinic acid protein solution, local has precipitation to generate, and solution ph declines, and continues to add liquor ferri trichloridi and reduces to 2 ~ 3 to solution ph, continue to stir half an hour, centrifugal.
Get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, be difficult to dissolve, the last solid still having a lot of indissoluble, filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 162g, for the homogeneous powder of brown color, yield is 81%, iron level is 5.1%.
Documents 2
In reaction vessel, add purified water 3L, add casein 200g, stir, constantly add 4mol/L sodium hydroxide solution and be about 50ml, dissolve rear pH value about 9.5, temperature of reaction room temperature, then slowly add Succinic anhydried 100g, edged 4mol/L sodium hydroxide solution in limit regulates the pH to 9.5 of reaction solution, adds in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, pH value 2.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 4mol/L sodium hydroxide solution and be about 80ml and make dissolving, dissolved rear pH value about 9.5 in 45 minutes, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 176g, in iron: succsinic acid albumen=0.18: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 151.2g, add water 8.2L, stirring and dissolving), liquor ferri trichloridi is added in succsinic acid protein solution, and add 4mol/L sodium hydroxide solution simultaneously and make pH value remain on 9.0 ~ 10.0, in reaction process, local has and precipitates generation on a small quantity, in suspension solution after liquor ferri trichloridi adds, continue to stir half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 250ml, pH value to 2.0, then filter, get precipitation, add water about 5L, strong stirring disperses, add 4mol/L sodium hydroxide solution in 30 minutes and be about 100ml, be stirred to dissolve, the pH value about 9.5 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 4mol/L sodium hydroxide solution in 30 minutes and be about 80ml, be stirred to dissolve, the pH value about 9.5 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.0, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, lyophilize, obtain dry product 170g, for the homogeneous powder of brown color, yield is 85%, iron level 8%.
Embodiment 1
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 930ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value 6.5 in 45 minutes, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 177g, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 127g, add water 2.54L, stirring and dissolving, then adds 0.2mol/L sodium hydrogen carbonate solution 3.8L while stirring), liquor ferri trichloridi is added in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 6 ~ 9, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 250ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 199.6g, for the homogeneous powder of brown color, yield is 99.8%, iron level is 14.9wt%.The infrared spectrogram of highly finished product is shown in Fig. 1.
Embodiment 2
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 930ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value 7.1, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 177g, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 127g, add water 2.54L, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 3.8L is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 6.0 ~ 7.0, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 300ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 198.4g, for the homogeneous powder of brown color, yield is 99.2%, iron level 14.2wt%.
Embodiment 3
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 930ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value 7.8, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 177g, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 127g, add water 2.54L, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 3.8L is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 8.5 ~ 9.0, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 300ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 198.6g, for the homogeneous powder of brown color, yield is 99.3%, iron level 13.9%.Highly finished product Mo&4&ssbauer spectrum under 295K, 24K is shown in Fig. 2 ~ 3.
Embodiment 4
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 930ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value 8.2, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 177g, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 127g, add water 2.54L, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 3.2L is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 7.0 ~ 8.5, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 300ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln in half an hour and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 197.8g, for the homogeneous powder of brown color, yield is 98.9%, iron level 13.8%.
Embodiment 5
Purified water 3L is added in reaction vessel, add casein 200g, stir, constantly add 2mol/L sodium hydroxide solution and be about 100ml, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 100g and 2mol/L sodium hydroxide solution is about 930ml, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 530ml, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 4.5L, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 160ml and make dissolving, dissolved rear pH value 8.6, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 177g, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 127g, add water 2.54L, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 4.4L is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 7.0 ~ 8.5, liquor ferri trichloridi adds rear continuation and stirs half an hour, centrifugal.
In filtrate, add 3mol/L hydrochloric acid soln in half an hour and be about 300ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 200ml, be stirred to dissolve, the pH value about 8 of last solution, stir about 3 hours altogether, dissolve completely and filter, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 130ml, pH value to 2.5, then filter, get precipitation, add water about 5L, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 160ml, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 4 hours, filter, filtrate 1.2 μm of filtering with microporous membrane, filtrate adds Acid precipitation, add 3mol/L hydrochloric acid soln and be about 60ml, pH value to 2.51, continue to stir half an hour, then filter, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 199.4g, for the homogeneous powder of brown color, yield is 99.7%, iron level 13.9wt%.The XRD figure of highly finished product is shown in Fig. 4.
Embodiment 6
Purified water 150Kg is added in 500L reactor, stir, add casein 12Kg, constantly add 2mol/L sodium hydroxide solution and be about 6L, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 6Kg and 2mol/L sodium hydroxide solution is about 72L, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 50L, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 220Kg, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 14L and make dissolving, dissolved rear pH value 9.0 in 45 minutes, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 10.4489Kg, in iron: succsinic acid albumen=0.15: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 7.5Kg, add 150Kg, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 225Kg is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 7.0 ~ 8.5, add alkali altogether and be about 6L, continue to stir half an hour, centrifugal.
