CN114249844A - Polysaccharide iron with controllable molecular weight and preparation method thereof - Google Patents
Polysaccharide iron with controllable molecular weight and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of polyferric polysaccharide with controllable molecular weight, which is characterized by comprising the following steps: (1) preparation of a mixture comprising Fe (III) ions and (OH)‑Controlling the particle size of ferric hydroxide sol in the colloidal aqueous solution to be 4-10 nm; (2) heating to 30-75 ℃, and adding polysaccharide for pre-complexing reaction; (3) the pre-complexing product is subjected to a complexing reaction at the temperature of 110-130 ℃. The molecular weight distribution range is narrow, and the molecular weight is controllable.
Description
Technical Field
The invention relates to the field of macromolecules, in particular to a polyferric polysaccharide with controllable molecular weight and a preparation method thereof.
Background
Iron is a trace element necessary for the growth and development of animals and is a component of various enzymes in the bodies of the animals. Iron Deficiency Anemia (IDA) is a pathological condition caused by iron deficiency in humans and mammals. Prophylaxis and treatment of IDA is generally carried out using preparations of organic or complex iron compounds. The dose and method of administration of the drug depends on the severity of the IDA disease, generally the IDA is mainly an oral preparation, and for severe IDA, a series of iron preparations such as Iron Dextran (ID) complex, iron complex with polyisomaltic acid, and organic salts of iron (saccharate, gluconate, fumarate) have been developed and developed, all of which are administered intravenously or intramuscularly.
The sugar-iron Preparation (PIC) belongs to the third generation iron preparation, and the polysaccharide-iron compound which is available on the market at home and abroad and can be administrated outside the intestine comprises high molecular iron dextran, low molecular iron dextran, ferric saccharate, ferric sodium gluconate, ferric carboxymaltose, polysaccharide superparamagnetic iron oxide nanoparticles, ferric isomaltose anhydride 1000 and the like.
PIC means a polymer formed by intermolecular forces in the form of non-covalent bonds with a saccharide substance, with iron as a central atom. The compound has stable chemical property, good water solubility, no any fishy smell and good palatability; because the polymer is more stable than the mononuclear complex, the chelate tends to polymerize in the placing process, and the non-sugar ligand and iron are complexed to form a polynuclear iron compound or polymer which is not easy to absorb; the glycoferric complex forms a polynuclear iron compound which is in a polymerization state but can be effectively absorbed in the storage process; absorption is fast, with a rate of absorption 1.8 times faster than ferrous sulfate, and intestinal villi are specifically selective for absorption of glycoferric complexes in preference to other iron agents such as FeSO4Absorption of (2); the glycoconjugates have stronger antibacterial activity, can solve the problem of drug resistance caused by using antibiotics, thereby improving the micro-ecological balance in animals.
PIC is structurally divided into iron oligosaccharides and iron polysaccharides. The iron oligosaccharide is obtained by complexing monosaccharide and disaccharide with iron, such as ferric saccharate, ferric sodium gluconate, ferric carboxymaltose, and ferric isomaltose. Complexing polysaccharide with iron to obtain iron polysaccharide, such as iron dextran, iron glucoheptonate, etc.
The preparation method of the sugar-iron complex is more, and the preparation method mainly comprises the following steps: (1) preparing iron core, reacting iron salt with alkaline substance, controlling reaction condition to generate FeOOH or Fe (OH)3. (2) Mixing the sugar solution and the iron liquid or the iron mud within a certain pH value, concentration and temperature range, and reacting to prepare the glycoferric complexing liquid stock solution. (3) Preparing raw material medicine dry powder, fully separating alkali metal and non-metal ions in stock solution of complexing solution, and preparing the dry powder by alcohol precipitation or spray drying and other methods.
Sugar-iron complexes are high molecular complexes formed from sugars and iron, and may vary from tens of thousands to millions in molecular weight. The methods do not solve the problem of controlling the molecular weight, and the preparation according to the provided conditions may cause the problems of uneven molecular weight distribution or no concentration of the product, and the like, thereby seriously affecting the drug effect of the product.
