CN110804107B - Method for preparing dextran iron aqueous solution by using dextran - Google Patents
Method for preparing dextran iron aqueous solution by using dextran Download PDFInfo
- Publication number
- CN110804107B CN110804107B CN201910929883.7A CN201910929883A CN110804107B CN 110804107 B CN110804107 B CN 110804107B CN 201910929883 A CN201910929883 A CN 201910929883A CN 110804107 B CN110804107 B CN 110804107B
- Authority
- CN
- China
- Prior art keywords
- solution
- dextran
- value
- hours
- controlling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
Abstract
A method for preparing dextran iron aqueous solution by dextran, belonging to the technical field of drug production. The preparation method comprises the following steps: 1) preparing an oxidizing solution; 2) adding FeCl3.6H2O solution to obtain mixed solution; 3) adding Na dropwise into the mixed solutionDripping OH aqueous solution while stirring; the dropping process comprises the following steps: controlling the pH value of the mixed solution to be 1.5-3.0 in 1-2 hours, controlling the pH value of the mixed solution to be 3.1-4.0 in 3-4 hours, and controlling the pH value of the mixed solution to be 6-6.5 in 5 hours; after the dropwise addition, curing the mixed solution for 20-30 minutes at 95-100 ℃; reducing the temperature to 25 ℃ at the speed of every 10 ℃/30 minutes to obtain complexing liquid; 4) and (3) ultrafiltering and desalting the complex solution to obtain a dextran iron aqueous solution. The iron dextran solution obtained by the method has low molecular weight, high clarity and low viscosity, and is suitable for being used as an injection.
Description
Technical Field
The invention relates to a method for preparing a dextran iron aqueous solution by using dextran, belonging to the technical field of drug production.
Background
Dextran is a high molecular glucose polymer synthesized by fermenting sucrose with leuconostoc mesenteroides, and is one of the best blood plasma substitutes at present. Dextran 20, which is dextran with weight average molecular weight of about 20000Da, has the effects of improving microcirculation, increasing plasma colloid osmotic pressure and osmotic diuresis.
Iron dextran is an antianemia drug, in the prior art, a complex of dextran with a weight average molecular weight of 5000-7500 Da and iron hydroxide is mostly adopted, wherein iron ions are effective active ingredients, and the iron dextran can be used for treating iron deficiency anemia, supplementing iron in a patient and accelerating the synthesis of hemoglobin. Currently, the iron dextran is prepared by activating with an alkalization method (sodium hydroxide) and then performing a complexing reaction with iron hydroxide in China. Iron dextran is used as iron supplementing injection, and because the molecule is large, it must be absorbed by lymph duct and then enter blood, so that the blood concentration after injection is slowly raised. And when the iron dextran with low molecular weight is used as an injection, the absorption is faster, and the iron supplementing effect is better.
The applicant has found that the following problems exist in the prior art: first, even low molecular weight iron dextran works better as an injection. However, most of the dextran iron for injection sold in the market at present has the weight average molecular weight of 5000-20000 Da, and the dextran iron for injection with smaller weight average molecular weight is difficult to sell. Is due to the difficulty in obtaining aqueous solutions of iron dextran for injection having a low molecular weight, high clarity, and low viscosity. Secondly, the existing iron dextran complexation process is not easy to control, and the problem of viscous and turbid iron dextran solution is easily caused. The injection has high requirements on the clarity and the viscosity of the solution. In the existing preparation method, when the dextran iron is prepared from the dextran with the weight-average molecular weight of less than 5000Da, the dextran iron aqueous solution system is easy to have the problems of viscosity and turbidity in the complexing process, and is finally difficult to be used as an injection. The iron dextran with small molecular weight is easier to be absorbed by human body, and the iron supplementing effect is better. At present, a preparation method of a dextran iron solution with low molecular weight, high clarity and low viscosity is urgently needed.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the method for preparing the dextran iron solution by using the low molecular weight dextran overcomes the defects of the prior art, and the dextran iron solution prepared by the method has low molecular weight, high clarity and low viscosity, and is suitable for being used as an injection.
The technical scheme adopted by the invention for solving the technical problem is as follows: the method for preparing the dextran iron aqueous solution by using the dextran comprises the following steps:
1) heating a dextran solution to 40-60 ℃, adjusting the pH value to 11-12 with alkali liquor, adding a sodium hypochlorite aqueous solution, and performing oxidation reaction to obtain an oxidation solution;
2) sequentially adding weak acid and strong acid into the oxidation solution, controlling the pH value of the oxidation solution to be 1-2 by using the strong acid, heating the oxidation solution to 95-98 ℃, and adding FeCl accounting for 40-50% of the oxidation solution by mass3.6H2O solution to obtain mixed solution;
3) dropwise adding 25-35% by mass of NaOH aqueous solution into the mixed solution while stirring; in the dropping process: controlling the pH value of the mixed solution to be 1.5-3.0 in 1-2 hours, controlling the pH value of the mixed solution to be 3.1-4.0 in 3-4 hours, and controlling the pH value of the mixed solution to be 6-6.5 in 5 hours; after the dropwise addition, curing the mixed solution for 20-30 minutes at 95-100 ℃; then reducing the temperature to 25 ℃ at the speed of every 10-15 ℃/30 minutes to obtain complexing liquid;
4) and (3) carrying out ultrafiltration and desalination on the complex solution to obtain the dextran iron aqueous solution.