Filtrate is transferred in reactor, add 3mol/L hydrochloric acid soln half an hour and be about 21L, pH value to 2.5, then centrifugal, precipitation is transferred in reactor, add water about 250Kg, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 10L, be stirred to dissolve, the pH value about 8 of last solution, stir about 5 hours altogether, dissolve completely centrifugal, filtrate is transferred in reactor, add Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 10L, pH value to 2.5, then centrifugal, precipitation is transferred in reactor, add water about 250Kg, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 8L, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 8 hours, centrifugal, filtrate is transferred in reactor, then 1.2 μm of millipore filtration Plate Filtrations, filtrate is transferred in the reactor cleaned up with water, add Acid precipitation, add 3mol/L hydrochloric acid soln and be about 8L, pH value to 2.51, continue to stir half an hour, then centrifugal, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 11.82Kg, yield is 98.5%, iron level is 14.8%.
Embodiment 7
Purified water 150Kg is added in 500L reactor, stir, add casein 12Kg, constantly add 2mol/L sodium hydroxide solution and be about 6L, dissolve rear pH value about 8, temperature of reaction room temperature, then adds Succinic anhydried 3Kg and 2mol/L sodium hydroxide solution is about 40L, makes the pH value of reaction solution remain on 7.0 ~ 8.5, add in three hours, then continue to stir half an hour, in solution, add 3mol/L hydrochloric acid soln be about 50L, add in about 45 minutes, make pH value 2.5 ~ 3.0, continue to stir half an hour, centrifugal, get precipitation; Precipitation be transferred in reactor, add water 220Kg, dispersed with stirring, adds 2mol/L sodium hydroxide solution and be about 14L and make dissolving, dissolved rear pH value 8.1 in 45 minutes, continues stirring 1 hour, centrifugal.
Get filtrate to survey solid content to calculate wherein succsinic acid albumen be 10.6512Kg, in iron: succsinic acid albumen=0.07: the ratio of 1 takes iron trichloride, obtain solution (iron trichloride 7.6Kg, add water 150.2Kg, stirring and dissolving, then 0.2mol/L sodium hydrogen carbonate solution 228Kg is added while stirring), liquor ferri trichloridi is added in two hours in succsinic acid protein solution, and add 2mol/L sodium hydroxide solution simultaneously and make pH value remain on 7.0 ~ 8.5, add and subtract about 6L altogether, continue to stir half an hour, centrifugal.
Filtrate is transferred in reactor, add 3mol/L hydrochloric acid soln half an hour and be about 10L, pH value to 2.52, then centrifugal, precipitation is transferred in reactor, add water about 250Kg, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 10L, be stirred to dissolve, the pH value about 8 of last solution, stir about 5 hours altogether, dissolve completely centrifugal, filtrate is transferred in reactor, add Acid precipitation, add 3mol/L hydrochloric acid soln half an hour and be about 9L, pH value to 2.51, then centrifugal, precipitation is transferred in reactor, add water about 250Kg, strong stirring disperses, add 2mol/L sodium hydroxide solution in 30 minutes and be about 8L, be stirred to dissolve, the pH value about 8 of last solution, continue stir about 8 hours, centrifugal, filtrate is transferred in reactor, then 1.2 μm of millipore filtration Plate Filtrations, filtrate is transferred in the reactor cleaned up with water, add Acid precipitation, add 3mol/L hydrochloric acid soln and be about 7L, pH value to 2.51, continue to stir half an hour, then centrifugal, wash precipitation with water at every turn, collecting precipitation, vacuum-drying, obtain dry product 11.95Kg, yield is 99.6%, iron level is 14.9%.
Table 2-analytical results (embodiment 1 ~ 7)
Stability test
The long-term stable experiment of embodiment 1 ~ 7 sample the results are shown in Table 3.
Table 3 long-term stable experiment result
Iron protein succinylate prepared by embodiment 6 preparation method is to the intervention effect of animal hypoferric anemia
Method: be divided into blank group, control group and experimental group after 60 SD rats make Anemia model according to Liao Shi method at random, blank group gives the physiological saline of equivalent, control group gives Ferplex oral liquid (Italfarmaco S. A., carry iron about 5%), experimental group gives the concentration of iron protein succinylate preparation prepared by the inventive method the solution (namely concentration be 5.33%) consistent with Ferplex, usage is: 10mg iron protein succinylate/kg body weight, Measuring hemoglobin (Hb), red corpuscle (RBC), serum ferritin (SF) after one month.
Table 4 iron protein succinylate is to the intervention effect of animal hypoferric anemia
The results are shown in Table 4, experimental group comparatively control group Hb, RBC, SF content significance increases.The iron protein succinylate prepared by present method can obviously improve Induced By Iron Deficiency Anemia In Rats Iron status, and is obviously better than control group.