Patent US2004016866 discloses a method for synthesizing a high molecular weight iron-sugar complex. The method comprises the following steps: (l) Providing an aqueous solution or dispersion comprising (i) OH-Fe (iii) ions and (ii) at least one saccharide in the presence of ions to form a reaction mixture, wherein the molar ratio of (i) to (ii) in the reaction mixture is from about 30:1 to about 1: 30; the temperature and pH of the reaction mixture are equal to or greater than the complex-complexing point. (2) Maintaining the temperature and pH at or above the complex complexation point for a period of time sufficient to form an iron-sugar complex having a molecular weight of about 25,000 daltons or greater, the present method is suitable for controllably synthesizing a wide range of iron-sugar complexes and/or chemical compositions of varying molecular weights, and the invention is specifically directed to hematinic products that are not suitable for use with polysaccharides or polysaccharides.
At present, no synthesis method with controllable molecular weight of polysaccharide or polysaccharide iron high molecular complex exists.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide a preparation method of the polysaccharide iron with controllable molecular weight, and the polysaccharide iron prepared by the method has narrow molecular weight distribution range and controllable molecular weight.
In order to achieve the purpose, the technical scheme of the invention is as follows: a preparation method of polysaccharide iron with controllable molecular weight is characterized by comprising the following steps:
(1) preparation of a mixture comprising Fe (III) ions and (OH)-Controlling the particle size of ferric hydroxide sol in the colloidal aqueous solution to be 4-10 nm;
(2) heating to 30-75 ℃, and adding polysaccharide for pre-complexing reaction;
(3) the pre-complexing product is subjected to a complexing reaction at the temperature of 110-130 ℃.
In the above scheme, a mixture of Fe (III) ions and (OH) ions is prepared-The method of the ionic colloidal aqueous solution comprises the following steps: under the condition of strong stirring, controlling the temperature of the system at 10-30 ℃, dropwise adding an inorganic alkali solution into the aqueous solution containing Fe (III) ions, controlling the amount of the dropwise added inorganic alkali until the aqueous solution just forms hydrosol, generating no precipitate, and controlling the dropwise addition within 0.1-2h to obtain the colloidal aqueous solution of the ferric hydroxide sol with the particle size of 4-10 nm.
The Fe (III) ions are provided by any one of ferric chloride, ferric nitrate, ferric sulfate, ferric acetate and ferric citrate, and the concentration of the Fe (III) ions is 0.10-3.00M.
The inorganic alkali is one of sodium carbonate, sodium bicarbonate and sodium hydroxide, and the concentration is 0.30-3.00M.
The method obtains the ferric hydroxide sol with controllable particle size range by controlling the concentration of Fe (III) ions, the concentration of alkali liquor and the speed of dripping the alkali liquor, and does not generate ferric hydroxide precipitate, thereby obtaining the complex with controllable molecular weight in the subsequent process. The dropping speed is too slow, the solution may be crystallized to generate precipitate during the preparation of the sol solution, and the dropping speed is too fast, so that the particle size of the generated ferric hydroxide colloid is uncontrollable.
By controlling the particle size of the iron hydroxide colloid, the molecular weight of the iron-sugar complex can be controlled. Experiments have found that the smaller the colloidal particle size, the smaller the molecular weight of the resulting iron-sugar complex, and that controlling the colloidal particle size can be the most effective means for controlling the molecular weight of the complex. The particle size range of the process produces iron-sugar complexes suitable for parenteral administration.
Too high a concentration of the reactants results in a reaction mixture that is too sensitive to subtle changes in process conditions and prone to coagulation.
And the addition of too much base should be prevented during the process resulting in precipitation of iron hydroxide, which would interfere with the formation of the iron-sugar complex. To aid in the contact and reaction between the ingredients, high speed stirring is maintained during the base addition.
The reaction system is an aqueous system in which both the ferric hydroxide colloid and the iron-sugar complex can exist in a stable form.
In the scheme, the method comprises the following steps: the molar ratio of Fe (III) ions to polysaccharide is 100:1-50: 1. The saccharide may be added in solid form or may be dissolved or dispersed in water before addition to the iron hydroxide component. The average molecular weight of the polysaccharide is 4000-6000. Experiments have found that the molecular weight can be effectively controlled by controlling the amount of glycans added, and to some extent, as the amount of sugars increases, the molecular weight decreases.
In the scheme, the method comprises the following steps: the polysaccharide is at least one of dextran, dextran sugar acid, and glucoheptose.