The specific operation of the step 1) is as follows: heating a dextran solution to 40-60 ℃, maintaining the pH value of the dextran solution at 11-12 by using a sodium hydroxide aqueous solution with the mass percent of 20-30%, then dropwise adding a sodium hypochlorite aqueous solution with the mass percent of 5% for 2-3 hours, maintaining the temperature at 40-60 ℃ after dropwise adding, and performing oxidation reaction at the pH value of 11-12 for 4 hours to obtain an oxidation solution.
The addition amount of the sodium hypochlorite aqueous solution in the step 1) is as follows: the molar ratio of the active chlorine to the terminal aldehyde group of the dextran molecule is 5:1 based on the active chlorine in the sodium hypochlorite aqueous solution.
The specific operation of the step 4) is as follows: adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution. In the step 4), ultrafiltration desalination does not need to replace an ultrafiltration membrane, so that the cost is saved and the production efficiency is improved. Preferably, the end of ultrafiltration is marked by: the iron content of the concentrated solution reaches 20 percent by mass. The iron content is the standard of dextran iron solution concentration, and the iron content of the dextran iron solution is 20 +/-1% according to pharmacopoeia standards. Preferably, after the ultrafiltration in step 4) is finished, phenol is added into the solution to a final concentration of 5 mass percent, and the phenol is a preservative.
The mass percentage concentration of the dextran solution in the step 1) is 18-25%, and the weight average molecular weight of the dextran is 2600-3800 Da.
The dextran used in the step 1) is dextran with the weight-average molecular weight of 2600-3800 Da in the market, or the dextran used in the step 1) is dextran with the weight-average molecular weight of 2600-3800 Da obtained by hydrolyzing or hydrolyzing the dextran with the high weight-average molecular weight by an enzyme method.
Preferably, the preparation method of the dextran used in the step 1) comprises the following steps: adding hydrochloric acid into a dextran solution with high weight-average molecular weight to adjust the pH value to be less than 2 for hydrolysis, neutralizing the solution with sodium hydroxide when the weight-average molecular weight is less than 3000 to adjust the pH value to be 6-7, stopping hydrolysis, adding 1% of activated carbon for decolorization, filtering, performing ultrafiltration with a 2000Da ultrafiltration membrane until the conductivity of filtrate is less than 100 mu S/cm, and performing spray drying to obtain dextran; the obtained dextran has a weight average molecular weight of 2800-3300 Da and a molecular distribution of 1.1-1.2. Wherein the weight average molecular weight measurement is monitored by gel chromatography (GPC). The weight average molecular weight of dextran with high weight average molecular weight used as raw material is 7000-25000 Da; the preferred dextran with high weight average molecular weight is dextran with weight average molecular weight of 16000-24000 Da (namely commercial product dextran 20). The preparation method can obtain 3000Da dextran with narrow molecular weight distribution, thereby being beneficial to further obtaining the iron dextran with narrow molecular weight distribution in the subsequent steps.
The mass ratio of the weak acid dosage in the step 2) to the dry weight of the dextran in the oxidation solution is 1: 10.
The weak acid in the step 2) is citric acid monohydrate. The weak acid can reduce the pH value and can be used as a pH value buffering agent to slow down the pH fluctuation of the subsequent process.
The strong acid in the step 2) is hydrochloric acid. The strong acid is used for regulating and controlling the pH of the mixed solution, and the pH of the mixed solution obtained in the step 2) is 1.0-1.8 and the temperature is 95-98 ℃.
Step 2) the FeCl3.6H2The mass ratio of O (crystal) to the dry weight of dextran in the oxidizing solution is 4.5: 1.
the specific operation of the dropping process in the step 3) is as follows: controlling the pH of the mixed solution to be 1.5-2.5 at 1 hour, controlling the pH of the mixed solution to be 2.6-3.0 at 2 hours, controlling the pH of the mixed solution to be 3.5-3.7 at 3 hours, controlling the pH of the mixed solution to be 3.8-4.0 at 4 hours, and controlling the pH of the mixed solution to be 6-6.5 at 5 hours. According to the method, the dextran iron aqueous solution is more difficult to generate turbidity and precipitation. And when the last period of time is finished, slowly dropwise adding the NaOH aqueous solution (the pH value at the dropwise adding speed is increased by 0.1-0.6/3 min), gradually transitioning the pH value of the mixed solution to the pH range of the next period of time, fluctuating in the pH range of the next period of time along with the progress of the complexation reaction, and repeating the operations until the time is finished.
