CN113461835A - Purification method of hydroxybutyl chitosan - Google Patents
Purification method of hydroxybutyl chitosan Download PDFInfo
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- CN113461835A CN113461835A CN202110904980.8A CN202110904980A CN113461835A CN 113461835 A CN113461835 A CN 113461835A CN 202110904980 A CN202110904980 A CN 202110904980A CN 113461835 A CN113461835 A CN 113461835A
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Abstract
The invention discloses a purification method of hydroxybutyl chitosan, which comprises the following steps: 1) adding the hydroxybutyl chitosan mixture solution into pure water at a certain temperature, wherein the volume ratio of the mixture solution to the pure water is 1:0.5-1: 100; 2) stirring to uniformly disperse the hydroxybutyl chitosan mixture solution and pure water and keeping the final temperature of the system between 30 and 70 ℃; 3) standing to separate out a precipitate, and then separating the precipitate from the solution in a centrifugal or filtration mode; 4) adding the precipitate into pure water again, and uniformly dispersing; standing for precipitation, and separating the precipitate from the solution again in a centrifugal or filtering mode; 5) repeating the step 4) until the conductivity of the centrifuged supernatant or the filtered filtrate is basically consistent with that of the used pure water; 6) drying to obtain the high-purity hydroxybutyl chitosan. The invention adopts low-cost pure water, avoids using a large amount of organic solvent, thereby reducing the waste liquid to be treated and reducing the potential safety hazard in the production process. The purification method has short time, greatly improves the separation and purification efficiency, and can prepare the high-purity hydroxybutyl chitosan meeting the requirements of medical products.
Description
Technical Field
The invention relates to a purification method of a temperature-sensitive chitosan derivative, in particular to a purification method of temperature-sensitive hydroxybutyl chitosan, belonging to the technical field of biological medicines.
Background
The chitosan-based materials have been developed over the decades and have progressed to the third stage.
The first generation of chitosan materials are chitin extracted from shells of crustaceans such as shrimp, crab, etc. and chitosan obtained by further deacetylation. Chitin is insoluble in common solvents, chitosan is soluble in partial dilute acid solution, but neither is soluble in neutral aqueous solution.
The second generation of chitosan material is prepared by grafting soluble groups on the molecules of chitin or chitosan to make them become water-soluble materials, and the representative materials are derivatives such as carboxymethyl chitin and carboxymethyl chitosan. The material solves the problem that the first generation chitosan material is insoluble in water, solves the problem that the acidic solution of the first generation chitosan material can not enter the body for use in the medical field, and greatly expands the application of the chitosan material in the human body.
The third generation of chitosan material is made into intelligent chitosan biomaterial by grafting intelligent groups on chitin or chitosan molecules, and comprises temperature sensitive intelligent material, pH sensitive biomaterial, pressure sensitive biomaterial, magnetic sensitive biomaterial and the like. Wherein the hydroxybutyl chitosan material obtained by grafting hydroxybutyl is a biomaterial having at least temperature sensitivity. The hydroxybutyl chitosan material not only solves the problem of water insolubility of the first generation of biological materials, but also has the temperature sensitivity.
Up to now, there are hundreds of chitosan products registered by the national food and drug administration for nursing burns, scalds, surgical incisions and the like, most of which use a first-generation chitosan material as a base material, the preparation method of the chitosan material is relatively simple and has low cost, but the chitosan material can only be dissolved in a partial acid solution and cannot be used in vivo, so the application range of the chitosan material is limited.
The product using the second generation chitosan material as the basic material is less than ten, the material overcomes the defect that the first generation material is insoluble in water, can be dissolved in a wide pH value range, has good biocompatibility, can be used in a human body, but the solution of the material has fluidity after being applied to the human body, and cannot stay in a diseased part for a long time to play a role.
The product taking the third generation chitosan as the basic material only has a product of temperature-sensitive hydroxybutyl chitosan wound dressing at present. The product is temperature sensitive, i.e. the product is in solution state at low temperature (below its gel temperature), and can be transformed into a gel state which can not flow after being heated up gradually and being higher than its gel temperature, for example, after reaching the body temperature of 37 ℃. This property allows the material to be immobilized and to function for a long period of time after it is applied to the affected area.
The temperature-sensitive hydroxybutyl chitosan wound dressing has good fluidity at low temperature, can be used on wound surfaces in almost any shape, including plane type, wrinkle type, gap type and the like, is changed into non-flowing gel after being used and is attached to the wound surfaces, and cannot be lost due to change of body positions, so that the long-term treatment effect is achieved, and the problems that the material such as second-generation carboxymethyl chitosan has high fluidity and is easy to leave the wound surface parts needing barriers are solved. Therefore, the hydroxybutyl chitosan material has good wound healing promotion and hemostasis performance.