In the scheme, the method comprises the following steps: the pre-complexation reaction comprises the following steps: adding polysaccharide into the colloidal water solution, controlling the temperature to be 30-75 ℃, stirring for reaction, then adding a sodium carbonate solution, adjusting the pH to be 3-7, and continuing the reaction until a pre-complex with the required molecular weight is formed. As can be seen from the gel chromatogram of FIG. 1, during the reaction, the peak on the left side is formed as the pre-complexed product, the peak area is large, the molecular weight distribution is wide, and then the peak of the complexed reactant on the right side is gradually formed through the subsequent complexing reaction, the peak area becomes small, and the molecular weight distribution becomes narrow.
In the scheme, the method comprises the following steps: and carrying out alcohol precipitation or membrane filtration on the pre-complexing reaction solution to obtain a pre-complex.
In the scheme, the method comprises the following steps: the alcohol precipitation method comprises adding the reaction solution into an alcohol precipitation system consisting of ethanol and water, filtering, and drying under normal pressure to obtain a pre-complexing product. The volume ratio of ethanol to water was 6: 4.
In the scheme, the method comprises the following steps: the steps of the complexing reaction of the pre-complexing product at 110-130 ℃ are as follows: dispersing the dried pre-complex into purified water again, heating to 60-80 ℃ for reaction for 1-3h, then sealing the tube under an oil bath at 110-130 ℃ for reaction for 2-8h, and after the reaction is finished, performing membrane filtration to obtain the product.
The complex "coordination point" is achieved by adjusting the pH, temperature and concentration. The complex coordination point depends on the interaction of various variables in the reaction mixture in which the iron-sugar complex is formed, that is to say that a suitable complex coordination point is not an individual value or a range of values for each process parameter, but results from a coordinated interaction of iron ion concentration, pH, glycan type and concentration, temperature. The invention can lead the reaction to be more effective by reasonably matching the points, and can better control the molecular weight and/or the molecular weight distribution of the iron-sugar complex, so that the molecular weight distribution is in the range of 1.15-2.5, and the product quality is better.
The second object of the present invention is achieved by: the polyferric polysaccharide with controllable molecular weight is prepared by the preparation method. The molecular weight distribution is 1.15-2.5.
The process of the invention can produce polysaccharide-iron complexes having an average molecular weight between the ranges quoted for any of the commercial products. In particular, polysaccharide-iron complexes having a molecular weight in daltons of about 25,000 to 800,000 may be produced. The molecular weights and molecular weight distributions determined for the iron-sugar products of the invention were characterized in part. The molecular weight values are reported as absolute weight average molecular weights Mw. The molecular weight distribution is reported in a standard manner as the ratio of Mw to Mn, the Mn being the absolute number average molecular weight, and is obtained using the same test method as the Mw described above. The process of the invention can be carried out to produce useful products having different molecular weight distributions.
The process of the present invention can produce products having a relatively narrow molecular weight distribution. Can reach 1.15-2.5.
Drawings
FIG. 1 is a gel chromatogram of example 2.
FIG. 2 is a gel chromatogram of example 3.
FIG. 3 is a gel chromatogram of example 4.
Detailed Description
The invention will be further illustrated by the following examples in conjunction with the accompanying drawings:
example 1
12.5 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.1M, and the solution is stirred to be clear, and the pH value is 1.6-1.7. Weighing 7.2g of sodium carbonate to prepare a 3M aqueous solution, stirring for dissolving, controlling the temperature to be 30 ℃, starting to dropwise add alkali liquor under the condition of strong stirring, completing dropwise addition of iron hydroxide sol liquid after 60 minutes to obtain iron hydroxide sol liquid, wherein the average particle size of the colloid is 9nm, heating to 40 ℃, adding 35 g of polysaccharide liquid (containing oxidized dextro-glycyl nucleotide 3.5g, the molecular weight is 5600, and the molar ratio of Fe (III) ions to the polysaccharide is 73.6:1), and completing dropwise addition in about 15 minutes. After stirring for 1 hour, the system was heated to 60 ℃ and a 16% sodium carbonate solution was added dropwise until the system pH became 3.0, and the reaction was continued for about 60 min. Then, a sodium carbonate solution with the mass concentration of 16% is added dropwise until the pH value of the system is 4.0, and the reaction is continued to be stirred for about 60 min. Then, a 16% sodium carbonate solution was added dropwise to the system until the system pH became 6.0. The temperature was maintained and the reaction was continued for about 1 h. Precipitating the reaction solution with ethanol, and keeping the ratio of ethanol to water of the system at 6:4 (V/V). Drying the filtered product at 60 ℃ under normal pressure, dispersing the dried product in 20ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube in an oil bath at 130 ℃ for reaction for 2h, and filtering the obtained product with a 0.22um filter membrane. The molecular weight was 174,000, and Mw/Mn was 1.43.