Compared with the prior art, the invention has the beneficial effects that:
1. one preparation method of the invention uses dextranThe obtained iron dextran solution has low molecular weight, high clarity and low viscosity, and is suitable for use as injection. Applicants have found that the molecular weight of dextran decreases with the weight average molecular weight of Fe3+The complex is more difficult, the production process is difficult to control, the complex process of the low molecular weight iron dextran is extremely unstable and easy to generate precipitation, so that the low molecular weight iron dextran solution obtained by the reaction is difficult to achieve high iron content and high clarity. The applicant controlled the rate of addition of the aqueous sodium hydroxide solution by precision: the pH value is controlled within the range of 1.5-3.0 in the period of 1-2 hours from the beginning of dripping, the pH value of the mixed solution is controlled within the range of 3.1-4.0 in the period of 3-4 hours from the beginning of dripping, and the pH value is controlled within the range of 6-6.5 in the period of 5 hours from the beginning of dripping, so that the generation of precipitation and turbidity is effectively avoided. The obtained iron solution of the dextran iron has high iron content, low molecular weight, high clarity and low viscosity, and the iron content of the iron dextran dry material can reach 45-48%.
2. The method for preparing the dextran iron aqueous solution by using the dextran has the advantages of easily controlled complexing process, convenient operation and suitability for large-scale industrial production. The applicant has found that in the prior art, the addition of other solutions to the oxidizing solution is often performed by simultaneous addition, such as FeCl3.6H2The O solution is added simultaneously with the sodium hydroxide solution, or, for example, FeCl is used3.6H2The O solution is added simultaneously with the sodium carbonate solution and then sodium hydroxide is added. The operation of simultaneously more than two components is extremely difficult to control the pH, and the simultaneous addition of the two components can cause the uncontrollable fluctuation of the pH of the mixed solution, thereby breaking the problems of stability, turbidity and precipitation of the complex in the aqueous solution. In industrial production, the dextran iron solution is produced by using a 5-ton storage tank, if turbidity is generated, and precipitates are generated and are irreversible and difficult to remove, so that the economic loss is huge, and the production and application of the low molecular weight dextran iron solution in the field of injection are not facilitated. The applicant adds weak acid into the oxidation solution in the step 3), the weak acid can reduce the pH and slow down the pH fluctuation, and the strong acid can be used for regulating and controlling the pH of the subsequent process; step 2) mixingThe oxidizing solution is maintained at a pH of 1-2 and a temperature of 95-98 ℃, which is a condition unfavorable for the complex reaction, and FeCl is added separately3.6H2The O solution does not need to strictly control the adding rate, and is very easy to implement in large-scale production; when the solution is dripped in the step 3), the complexation can be effectively controlled only by controlling the group of variables of the addition amount, the time and the pH value of the sodium hydroxide solution, which is very easy to implement in large-scale production. The applicant determines the optimum pH change interval in the dripping process through research, and can realize on-line monitoring by setting time and the pH change interval in large-scale production.
3. The method for preparing the dextran iron solution by using the dextran has the advantages that the obtained dextran iron has narrow molecular weight distribution, and is not easy to generate side effects when used as an injection.
Detailed Description
The present invention will be described in further detail with reference to specific examples and tables.
The dextran used in the embodiments 1-2 is obtained by hydrolysis, and the preparation method of the dextran used in the step 1) comprises the following steps: adding hydrochloric acid into the dextran 20 solution to adjust the pH value to be less than 2 for hydrolysis, neutralizing the solution with sodium hydroxide until the pH value is 6-7 when the weight average molecular weight is less than 3000, stopping hydrolysis, adding 1% of activated carbon for decolorization, filtering, performing ultrafiltration with a 2000Da ultrafiltration membrane until the conductivity of the filtrate is less than 100 mu S/cm, and performing spray drying to obtain the dextran. The obtained dextran has the weight average molecular weight of 2800-3300 Da and the molecular distribution of 1.15. Wherein the weight average molecular weight measurement is monitored by gel chromatography (GPC). Dextran 20 generally refers to dextran with a weight average molecular weight below 20000 Da.
Example 3-5 the dextran used in step 1) is dextran 3 produced by Hanbang Cyclo polysaccharide Biotechnology (Heyuan) Co., Ltd, and the weight average molecular weight is 2700-3300 Da; physical properties: a white powder; the drying weight loss is less than or equal to 7.0% w/w; ash content is less than or equal to 2.0; pH4.5-7.0; solubility, soluble in cold water.