Both patent application publication No. CN 102276756 a and patent application publication No. CN 101284884 a disclose that the mixture containing hydroxybutyl chitosan is obtained by further purifying the extracted chitosan, alkalizing, adding isopropanol, 1, 2-butylene oxide, etc., and reacting at room temperature, under heating or under microwave for a certain period of time. Then, the obtained mixture is precipitated by using organic solvents such as ethanol, acetone and the like, washed or centrifuged, and dried in vacuum to obtain the hydroxybutyl chitosan with high purity.
Patent application publication No. CN 104761657A discloses a method for separating and purifying hydroxybutyl chitosan by phase transition, which comprises precipitating hydroxybutyl chitosan solution with sodium chloride solution of different concentrations, desalting with organic solvent of different concentrations such as ethanol and acetone, and vacuum drying to obtain relatively pure hydroxybutyl chitosan.
However, the purification method of hydroxybutyl chitosan in the above patent application requires the use of organic solvent in multiples or even tens of times. In industrial production, these methods not only result in high production cost, generate a large amount of waste liquid to be treated, but also cause greater safety problems in the production field, which puts higher requirements on the site area, the structural design, the fire fighting equipment, the maintenance and the like of the production field.
Disclosure of Invention
In view of the above problems, the present invention aims to provide a method for purifying hydroxybutyl chitosan, which is a temperature-sensitive chitosan derivative with high efficiency, safety and low cost, and avoids the use of a large amount of organic solvents, thereby reducing the waste liquid to be treated and reducing the potential safety hazard in the production process.
The hydroxybutyl chitosan mixture to be purified according to the present invention is prepared according to the method described in the chinese patent application with publication No. CN 102276756 a: chitosan is used as a raw material, 1, 2-epoxybutane is used as an etherifying agent, in an isopropanol aqueous solution dispersion system, under the action of microwaves, the reaction temperature and time are controlled to carry out hydroxybutylation modification on the chitosan, the hydroxybutyl chitosan is prepared, and the pH value of the system is adjusted to be neutral. Since a high-concentration (about 50%) alkaline solution is used in the early stage of the reaction and the pH is adjusted to neutral with an acid after the reaction is completed, the mixture contains a large amount of salts and other reaction by-products in addition to the hydroxybutyl chitosan formed. The principle of purification of the invention is that according to the property that hydroxybutyl chitosan is easy to dissolve in cold water and difficult to dissolve in hot water, the mixture obtained after neutralization is directly added into pure water at a certain temperature, so that the hydroxybutyl chitosan is separated out due to difficult dissolution at the temperature; in addition, the presence of the salt in the mixture further promotes the precipitation of the hydroxybutyl shell in water, and other reaction by-products and salts in the reaction mixture are dissolved in pure water and removed. Further separating the precipitate and the aqueous solution by conventional separation methods such as filtration, centrifugation and the like to obtain the high-purity hydroxybutyl chitosan.
The specific technical scheme of the invention is as follows:
the invention separates and purifies the hydroxybutyl chitosan mixture prepared after the early-stage chemical reaction and neutralization, and the specific process comprises the following steps:
1) adding the hydroxybutyl chitosan mixture solution into pure water at a certain temperature, wherein the volume ratio of the mixture solution to the pure water is 1:0.5-1: 100;
2) stirring to uniformly disperse the hydroxybutyl chitosan mixture solution and pure water and keeping the final temperature of the system between 30 and 70 ℃;
3) standing to separate out a precipitate, and then separating the precipitate from the solution in a centrifugal or filtration mode;
4) adding the precipitate into pure water again, and uniformly dispersing; standing for precipitation, and separating the precipitate from the solution again in a centrifugal or filtering mode;
5) repeating the step 4) until the conductivity of the centrifuged supernatant or the filtered filtrate is basically consistent with that of the used pure water;
6) drying to obtain the high-purity hydroxybutyl chitosan.
The temperature of the pure water in the step 1) is 30-70 ℃, and the preferred temperature is 30-50 ℃; the volume ratio of the preferred hydroxybutyl chitosan mixture solution to pure water is 1:1-1: 10.
The temperature of the pure water in the step 4) is 30-70 ℃.
The drying mode in the step 6) is vacuum drying, freeze drying or other conventional drying modes.
The invention has the advantages that:
1) the purification method of the invention utilizes the special property that hydroxybutyl chitosan is easy to dissolve in cold water and difficult to dissolve in hot water, only uses low-price pure water but not expensive organic solvent in the purification process, avoids various problems caused by using a large amount of organic solvent, reduces the production cost, reduces the waste liquid needing to be treated, reduces the potential safety hazard in the production process, and does not need to apply higher-level safety protection to the production site.
2) The purification method can further remove the impurity protein (the content of the impurity protein is one of the indexes of medical-grade products, the content of the impurity protein is high, the possibility of generating immunogenicity to a human body is high), and the purity of the product is improved.