Claims (7)
1. a preparation method for high Fe contained iron protein succinylate, is characterized in that, comprises the steps:
(1) acidylate: add Succinic anhydried reaction in casein solution, keep reacting liquid pH value 6 ~ 9 by constantly adding sodium hydroxide solution, after having reacted, acid adding makes reacting liquid pH value 1 ~ 4, filters to obtain precipitation;
(2) iron is carried: the precipitation that step (1) obtains be dispersed in water, adding the stirring of appropriate sodium hydroxide solution makes it dissolve, to dissolving in gained succsinic acid protein solution the liquor ferri trichloridi dripped containing sodium bicarbonate, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution simultaneously, reacted rear filtration, removing insolubles obtains iron protein succinylate solution;
(3) refining: iron protein succinylate solution refining step (2) obtained, removing insolubles, then adds Acid precipitation, filters out precipitation, dry after washing.
2. preparation method according to claim 1, it is characterized in that, in step (1), take casein as raw material, add the water of 15 times of weight and appropriate sodium hydroxide solution stirring and dissolving, dissolve rear pH value 6 ~ 9, added Succinic anhydried reaction, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution, add in three hours, and continue to stir half an hour, then making pH value 1 ~ 4 by adding appropriate hydrochloric acid solution, filtering to obtain precipitation.
3. preparation method according to claim 1, it is characterized in that, in step (2), the liquor ferri trichloridi containing sodium bicarbonate is dripped in succsinic acid protein solution, drip the pH value 6 ~ 9 that sodium hydroxide solution maintains reaction solution simultaneously, liquor ferri trichloridi adds for 2 ~ 3 hours, and continues to stir half an hour.
4. preparation method according to claim 1, it is characterized in that, in step (3), the iron protein succinylate solution weight that step (2) obtains is added with Acid precipitation, sedimentation and filtration, adds alkali dissolution, crosses the operation filtering insolubles, then filtrate obtains iron protein succinylate solution through the filter of millipore filtration essence.
5. preparation method according to claim 4, it is characterized in that, in step (3), in the iron protein succinylate solution that step (2) obtains, add appropriate hydrochloric acid solution makes pH value 1 ~ 4 make precipitation, filters to obtain precipitation, precipitation is dispersed in water, strong stirring, add appropriate sodium hydroxide solution and make dissolving, the pH value of last solution, 6 ~ 9, filters to obtain solution; Then adding hydrochloric acid soln makes pH value 1 ~ 4 make precipitation, filters to obtain precipitation, precipitation is dispersed in water, strong stirring, adds appropriate sodium hydroxide solution and make dissolving, and the pH value of last solution is 6 ~ 9, and filter, filtrate filters to obtain iron protein succinylate solution through millipore filtration essence.
6. preparation method according to claim 1, is characterized in that, in described step (1) is food grade caseins, and the mass ratio that itself and Succinic anhydried react is 4 ~ 2: 1.
7. preparation method according to claim 1, it is characterized in that, liquor ferri trichloridi iron trichloride, water and 0.2mol/L sodium hydrogen carbonate solution preparation in step (2), the weight ratio of the sodium hydrogen carbonate solution of iron trichloride, water and 0.2mol/L is: 1:20:(25 ~ 35).
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Cited By (5)
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| CN106589103A (en) * | 2016-12-21 | 2017-04-26 | 武汉华科大生命科技有限公司 | Preparation method of iron proteinsuccinylate |
| CN108794616A (en) * | 2018-07-03 | 2018-11-13 | 湖北华世通生物医药科技有限公司 | Iron protein succinylate crude product refining method |
| CN108864271A (en) * | 2017-05-11 | 2018-11-23 | 武汉先路医药科技股份有限公司 | A kind of preparation method of iron protein succinylate |
| CN110903379A (en) * | 2019-12-20 | 2020-03-24 | 北京海泰天正医药科技有限公司 | Iron protein succinate and method for industrially preparing iron protein succinate |
| CN111004314A (en) * | 2019-03-22 | 2020-04-14 | 江苏中天药业有限公司 | Preparation method of iron protein succinate with high iron loading capacity |
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| CN108864271B (en) * | 2017-05-11 | 2022-01-18 | 武汉先路医药科技股份有限公司 | Preparation method of iron protein succinate |
| CN108794616A (en) * | 2018-07-03 | 2018-11-13 | 湖北华世通生物医药科技有限公司 | Iron protein succinylate crude product refining method |
| CN111004314A (en) * | 2019-03-22 | 2020-04-14 | 江苏中天药业有限公司 | Preparation method of iron protein succinate with high iron loading capacity |
| CN110903379A (en) * | 2019-12-20 | 2020-03-24 | 北京海泰天正医药科技有限公司 | Iron protein succinate and method for industrially preparing iron protein succinate |
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