The manufacturers and the brands of the used raw material auxiliaries and instruments are as follows:
sodium hypochlorite is the iron tower brand of the Yantai far east fine chemical Co., Ltd;
sodium hydroxide is Zibo Jun Zha Jing Dao Co Ltd;
the hydrochloric acid is Zibo Jun Zhang Jing Mao Co Ltd;
ferric trichloride hexahydrate is a chemical preparation factory in Jiangsu Qidong;
the dextran 20 is provided by Shandong Jinyang pharmaceutical industry Co., Ltd, and is 16000-24000 Da;
phenol is a product of the Nicoti Yunto Fine chemical Co., Ltd., iron tower brand;
citric acid monohydrate is; the tobacco pipe far east fine chemical company, iron tower brand;
the conductivity meter is Shanghai apparatus, electro-scientific instruments, Inc., thunder magnet;
the peristaltic pump is a Signal fluid, Baodingsinuo fluid science and technology, Inc.;
the PH meter is Shanghai apparatus, electro-scientific instruments, Inc., thunder magnet;
the roll type membrane small-sized experimental machine is a membrane engineering equipment company Limited, Ododong, great Lian;
the liquid chromatogram-differential refraction detector is Shimadzu-20A type;
the chromatographic column is phenomenex poxylsep-GFC-p 4000.
Example 1
1) Heating a dextran solution to 55-60 ℃, maintaining the pH value of the dextran solution to 11.5-11.8 by using a sodium hydroxide aqueous solution with the mass percent of 20%, then dropwise adding a sodium hypochlorite aqueous solution with the mass percent of 5% (calculated by active chlorine in the sodium hypochlorite aqueous solution, the molar ratio of the active chlorine to aldehyde groups at the tail ends of dextran molecules is 5: 1), wherein the dropwise adding time is 2 hours, maintaining the temperature of 55-60 ℃ and the pH value of 11.5-11.8 after the dropwise adding is finished, and carrying out an oxidation reaction for 4 hours to obtain an oxidation solution;
2) adding citric acid monohydrate to the oxidizing solution in sequence (the mass ratio of the citric acid monohydrate to the dry weight of the dextran in the oxidizing solution is 1: 10) and hydrochloric acid, controlling the pH value of the oxidation solution to be 1.2-1.5 by using the hydrochloric acid, heating the oxidation solution to 95-98 ℃, and adding FeCl accounting for 45 mass percent into the oxidation solution3.6H2O solution (FeCl)3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) obtaining a mixed solution;
3) dripping 30 mass percent of NaOH aqueous solution into the mixed solution (the pH is 1.2-1.5, the temperature is 95-98 ℃), and stirring while dripping; in the dropping process: controlling the pH value of the mixed solution to be 1.5-1.8 at 1 hour, controlling the pH value of the mixed solution to be 2.8-3.0 at 2 hours, controlling the pH value of the mixed solution to be 3.5-3.6 at 3 hours, controlling the pH value of the mixed solution to be 3.8-3.9 at 4 hours, and controlling the pH value of the mixed solution to be 6.3-6.5 at 5 hours; after the dropwise addition, curing the mixed solution for 30 minutes at 95-100 ℃; then reducing the temperature to 25 ℃ at the speed of every 10 ℃/30 minutes to obtain complexing liquid;
4) adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
Example 2
1) Heating a dextran solution to 55-60 ℃, maintaining the pH value of the dextran solution to 11.2-11.5 by using a sodium hydroxide aqueous solution with the mass percent of 20%, then dropwise adding a sodium hypochlorite aqueous solution with the mass percent of 5% (calculated by active chlorine in the sodium hypochlorite aqueous solution, the molar ratio of the active chlorine to aldehyde groups at the tail ends of dextran molecules is 5: 1), wherein the dropwise adding time is 2.5 hours, maintaining the temperature of 55-60 ℃, the pH value of the dextran solution to 11.2-11.5 after the dropwise adding is finished, and carrying out an oxidation reaction for 4 hours to obtain an oxidation solution;
2) adding citric acid monohydrate to the oxidizing solution in sequence (the mass ratio of the citric acid monohydrate to the dry weight of the dextran in the oxidizing solution is 1: 10) and hydrochloric acid, controlling the pH value of the oxidation solution to be 1.5-1.8 by using the hydrochloric acid, heating the oxidation solution to 95-98 ℃, and adding 50 mass percent of FeCl into the oxidation solution3.6H2O solution (FeCl)3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) obtaining a mixed solution;
3) dripping 30 mass percent of NaOH aqueous solution into the mixed solution (the pH is 1.5-1.8, the temperature is 95-98 ℃), and stirring while dripping; in the dropping process: controlling the pH value of the mixed solution to be 1.8-2.0 at 1 hour, controlling the pH value of the mixed solution to be 2.6-2.8 at 2 hours, controlling the pH value of the mixed solution to be 3.6-3.7 at 3 hours, controlling the pH value of the mixed solution to be 3.9-4.0 at 4 hours and controlling the pH value of the mixed solution to be 6.0-6.3 at 5 hours; after the dropwise addition, curing the mixed solution for 30 minutes at 100 ℃; then reducing the temperature to 25 ℃ at the speed of every 15 ℃/30 minutes to obtain complexing liquid;
4) adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
Example 3
1) Heating a dextran solution to 45-50 ℃, maintaining the pH value of the dextran solution to 11.0-11.3 by using a sodium hydroxide aqueous solution with the mass percent of 20%, then dropwise adding a sodium hypochlorite aqueous solution with the mass percent of 5% (calculated by active chlorine in the sodium hypochlorite aqueous solution, the molar ratio of the active chlorine to aldehyde groups at the tail ends of dextran molecules is 5: 1), wherein the dropwise adding time is 3 hours, maintaining the temperature of 45-55 ℃, the pH value of the dextran solution to 11.0-11.3 after the dropwise adding is finished, and carrying out an oxidation reaction for 4 hours to obtain an oxidation solution;