3) The purification method of the invention needs short time, thereby saving a large amount of separation time and greatly improving the efficiency of separation and purification.
4) Through multiple purification, the high-purity hydroxybutyl chitosan raw material meeting the requirements of medical products can be prepared.
Drawings
FIG. 1 is a gas chromatogram of isopropanol (25. mu.g/mL) and 1, 2-butylene oxide (2.5. mu.g/mL) standards.
FIG. 2 is a gas chromatogram of the headspace sample injection of the 2% solution of hydroxybutyl chitosan purified in example 1.
Detailed Description
The invention is explained in further detail below by means of specific embodiments with reference to the drawings.
Example 1:
1) 500g of chitosan was used as a starting material and a hydroxybutyl chitosan mixture was prepared in a volume of about 30L after a preliminary chemical reaction and neutralization according to the method disclosed in the patent application CN 102276756A.
2) Adding into 300L of pure water of 35 deg.C, stirring to disperse uniformly, and ensuring the final temperature of the system to be 30-35 deg.C.
3) Standing to separate out precipitate, filtering, collecting filter cake, uniformly dispersing into 300L of purified water at 35 deg.C, and filtering for separation.
4) Repeating the step of dispersion filtration until the conductivity of the filtrate is substantially the same as the conductivity of the purified water;
5) vacuum drying to obtain high-purity hydroxybutyl chitosan; the purity of the purified hydroxybutyl chitosan is about 95 percent through determination, the majority of the rest is water, and the purity is far higher than the industrial standard (not lower than 85 percent is required).
The hydroxybutyl chitosan obtained in example 1 was prepared into a 2% aqueous solution, and tested by using a gas chromatography headspace sampling method, to obtain the gas chromatogram of fig. 2. With the peak time of 2.829min for 1, 2-butylene oxide and the peak time of 3.583min for isopropanol in the gas chromatogram of the standard in fig. 1 as reference, it can be seen from fig. 2 that the purified hydroxybutyl chitosan does not detect the peaks of 1, 2-butylene oxide and isopropanol, i.e. the content of the sample is below the detection limit: the content of 1, 2-epoxybutane is less than 1 mu g/mL, and the content of isopropanol is less than 10 mu g/mL.
The hydroxybutyl chitosan obtained in example 1 was tested for its main properties according to reference standard YY/T1699-.
TABLE 1 Main Performance index of example 1 purified hydroxybutyl chitosan
| Test items | Standard requirements | Test results |
| Appearance of the product | White or pale yellow powder or sponge | Meets the requirements |
| Purity of | More than 85 percent | 95.0% |
| Protein content | ＜0.2% | 0.08% |
| Residue on ignition | ＜1% | 0.27% |
| Heavy metal content | ＜10μg/g | ＜10μg/g |
| 1, 2-butylene oxide content | ＜10μg/g | ＜10μg/g |
| Asepsis (for sterilized products) | Should be sterile | Meets the requirements |
As can be seen from Table 1, the hydroxybutyl chitosan purified by the method of the present invention meets the standard requirements of medical chitosan materials.
Example 2:
using 500g of chitosan as a starting material, a hydroxybutyl chitosan mixture was prepared in a volume of about 30L after a preliminary chemical reaction and neutralization as disclosed in the patent application CN 102276756A. Adding into 30L of 70 deg.C pure water, stirring to disperse uniformly, and making the final temperature of the system not lower than 60 deg.C. Centrifuging, collecting precipitate, dispersing in 70 deg.C pure water, and centrifuging. And repeating the dispersion and centrifugation steps until the conductivity of the supernatant is basically the same as that of pure water, adding a little pure water into the water-containing precipitate, dispersing and swelling at low temperature, and freeze-drying to obtain the high-purity hydroxybutyl chitosan.
Example 3:
using 500g of chitosan as a starting material, a hydroxybutyl chitosan mixture was prepared in a volume of about 30L after a preliminary chemical reaction and neutralization as disclosed in the patent application CN 102276756A. Adding into 100L of purified water of 50 deg.C, stirring to disperse uniformly, and making the final temperature of the system not lower than 45 deg.C. Standing to separate out precipitate, filtering, collecting filter cake, dispersing in purified water at 50 deg.C, and filtering. And repeating the dispersion filtering step until the conductivity of the filtrate is basically the same as that of pure water, and performing vacuum drying to obtain the high-purity hydroxybutyl chitosan.
Example 4:
about 0.45g of each of 7 parts of hydroxybutyl chitosan purified in example 3 was placed in 7 test tubes, 25mL of pure water was added, the tubes were incubated at 4 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃ and 70 ℃ for about 24 hours, the dissolved state was observed, about 10mL of the supernatant was taken, the supernatant was placed in an oven at 105 ℃ for drying, the mass of the remaining dried material was measured, and the solubility was evaluated.