Example 2
15.0 g (0.0555mol) of ferric trichloride hexahydrate are weighed out to prepare a 1.7M ferric trichloride solution. Weighing 7.6g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is clear, controlling the temperature to be 28 ℃, starting to dropwise add alkali liquor under the condition of strong stirring, and completing dropwise addition for 30 minutes to obtain the iron hydroxide sol solution with the average particle size of 8 nm. The temperature is raised to 30 ℃, 40 g of polysaccharide solution (containing 3.5g of glucoheptylic acid, the average molecular weight is 6000, and the mole is 0.00058mol) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 4.3, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 3h, sealing the tube under 130 ℃ oil bath for reaction for 2h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 58,000, and Mw/Mn was 1.35.
Example 3
15.0 g (0.0555mol) of ferric trichloride hexahydrate are weighed out to prepare a 1.7M ferric trichloride solution. Weighing 7.6g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is clear, controlling the temperature to be 28 ℃, starting to dropwise add alkali liquor under the condition of strong stirring, and completing dropwise addition for 30 minutes to obtain the iron hydroxide sol solution with the average particle size of 8 nm. The temperature is raised to 30 ℃, 40 g of polysaccharide solution (containing 3.5g of glucoheptylic acid, the average molecular weight is 6000, and the mole is 0.00058mol) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 7, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction to about 3, sealing the tube under 130 ℃ oil bath for reaction for 2h, and filtering through a 0.22um filter membrane to obtain the product. The molecular weight was 56,000, and Mw/Mn was 1.15.
Example 4
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. 7.6g of sodium carbonate were weighed out to prepare a 1.6M sodium carbonate solution. And (3) dropwise adding alkali liquor under the condition of controlling the temperature to be 10 ℃ and stirring strongly, and completing dropwise adding in 30 minutes to obtain the ferric hydroxide sol solution with the average particle size of 7 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid and the average molecular weight of 6000) is added, and the mixture is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. And (3) precipitating the reaction solution by alcohol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 1h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering through a 0.22um filter membrane to obtain the product. The molecular weight was 52,000, and Mw/Mn was 1.22.
Example 5
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 3M, and the solution is stirred and dissolved at the temperature of 20 ℃. Weighing 7.2g of sodium carbonate to prepare a 3M sodium carbonate solution, after the iron solution is dissolved, controlling the temperature to be 20 ℃, starting to dropwise add alkali liquor under the condition of strong stirring, and completing dropwise addition within 10 minutes to obtain the iron hydroxide sol solution with the average particle size of 6 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid and the average molecular weight of 6000) is added, and the mixture is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 47,000, and Mw/Mn was 1.25.
Example 6
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is clear, dropwise adding alkali liquor under strong stirring, and completing dropwise adding within 60 minutes to obtain the iron hydroxide sol solution with the average particle size of 7 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 54,000, and Mw/Mn was 1.20.
Example 7
7.9 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. 3.7g of sodium carbonate is weighed to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, alkali liquor is dripped under the condition of controlling the temperature to be 28 ℃ and stirring intensely, and dripping is finished in 60 minutes to obtain the iron hydroxide sol solution with the average particle size of 6 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid and the average molecular weight of 6000) is added, and the mixture is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 42,000, and Mw/Mn was 1.23.
Example 8
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 30 ℃. Weighing 7.6g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropping within 30 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 8 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid and the average molecular weight of 6000) is added, and the mixture is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 57,000, and Mw/Mn was 1.20.
Example 9
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, controlling the temperature and starting dropwise adding alkali liquor under strong stirring after the iron solution is dissolved, and finishing dropwise adding for 2 hours. Obtaining the ferric hydroxide sol solution with the average grain diameter of 12 nm. The temperature is raised to 30 ℃, 45 g of sugar solution (containing 4.0g of glucoheptylic acid) is added, and the mixture is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 63,000, and Mw/Mn was 1.25.