2) adding citric acid monohydrate to the oxidizing solution in sequence (the mass ratio of the citric acid monohydrate to the dry weight of the dextran in the oxidizing solution is 1: 10) and hydrochloric acid, controlling the pH value of the oxidation solution to be 1.3-1.5 by using the hydrochloric acid, heating the oxidation solution to 95-98 ℃, and adding FeCl accounting for 40 mass percent into the oxidation solution3.6H2O solution (FeCl)3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) obtaining a mixed solution;
3) dropwise adding 32 mass percent of NaOH aqueous solution into the mixed solution (the pH is 1.3-1.5, the temperature is 95-98 ℃), and stirring while dropwise adding; in the dropping process: controlling the pH of the mixed solution to be 2.1-2.4 at 1 hour, controlling the pH of the mixed solution to be 2.6-2.8 at 2 hours, controlling the pH of the mixed solution to be 3.5-3.6 at 3 hours, controlling the pH of the mixed solution to be 3.8-3.9 at 4 hours, and controlling the pH of the mixed solution to be 6-6.3 at 5 hours; after the dropwise addition, curing the mixed solution for 28 minutes at 98 ℃; then reducing the temperature to 25 ℃ at the speed of every 10 ℃/30 minutes to obtain complexing liquid;
4) adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
Example 4
1) Heating a dextran solution to 50-55 ℃, maintaining the pH value of the dextran solution at 11.6-12.0 by using a 25 mass percent sodium hydroxide aqueous solution, then dropwise adding a 5 mass percent sodium hypochlorite aqueous solution (the molar ratio of active chlorine to aldehyde groups at the tail ends of dextran molecules is 5:1 in terms of active chlorine in the sodium hypochlorite aqueous solution), wherein the dropwise adding time is 2 hours, and after the dropwise adding is finished, maintaining the temperature of 50-55 ℃ and performing an oxidation reaction at the pH value of 11.6-12.0 for 4 hours to obtain an oxidation solution;
2) adding citric acid monohydrate to the oxidizing solution in sequence (the mass ratio of the citric acid monohydrate to the dry weight of the dextran in the oxidizing solution is 1: 10) and hydrochloric acid, controlling the pH value of the oxidation solution to be 1.5-1.8 by using the hydrochloric acid, heating the oxidation solution to 97 ℃, and adding 49 mass percent of FeCl into the oxidation solution3.6H2O solution (FeCl)3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) obtaining a mixed solution;
3) dropwise adding 34 mass percent of NaOH aqueous solution into the mixed solution (the pH is 1.5-1.8, the temperature is 95-98 ℃), and stirring while dropwise adding; in the dropping process: when the pH value is controlled to fluctuate within the range of 1.5-3.0 in the period of 1-2 hours, when the pH value is controlled to fluctuate within the range of 3.1-4.0 in the period of 3-4 hours, and when the pH value is controlled to fluctuate within the range of 6-6.5 in the period of 5 hours; after the dropwise addition, curing the mixed solution for 20 minutes at 99 ℃; then reducing the temperature to 25 ℃ at the speed of every 10 ℃/30 minutes to obtain complexing liquid;
4) adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
Example 5
1) Heating a dextran solution to 40-45 ℃, maintaining the pH value of the dextran solution to 11.3-11.5 by using a 30 mass percent sodium hydroxide aqueous solution, then dropwise adding a 5 mass percent sodium hypochlorite aqueous solution (the molar ratio of active chlorine to terminal aldehyde groups of dextran molecules is 5:1 in terms of active chlorine in the sodium hypochlorite aqueous solution), wherein the dropwise adding time is 2 hours, and after the dropwise adding is finished, maintaining the temperature of 40-45 ℃ and performing an oxidation reaction for 4 hours at the pH value of 11.3-11.5 to obtain an oxidation solution;
2) adding citric acid monohydrate to the oxidizing solution in sequence (the mass ratio of the citric acid monohydrate to the dry weight of the dextran in the oxidizing solution is 1: 10) and hydrochloric acidControlling the pH value of the oxidation solution to be 1.0-1.3 by hydrochloric acid, heating the oxidation solution to 95-98 ℃, and adding 49 mass percent of FeCl into the oxidation solution3.6H2O solution (FeCl)3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) obtaining a mixed solution;
3) dropwise adding 32 mass percent of NaOH aqueous solution into the mixed solution (the pH is 1.0-1.3, the temperature is 95-98 ℃), and stirring while dropwise adding; in the dropping process: controlling the pH value of the mixed solution to be 1.6-1.9 at 1 hour, controlling the pH value of the mixed solution to be 2.2-2.5 at 2 hours, controlling the pH value of the mixed solution to be 3.5-3.6 at 3 hours, controlling the pH value of the mixed solution to be 3.7-3.9 at 4 hours, and controlling the pH value of the mixed solution to be 6.0-6.3 at 5 hours; after the dropwise addition, curing the mixed solution for 25 minutes at 98 ℃; then reducing the temperature to 25 ℃ at the speed of every 10 ℃/30 minutes to obtain complexing liquid;
4) adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
Comparative example 1
The operation of steps 1-4) is the same as that of example 1, except that:
the dropping process in the step 3): and (3) raising the pH at a constant speed, raising the pH by 1.3 per hour, and dropwise adding for 5 hours until the pH of the mixed solution is 6.4-6.5.