TABLE 2 solubility test data for hydroxybutyl chitosan
| Serial number | Temperature/. degree.C | HBC mass/g | Adding the mass of the clear liquid per gram | Mass/g of dried constant weight material | HBC content of supernatant% | Total dissolved calculated concentration | Percent dissolution | Maximum dissolved concentration | Solubility in water |
| 1 | 4 | 0.4665 | 10.034 | 0.1865 | 1.86% | 1.87% | 99.95% | ＞1.87% | Soluble or freely soluble |
| 2 | 15 | 0.4521 | 10.0771 | 0.1662 | 1.65% | 1.81% | 91.90% | 1.662% | Soluble in water |
| 3 | 20 | 0.4205 | 10.038 | 0.0264 | 0.26% | 1.68% | 15.70% | 0.264% | Slightly soluble |
| 4 | 25 | 0.4530 | 10.0168 | 0.0064 | 0.06% | 1.81% | 3.53% | 0.064% | Slightly soluble |
| 5 | 30 | 0.4354 | 10.0488 | 0.0003 | 0.00% | 1.74% | 0.17% | 0.003% | Is difficult to dissolve |
| 6 | 40 | 0.4377 | 10.0292 | 0.0002 | 0.00% | 1.75% | 0.11% | 0.002% | Is difficult to dissolve |
| 7 | 50 | 0.4598 | 10.0025 | 0.0007 | 0.01% | 1.84% | 0.38% | 0.007% | Is difficult to dissolve |
| 8 | 60 | 0.4414 | 10.0037 | 0.0002 | 0.00% | 1.77% | 0.11% | 0.002% | Is difficult to dissolve |
| 9 | 70 | 0.4514 | 10.0173 | 0.0003 | 0.00% | 1.81% | 0.17% | 0.003% | Is difficult to dissolve |
As can be seen from the data in the table, the solubility of the material gradually decreased with increasing dissolution temperature, being soluble or freely soluble at 4 deg.C, soluble at 15 deg.C, slightly soluble at 20 deg.C and 25 deg.C, and insoluble at 30 deg.C to 70 deg.C. This data also provides data support for temperature selection of the system during purification.
Finally, it should be noted that: the above embodiments are only intended to illustrate the technical solution of the present invention and not to limit the same, and a person of ordinary skill in the art can make modifications or equivalents to the specific embodiments of the present invention with reference to the above embodiments, and any modifications or equivalents without departing from the spirit and scope of the present invention are within the scope of the claims of the present invention.
Claims (6)
1. A method for purifying hydroxybutyl chitosan is characterized by comprising the following steps:
1) adding the hydroxybutyl chitosan mixture solution into pure water at a certain temperature, wherein the volume ratio of the mixture solution to the pure water is 1:0.5-1: 100;
2) stirring to uniformly disperse the hydroxybutyl chitosan mixture solution and pure water and keeping the final temperature of the system between 30 and 70 ℃;
3) standing to separate out a precipitate, and then separating the precipitate from the solution in a centrifugal or filtration mode;
4) adding the precipitate into pure water again, and uniformly dispersing; standing for precipitation, and separating the precipitate from the solution again in a centrifugal or filtering mode;
5) repeating the step 4) until the conductivity of the centrifuged supernatant or the filtered filtrate is basically consistent with that of the used pure water;
6) drying to obtain the high-purity hydroxybutyl chitosan.
2. The method for purifying hydroxybutyl chitosan according to claim 1, wherein the temperature of pure water in step 1) is from 30 ℃ to 70 ℃.
3. The method for purifying hydroxybutyl chitosan according to claim 1, wherein the ratio of the hydroxybutyl chitosan mixture solution to pure water in step 1) is from 1:1 to 1:10 by volume.
4. The method for purifying hydroxybutyl chitosan according to claim 1 or 2, wherein the temperature of pure water in step 1) is from 30 ℃ to 50 ℃.
5. The method for purifying hydroxybutyl chitosan according to claim 1, wherein the temperature of pure water in step 4) is from 30 ℃ to 70 ℃.
6. The method for purifying hydroxybutyl chitosan of claim 1, wherein the drying in step 6) is vacuum drying or freeze drying.
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| CN116143954A (en) * | 2023-03-15 | 2023-05-23 | 智元柏迈(杭州)科技有限公司 | Preparation and purification method of hydroxybutyl chitosan-gallic acid |
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| 张娟等: "羟丁基壳聚糖护创敷料无菌检查方法的建立", 《北京生物医学工程》 * |
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| CN116143954A (en) * | 2023-03-15 | 2023-05-23 | 智元柏迈(杭州)科技有限公司 | Preparation and purification method of hydroxybutyl chitosan-gallic acid |
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