Example 10
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropwise adding within 10 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 4 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Filtering, performing membrane (molecular weight is 2000 accessible) filtration on the filtrate, concentrating the mother liquor to about 21g under reduced pressure when the conductivity is less than 3.0mS/cm, heating the system to 80 ℃ for reaction for about 1h, sealing the tube under 130 ℃ oil bath for reaction for 3h, and filtering with 0.22um filter membrane to obtain the product. The molecular weight was 44,000, and Mw/Mn was 1.30.
Example 11
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropwise adding within 10 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 4 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Filtering, performing membrane (molecular weight is 2000 accessible) filtration on the filtrate, concentrating the mother liquor to about 21g under reduced pressure when the conductivity is less than 3.0mS/cm, heating the system to 60 ℃ for reaction for about 3h, sealing the tube under 130 ℃ oil bath for reaction for 8h, and filtering with 0.22um filter membrane to obtain the product. The molecular weight was 45,000, and Mw/Mn was 1.15.
Example 12
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropwise adding within 10 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 4 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Filtering, performing membrane (molecular weight is 2000 accessible) filtration on the filtrate, concentrating the mother liquor to about 21g under reduced pressure when the conductivity is less than 3.0mS/cm, heating the system to 80 ℃ for reaction for about 2h, sealing the tube under 110 ℃ oil bath for reaction for 4h, and filtering with 0.22um filter membrane to obtain the product. The molecular weight was 42,000, and Mw/Mn was 2.1.
Example 13
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 0.1M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 0.3M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropwise adding within 50 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 4 nm. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Filtering, performing membrane (molecular weight is 2000 accessible) filtration on the filtrate, concentrating the mother liquor to about 21g under reduced pressure when the conductivity is less than 3.0mS/cm, heating the system to 80 ℃ for reaction for about 1h, filtering the reaction solution with a 0.22um filter membrane, and performing tube sealing reaction for 3h at 130 ℃ in an oil bath to obtain the product. The molecular weight was 43,000, and Mw/Mn was 1.31.
Example 14
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 5 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, controlling the temperature to be 5 ℃ after the iron solution is dissolved, starting dropwise adding alkali liquor under the condition of strong stirring, and completing dropwise adding within 30 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 7 nm. 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring was continued for 1 hour, 16% sodium carbonate was added dropwise until the pH of the system became 6.0, the system thickened, and a solid precipitated. The temperature for making colloid is too low, and complexation can not be performed.
Example 15
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 35 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, controlling the temperature to be 35 ℃ after the iron solution is dissolved, starting dropwise adding alkali liquor under the condition of strong stirring, and completing dropwise adding within 30 minutes. Obtaining ferric hydroxide sol solution with the average grain diameter of 11 nm. 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under 130 ℃ oil bath for reaction for 4h, and filtering with a 0.22um filter membrane to obtain the product. The molecular weight was 82,000, and Mw/Mn was 1.36. The colloid has high temperature and large molecular weight.
Example 16
15.0 g of ferric trichloride hexahydrate is weighed to prepare a ferric trichloride solution with the concentration of 1.7M, and the solution is stirred and dissolved at the temperature of 25 ℃. Weighing 7.2g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is dissolved, dropwise adding alkali liquor under strong stirring, and completing dropping within 30 minutes. The temperature is raised to 30 ℃, 40 g of sugar solution (containing 3.5g of glucoheptylic acid) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 6.0, and the reaction was stirred for about 1 hour. And (3) precipitating the reaction solution by alcohol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 2h, sealing the tube under an oil bath at 80 ℃ for reaction for 12h, and filtering by using a 0.22-micron filter membrane, wherein no product is generated.