Comparative example 2
The operation of steps 1-4) is the same as that of example 1, except that:
the dropping process in the step 3): controlling the pH value of the mixed solution to be 1.1-1.4 at 1 hour, controlling the pH value of the mixed solution to be 3.1-3.3 at 2 hours, controlling the pH value of the mixed solution to be 3.5-3.6 at 3 hours, controlling the pH value of the mixed solution to be 3.9-4.0 at 4 hours, and controlling the pH value of the mixed solution to be 6.4-6.5 at 5 hours;
comparative example 3
The operation of steps 1-4) is the same as that of example 1, except that:
the dropping process in the step 3): controlling the pH value of the mixed solution to be 1.5-1.6 at 1 hour, controlling the pH value of the mixed solution to be 2.8-3.0 at 2 hours, controlling the pH value of the mixed solution to be 4.1-4.3 at 3 hours, controlling the pH value of the mixed solution to be 5.5-5.8 at 4 hours, and controlling the pH value of the mixed solution to be 6.4-6.5 at 5 hours;
comparative example 4
The operation of steps 1-4) is the same as that of example 1, except that:
the dropping process in the step 3): controlling the pH value of the mixed solution to be 1.5-1.6 at 1 hour, controlling the pH value of the mixed solution to be 2.8-3.0 at 2 hours, controlling the pH value of the mixed solution to be 3.5-3.6 at 3 hours, controlling the pH value of the mixed solution to be 4.1-4.5 at 4 hours, and controlling the pH value of the mixed solution to be 7.0-7.2 at 5 hours;
comparative example 5
Step 1) same as step 1) of example 1;
step 2) adding citric acid monohydrate into the oxidation solution, controlling the pH value of the oxidation solution to be 1-2 by using hydrochloric acid, heating the oxidation solution to 95-98 ℃, and simultaneously dropwise adding FeCl accounting for 40-50% of the mass percentage into the oxidation solution3.6H2O solution and 25-35% NaOH aqueous solution (FeCl) by mass3.6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1) (ii) a Stirring while dripping; the pH and time control during the dropwise addition was the same as in example 1; after the dropwise addition, the curing and cooling processes are the same as those of example 1;
step 3) is the same as step 4) of example 1.
Comparative example 6
Step 1) same as step 1) of example 1;
step 2) adding FeCl with mass concentration of 40 mass percent into the oxidizing solution while stirring3.6H2O solution and 25% by mass of NaCO3Controlling the pH value of a solution system to be 4-5 in the dripping process of the aqueous solution, controlling the reaction temperature to be 35-55 ℃ and controlling the reaction time to be 5.5 h; after the dripping is finished, the reaction is kept for 30 min; then adding 25-35% by mass of NaOH aqueous solution into the solution, adjusting the pH value of the system to 11 within 1 h, heating to 85 ℃, and carrying out curing reaction for 5.5h to obtain a complexing solution;
step 3) is the same as step 4) of example 1.
Performance testing
In order to prove that the invention really achieves the technical effects, detection equipment and a detection method are provided, and experimental data are provided.
Detecting the performance name:
viscosity: the measurement was performed using a viscometer.
Molecular distribution: the measurements were carried out according to the pharmacopoeial method (see standard USP 38-iron dextran).
Molecular weight: the measurements were carried out according to the pharmacopoeial method (see standard USP 38-iron dextran).
The iron content is as follows: the measurements were carried out according to the pharmacopoeial method (see standard USP 38-iron dextran).
Dextran content: the high performance liquid chromatography-differential refraction detection method (Shimadzu-20A type) is adopted, the chromatographic column is phenomenex poxylsep-GFC-p 4000, the mobile phase is 0.7% sodium sulfate solution, the flow rate is 0.5 ml/min, the column temperature is 35 ℃, the sample injection amount is 20 mu l, the differential refraction detector is adopted, and the detection pool temperature is 40 ℃.
Specific detection operation:
and (3) accurately weighing 100mg of a dextran 3000 (dextran with the weight-average molecular weight of 3000 Da) working reference substance in the reference substance solution, placing the reference substance solution in a 10ml volumetric flask, adding the mobile phase for dissolving, and diluting to a scale to obtain the reference substance storage solution.
Respectively diluting into series of reference substance solutions with final concentrations of 1mg/ml, 2 mg/ml, 5 mg/ml, 8 mg/ml and 10 mg/ml, detecting according to the chromatographic conditions, recording peak areas, performing linear regression by taking dextran 3000 concentration (mg/ml) as abscissa and peak areas as ordinate, wherein the dextran 3000 has a better linear relation in the range of 1-10 mg/ml.
And putting 1mL of sample solution into a 10mL volumetric flask, adding 2mL of 4mol/L sodium dihydrogen phosphate solution, shaking uniformly, standing overnight, adding water to 10mL, filtering to obtain a clear solution, and monitoring according to the chromatographic conditions.
Solubility: 0.5ml of 20% iron dextran solution is taken and added into a 50ml colorimetric tube to be uniformly mixed to obtain clear and transparent red colloidal solution.
Filtering property: taking 10ml of 20% iron dextran solution, adding water to 50ml, filtering through a 0.45 mu m membrane, and rapidly passing through the membrane under the vacuum degree of 0.08 Mpa.
TABLE 1 Performance test of iron dextran aqueous solution obtained in examples 1 to 5
TABLE 2 Performance test of iron dextran aqueous solution obtained in comparative examples 1-6
As can be seen from tables 1-2: by adopting the complexing process in the step 2-3), the obtained iron dextran has good solubility (namely clarity), low viscosity and high iron content. The uniform dropping is adopted in the comparative example 1, the dropping rate of the comparative examples 2-4 is different from that of the examples, and the solubility and the viscosity of the finally obtained iron dextran aqueous solution are not ideal. Comparative example 5 simultaneous FeCl addition3.6H2The obtained iron dextran solution has unsatisfactory solubility, large pH fluctuation during dropping, difficult control when the dropping is close to a pH critical point, and high probability of turbidity and viscosity of the solution. Comparative example 6 is a prior art with the simultaneous addition of FeCl3.6H2O solution and NaCO3And adding NaOH aqueous solution into the aqueous solution, wherein the method has the problems of large pH fluctuation of the solution, easy precipitation and more than 2 times of the time consumption of the embodiment.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (8)
1. A method for preparing dextran iron aqueous solution by using dextran is characterized by comprising the following steps: the preparation method comprises the following steps:
1) heating a dextran solution to 40-60 ℃, adjusting the pH value to 11-12 with alkali liquor, adding a sodium hypochlorite aqueous solution, and performing oxidation reaction to obtain an oxidation solution;
2) sequentially adding weak acid and strong acid into the oxidation solution, controlling the pH value of the oxidation solution to be 1-2 by using the strong acid, heating the oxidation solution to 95-98 ℃, and adding FeCl accounting for 40-50% of the oxidation solution by mass3· 6H2O solution to obtain mixed solution;
3) dropwise adding 25-35% by mass of NaOH aqueous solution into the mixed solution while stirring; in the dropping process: controlling the pH value of the mixed solution to be 1.5-3.0 in 1-2 hours, controlling the pH value of the mixed solution to be 3.1-4.0 in 3-4 hours, and controlling the pH value of the mixed solution to be 6-6.5 in 5 hours; after the dropwise addition, curing the mixed solution for 20-30 minutes at 95-100 ℃; then reducing the temperature to 25 ℃ at the speed of every 10-15 ℃/30 minutes to obtain complexing liquid;
4) ultrafiltering and desalting the complex solution to obtain dextran iron water solution;
the specific operation of the dropping process in the step 3) is as follows: controlling the pH value of the mixed solution to be 1.5-2.5 at 1 hour, controlling the pH value of the mixed solution to be 2.6-3.0 at 2 hours, controlling the pH value of the mixed solution to be 3.5-3.7 at 3 hours, controlling the pH value of the mixed solution to be 3.8-4.0 at 4 hours, and controlling the pH value of the mixed solution to be 6-6.5 at 5 hours;
the mass percentage concentration of the dextran solution in the step 1) is 18-25%, and the weight average molecular weight of the dextran is 2600-3800 Da.
2. The method for preparing the dextran iron solution by using the dextran according to the claim 1, wherein the concrete operation of the step 1) is as follows: heating a dextran solution to 40-60 ℃, maintaining the pH value of the dextran solution at 11-12 by using a sodium hydroxide aqueous solution with the mass percent of 20-30%, then dropwise adding a sodium hypochlorite aqueous solution with the mass percent of 5% for 2-3 hours, maintaining the temperature at 40-60 ℃ after dropwise adding, and performing oxidation reaction at the pH value of 11-12 for 4 hours to obtain an oxidation solution.
3. The method for preparing dextran iron solution by using dextran according to claim 1, characterized in that the addition amount of said sodium hypochlorite aqueous solution in step 1) is: the molar ratio of the active chlorine to the terminal aldehyde group of the dextran molecule is 5:1 based on the active chlorine in the sodium hypochlorite aqueous solution.