Example 17
15.0 g (0.0555mol) of ferric trichloride hexahydrate are weighed out to prepare a 1.7M ferric trichloride solution. Weighing 7.6g of sodium carbonate to prepare 1.6M sodium carbonate solution, after the iron solution is clear, dropwise adding alkali liquor under strong stirring at 28 ℃, and completing dropwise adding within 30 minutes to obtain iron hydroxide sol solution with the average particle size of 8 nm. The temperature is raised to 30 ℃, 40 g of polysaccharide solution (containing 3.5g of glucoheptylic acid, the average molecular weight is 6000, and the mole is 0.00058mol) is added, and the solution is dripped off in about 15 min. After stirring for 1 hour, 16% sodium carbonate was added dropwise until the system pH was 4.3, and the reaction was stirred for about 1 hour. Precipitating the reaction solution with ethanol, keeping the ratio of ethanol to water of the system at 6:4, filtering, drying the filtered product at 50 ℃ under normal pressure, dispersing the dried product in 17ml of purified water, heating to 80 ℃ for reaction for about 1h, filtering the reaction solution with a 0.22um filter membrane, and performing oil bath at 130 ℃ for tube sealing reaction for 3h to obtain the product. The molecular weight was 57,000, and Mw/Mn was 1.32.
The present invention is not limited to the above-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.
Claims (12)
1. A preparation method of polysaccharide iron with controllable molecular weight is characterized by comprising the following steps:
(1) preparation of a mixture comprising Fe (III) ions and (OH)-Controlling the particle size of ferric hydroxide sol in the colloidal aqueous solution to be 4-10 nm;
(2) heating to 30-75 ℃, and adding polysaccharide for pre-complexing reaction;
(3) the pre-complexing product is subjected to a complexing reaction at the temperature of 110-130 ℃.
2. The method of claim 1, wherein the iron (ll) polysaccharide is prepared to contain Fe (III) ions and (OH)-The method of the ionic colloidal aqueous solution comprises the following steps: under the condition of strong stirring, controlling the temperature of the system at 10-30 ℃, dropwise adding an inorganic alkali solution into the aqueous solution containing Fe (III) ions, controlling the amount of the dropwise added inorganic alkali until the aqueous solution just forms hydrosol, generating no precipitate, and controlling the dropwise addition within 0.1-2h to obtain the colloidal aqueous solution of the ferric hydroxide sol with the particle size of 4-10 nm.
3. The method of claim 2, wherein the step of preparing the iron polysaccharide comprises: the Fe (III) ions are provided by any one of ferric chloride, ferric nitrate, ferric sulfate, ferric acetate and ferric citrate, and the concentration of the Fe (III) ions is 0.10-3.00M.
4. The method of claim 2, wherein the step of preparing the iron polysaccharide comprises: the inorganic alkali is one of sodium carbonate, sodium bicarbonate and sodium hydroxide, and the concentration is 0.30-3.00M.
5. The method for preparing the iron polysaccharide with controllable molecular weight according to any one of claims 1 to 4, wherein: the molar ratio of Fe (III) ions to polysaccharide is 100:1-50: 1.
6. the method of claim 5, wherein the step of preparing the iron polysaccharide comprises: the polysaccharide is at least one of dextran, dextran sugar acid, and glucoheptose.
7. The method for preparing the polysaccharide iron with controllable molecular weight according to claim 5, wherein the pre-complexation reaction comprises the following steps: adding polysaccharide into the colloidal water solution, controlling the temperature to be 30-75 ℃, stirring for reaction, then adding a sodium carbonate solution, adjusting the pH to be 3-7, and continuing the reaction until a pre-complex with the required molecular weight is formed.
8. The method of claim 7, wherein the step of preparing the iron polysaccharide comprises: and carrying out alcohol precipitation or membrane filtration on the pre-complexing reaction solution to obtain a pre-complex.
9. The method for preparing polyferric polysaccharide with controllable molecular weight as claimed in claim 8, wherein the alcohol precipitation is carried out by adding the reaction solution into alcohol precipitation system composed of ethanol and water, filtering, and drying under normal pressure to obtain pre-complex product.
10. The method for preparing polyferric with controllable molecular weight as claimed in claim 1, wherein the step of performing the complexation reaction of the pre-complexed product at 110-130 ℃ comprises: dispersing the dried pre-complex into purified water again, heating to 60-80 ℃ for reaction for 1-3h, then sealing the tube under an oil bath at 110-130 ℃ for reaction for 2-8h, and after the reaction is finished, performing membrane filtration to obtain the product.
11. A ferric polysaccharide obtainable by the method of any one of claims 1 to 9 for the preparation of a molecular weight controlled ferric polysaccharide.
12. The iron polysaccharide of claim 11, wherein: the molecular weight distribution is 1.15-2.5.
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