4. The method for preparing the dextran iron solution by using the dextran according to the claim 1, wherein the concrete operation of the step 4) is as follows: adding purified water into the complexing solution, passing through an ultrafiltration membrane of 3000Da for desalting until the conductivity of the filtrate is less than 100 mu S/cm, stopping adding the purified water, continuing ultrafiltration, and finishing ultrafiltration to obtain the dextran iron aqueous solution.
5. The method for preparing the dextran iron solution by using the dextran according to claim 1, wherein the mass ratio of the weak acid in the step 2) to the dry weight of the dextran in the oxidizing solution is 1: 10.
6. The method of claim 1, wherein the weak acid of step 2) is citric acid monohydrate.
7. The method of claim 1, wherein the strong acid in step 2) is hydrochloric acid.
8. The method for preparing dextran iron solution using dextran according to claim 1, wherein said FeCl of step 2)3· 6H2The mass ratio of the O to the dry weight of the dextran in the oxidizing solution is 4.5: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910929883.7A CN110804107B (en) | 2019-09-29 | 2019-09-29 | Method for preparing dextran iron aqueous solution by using dextran |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910929883.7A CN110804107B (en) | 2019-09-29 | 2019-09-29 | Method for preparing dextran iron aqueous solution by using dextran |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110804107A CN110804107A (en) | 2020-02-18 |
| CN110804107B true CN110804107B (en) | 2021-08-31 |
Family
ID=69487909
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910929883.7A Active CN110804107B (en) | 2019-09-29 | 2019-09-29 | Method for preparing dextran iron aqueous solution by using dextran |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110804107B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK173138B1 (en) * | 1998-11-20 | 2000-02-07 | Pharmacosmos Holding As | Process for Preparing an Iron Dextran Compound, Iron Dextran Compound Prepared by the Process, Pharmaceutical |
| ITMO20050056A1 (en) * | 2005-03-15 | 2006-09-16 | Biofer Spa | PROCESS FOR THE PREPARATION OF TRIVALENT IRON COMPLEXES WITH MONO-, DI- AND POLISACCARIDI SUGARS. |
| CN106543294A (en) * | 2015-09-18 | 2017-03-29 | 瑞普（天津）生物药业有限公司 | A kind of preparation method of iron-dextrin |
| CN107201387B (en) * | 2017-07-26 | 2021-01-15 | 合肥工业大学 | Preparation method of iron dextran |
| CN110218267B (en) * | 2019-07-04 | 2020-08-07 | 汉邦环宇多糖生物科技（河源）有限公司 | Preparation method and application of iron dextran |
-
2019
- 2019-09-29 CN CN201910929883.7A patent/CN110804107B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110804107A (en) | 2020-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1215624A3 (en) | Method of producing polymer solution for extracting petroleum | |
| LaMer et al. | Kinetics of the formation of monodispersed sulfur sols from thiosulfate and acid | |
| CN107201387B (en) | Preparation method of iron dextran | |
| CN103435714B (en) | The preparation of the thick polysaccharide of a kind of fig and purification process and purposes | |
| EP0111518A1 (en) | Polymer solutions. | |
| CN103554303B (en) | A kind of method of purifying cm-chitosan | |
| CN111647100B (en) | Preparation method of high molecular weight zinc hyaluronate | |
| CN110804107B (en) | Method for preparing dextran iron aqueous solution by using dextran | |
| Creeth et al. | 214. Deoxypentose nucleic acids. Part III. Viscosity and streaming birefringence of solutions of the sodium salt of the deoxypentose nucleic acid of calf thymus | |
| CN108949850B (en) | Online separation and purification method of rhamnolipid fermentation liquor | |
| CN113105651A (en) | Sprayable hydrogel and preparation method and application thereof | |
| Ogawa | Osmotic pressure measurements for gellan gum aqueous solutions | |
| WO2023124542A1 (en) | Method for preparing resistant dextrin | |
| US20240024357A1 (en) | Methods of preparing iron complexes | |
| CN109431996B (en) | Minoxidil-containing external preparation composition and preparation method thereof | |
| JP2005508406A (en) | Acetylation method of chitosan | |
| CN110218267B (en) | Preparation method and application of iron dextran | |
| CN112168844A (en) | Preparation method of iron hydroxide carbohydrate compound | |
| Yamada et al. | Effect of citric acid on potato starch gelatinization | |
| CN103149170B (en) | Solution concentration of nadroparin calcium determined by phenanthroline-zinc sulfate ultraviolet spectroscopy | |
| JP2000007705A (en) | Wet-heat-treated xanthan gum and its preparation | |
| CN106315697B (en) | The method of rhodium chloride continuous crystallisation | |
| CN112646175B (en) | Preparation method of cosmetic-grade high-molecular-weight gamma-polyglutamic acid | |
| KR20200062940A (en) | Agar oligosaccharides Manufacturing Method | |
| CN113116921B (en) | Sodium bicarbonate injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |