CN111574642B - Purification method of sugammadex sodium - Google Patents
Purification method of sugammadex sodium Download PDFInfo
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- CN111574642B CN111574642B CN202010582785.3A CN202010582785A CN111574642B CN 111574642 B CN111574642 B CN 111574642B CN 202010582785 A CN202010582785 A CN 202010582785A CN 111574642 B CN111574642 B CN 111574642B
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Abstract
The invention discloses a method for purifying sugammadex sodium, which comprises the following steps: firstly, carrying out pretreatment on Egret Z (Carborafin) activated carbon, wherein the first pretreatment method mainly comprises the steps of adding the activated carbon into water at the temperature of 10-50 ℃ and introducing inert gas while stirring, the second method mainly comprises the steps of adding the activated carbon into the water at the temperature of 10-50 ℃ and adding a reducing agent under the protection of the inert gas and stirring, and the third method mainly comprises the steps of adding the activated carbon into the water, heating to the temperature of 60-95 ℃ under the protection of the inert gas and preserving heat for 0.1-5 h; and then adding pretreated aigrette Z (CARBORAFIN) activated carbon into the aqueous solution of the crude sugammadex sodium product under the protection of inert gas, stirring and adsorbing, filtering, and evaporating to dryness or crystallizing to separate out to obtain the sugammadex sodium with the purity of more than 99.50 percent and the single impurity content of less than 0.1 percent. The purification method of the invention has simple operation, low cost, obvious effect and high product purity, and can be used for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and relates to a method for purifying sugammadex sodium, in particular to a method for purifying sugammadex sodium by adopting pretreated aigrette Z (CARBORAFIN) activated carbon.
Background
Sugammadex sodium, a derivative of gamma-cyclodextrin, is a selective muscle relaxant antagonist, first developed by the company ogannol, which was purchased by the company pionship (Schering-plus) in 2007, and combined with Merck (Merck) in 2009. Sugammadex sodium is currently owned and sold by merck. The structure of the molecular compound is as follows:
sugammadex sodium is a modified gamma cyclodextrin, a cyclic structure of 8 glucopyranoses, that forms a complex with the neuromuscular blocking agents rocuronium bromide and vecuronium bromide, reducing the amount of neuromuscular blocking agent available for nicotinic cholinergic receptors bound to the neuromuscular junction. This resulted in reversal of the neuromuscular blockade induced by rocuronium and vecuronium bromide. The product is the first and only selective relaxation antagonist.
The sugammadex sodium synthesis process reported in the literature at present firstly carries out halogenation on hydroxyl of gamma-cyclodextrin to obtain an intermediate 6-per-deoxy-6-per-halo-gamma-cyclodextrin, and the intermediate is subjected to substitution reaction with 3-mercaptoacetic acid or 3-mercaptoacetic ester to prepare a product, wherein the main difference is that the adopted halogenation modes are different. In addition, there have been studies on converting a cyclodextrin hydroxyl group into a mercapto group and then subjecting it to a subsequent reaction with a halogenated acid (ester, sodium salt, amide, acrylic acid, etc.). The sugammadex sodium is a chiral compound, 8 sugar rings are arranged in a molecular structure, reaction sites are more, the reaction process is complex, a high-purity product is difficult to obtain through reaction, main impurities are monosubstituted impurities of various groups of a side chain, and further purification is needed.
The purification methods of the prior art for sugammadex sodium include chromatographic purification, recrystallization purification and adsorption purification.
Patent document WO2014125501A discloses the preparation of sugammadex sodium by improving the synthetic route of the original patent, wherein the purity of the product is increased by means of activated carbon adsorption, and the activated carbon used is not pretreated or selected in kind. Therefore, patent document CN107892727A has identified that activated carbon is pretreated and the types of activated carbon are screened, and that a purpose-made aigret (tokuseishiragai) or aigret a (shirasagaia) using activated carbon is used to improve the purity of sugammadex sodium. Patent document CN107892727A suggests that the activated carbon from each manufacturer has great differences in the size and distribution of the pore diameter of the skeleton due to the differences in the production process and material sources, and it suggests through comparison and verification that the high-purity sugammadex sodium product cannot be obtained from any other kind of activated carbon products except the specific aigret (tokuseishiragai) activated carbon and aigret a (shirasagaia) activated carbon. In the process of research and development of sugammadex sodium, the applicant finds that patent document CN107892727A has a technical prejudice, and in order to overcome the technical prejudice and further enrich and develop a new method for improving the purity of sugammadex sodium, more research and development work needs to be carried out.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for purifying sugammadex sodium, which is simple and convenient to operate, low in cost, very high in purity and applicable to industrialization.
In order to solve the technical problems, the invention adopts the following technical scheme.
A purification method of sugammadex sodium, comprising the following steps:
(1) carrying out pretreatment on the Egret Z (CARBORAFIN) activated carbon by adopting a first method, a second method or a third method:
the main process of the first method is as follows: adding the Egret Z (CARBORAFIN) active carbon into water, stirring and dispersing, then introducing inert gas while stirring at 10-50 ℃ to replace oxygen adsorbed by the active carbon, and then filtering under the protection of the inert gas to obtain pretreated Egret Z (CARBORAFIN) active carbon;
the main process of the second method is as follows: adding the active carbon of the aigret Z (carborafin) into water, stirring and dispersing, adding a reducing agent and stirring at the temperature of 10-50 ℃ under the protection of inert gas, then filtering under the protection of inert gas, and washing with saturated inert gas water to obtain pretreated active carbon of the aigret Z (carborafin);
the main process of the third method is as follows: adding the Egret Z (CARBORAFIN) active carbon into water, stirring and dispersing, then heating to 60-95 ℃ under the protection of inert gas, preserving heat for 0.1-5 h, cooling to room temperature, and filtering under the protection of inert gas to obtain pretreated Egret Z (CARBORAFIN) active carbon;
(2) mixing and dissolving the crude sugammadex sodium product and water, adding the pretreated aigret Z (carborafin) activated carbon obtained in the step (1), adsorbing under the protection of inert gas, filtering to remove the activated carbon after adsorption, and evaporating to dryness or crystallizing to separate out the sugammadex sodium.
Preferably, in the first method in the step (1), the mass ratio of the aigrette Z (CARBORAFIN) activated carbon to water is 1: 1-500, and the inert gas is introduced while stirring for 0.1-24 hours; in the second method in the step (1), the mass ratio of the Egret Z (CARBORAFIN) active carbon to the water is 1: 1-500, and the stirring time is 0.1-24 h; in the third method in the step (1), the mass ratio of the Egret Z (CARBORAFIN) activated carbon to the water is 1: 1-200, and the heat preservation time is 0.5-1 hour.
Preferably, in the second method in step (1), the reducing agent is one or more of sodium thiosulfate, sodium sulfite and sodium dithionite, and the addition amount of the reducing agent is 0.1-20% of the mass of the aigrette Z (CARBORAFIN) activated carbon.
In the method for purifying sugammadex sodium, preferably, in the first, second and third methods of step (1), after the pretreated aigret z (carborafin) activated carbon is obtained, inert gas is filled into the activated carbon and the activated carbon is sealed for standby.
Preferably, in the step (2), the mass ratio of the crude sugammadex sodium product to water is 1: 2-10, and the mass of the pretreated aigret Z (CARBORAFIN) activated carbon is 2-100% of the mass of the crude sugammadex sodium product.
In the method for purifying sugammadex sodium, in the step (2), the mass of the pretreated aigret z (carborafin) activated carbon is preferably 10% to 30% of the mass of the crude sugammadex sodium product.
In the method for purifying sugammadex sodium, in the step (2), the adsorption is stirred adsorption, the stirring adsorption time is 0.1 to 24 hours, and the stirring adsorption temperature is 0 to 50 ℃.
In the method for purifying sugammadex sodium, in the step (2), the temperature for stirring and adsorbing is preferably 20 to 30 ℃.
In the method for purifying sugammadex sodium, preferably, in the step (1) and the step (2), the inert gas includes nitrogen and/or argon, and the water is purified water; in the second method in the step (1), the inert gas saturated water is nitrogen saturated water and/or argon saturated water, the nitrogen saturated water is nitrogen saturated purified water, and the argon saturated water is argon saturated purified water.
In the method for purifying sugammadex sodium, in the step (2), the evaporation to dryness includes reduced pressure evaporation to dryness, and the crystallization includes dropwise adding a poor solvent to crystallize out.
In the method for purifying sugammadex sodium, preferably, in the step (2), the poor solvent includes one or more of methanol, ethanol, acetone, acetonitrile and N, N-dimethylformamide.
In the purification method of the sugammadex sodium, the purity of the obtained sugammadex sodium is more than 99.5%, and the single impurity content is less than 0.1%.
In the invention, the filtration under the protection of inert gas comprises pressure filtration under the protection of inert gas and suction filtration under the protection of inert gas.
Compared with the prior art, the invention has the advantages that:
the sugammadex sodium is dissolved in water, pretreated active carbon aigret Z (CARBORAFIN) is added, the oxidization of the aigret Z (CARBORAFIN) is reduced through pretreatment, high-purity sugammadex sodium water solution is obtained through filtration after stirring, adsorption and purification, and high-purity sugammadex sodium is obtained through evaporation or crystallization precipitation. The purified sugammadex sodium of the invention has less than 0.1 percent of single impurity, the purity of more than 99.50 percent and very high purity. And the Egret Z (carborafin) activated carbon used in the invention is produced industrially, is easy to obtain, the pretreatment method is simple and convenient to operate, the cost is lower, and the purification of the sugammadex sodium by using the pretreated Egret Z (carborafin) has good industrial prospect.
In the pretreatment method of the aigret Z (carborafin) activated carbon, the first method and the second method are completely different from the treatment mode in the prior art, and the third method mainly aims at breakthrough of heating temperature and heating time and is greatly different from the prior art. The pretreatment method of the three kinds of activated carbon designed by the invention is mainly used for removing oxygen adsorbed in the activated carbon or other oxidizing impurities introduced in the production process of the activated carbon, the main essence of the pretreatment method is not activation mentioned in the prior art, but the deoxidation essence, the activation generally refers to the increase of the activity of reactants through pretreatment, and the essence of the pretreatment of the activated carbon is that the oxidation property of the activated carbon is too strong, so that sugammadex sodium generates larger oxidizing impurities, so the pretreatment method of the activated carbon is designed, the adsorption property of the activated carbon to the impurities is kept, and the oxidation property of the activated carbon is removed.
Drawings
FIG. 1 is an HPLC chart of sugammadex sodium obtained by the method for purifying sugammadex sodium of example 1 of the present invention.
FIG. 2 is an HPLC plot of sugammadex sodium obtained by the method of purifying sugammadex sodium of example 2 of the present invention.
FIG. 3 is an HPLC plot of sugammadex sodium obtained by the method of purifying sugammadex sodium of example 3 of the present invention.
Figure 4 is an HPLC plot of the sugammadex sodium obtained from the non-pretreated aigret Z purification of comparative example 1.
Figure 5 is an HPLC plot of the sugammadex sodium purified from a prior art pre-treated tailored aigrette of comparative example 2.
Figure 6 is an HPLC plot of the sugammadex sodium purified from prior art pretreated aigrette a of comparative example 3.
FIG. 7 is an HPLC plot of sulgammadex sodium purified from comparative example 4 pretreated pharmaceutical activated carbon (method one).
Detailed Description
The invention is further described below with reference to the drawings and specific preferred embodiments of the description, without thereby limiting the scope of protection of the invention. The materials and equipment used in the following examples are commercially available.
The crude sugammadex sodium used in the following examples is obtained by halogenating the hydroxyl group of gamma-cyclodextrin as known to those skilled in the art to obtain an intermediate 6-per-deoxy-6-per-halo-gamma-cyclodextrin, which is then reacted with 3-mercaptopropionic acid to obtain a crude product, or subjected to substitution reaction with 3-mercaptopropionate, and hydrolyzed to obtain a crude product, but is not limited thereto.
Example 1
The purification method of sugammadex sodium comprises the following steps:
(1) adding 5g of aigret Z (CARBORAFIN) activated carbon into a three-neck flask, adding 100mL of purified water into the three-neck flask, inserting a nitrogen pipe below the liquid level, continuously filling nitrogen at room temperature (20-30 ℃) and stirring for half an hour, performing suction filtration under the protection of nitrogen to obtain pretreated aigret Z (CARBORAFIN) activated carbon, filling nitrogen, sealing and storing.
(2) Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of pretreated aigret Z (CARBORAFIN) activated carbon obtained in the step (1), stirring and adsorbing for 1 hour at room temperature (20-30 ℃) under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 720mL of methanol into filtrate for crystallization, separating out solids, filtering and drying to obtain the sugammadex sodium, and detecting that the purity of the obtained sugammadex sodium is 99.653% (sugammadex sodium + monohydroxy sugammadex sodium), wherein an HPLC chart is shown in FIG. 1.
Example 2
The purification method of sugammadex sodium comprises the following steps:
(1) adding 5g of aigret Z (CARBORAFIN) activated carbon into a three-neck flask, adding 100mL of water into the flask, vacuumizing for nitrogen replacement, adding 0.5g of sodium thiosulfate at room temperature (20-30 ℃) under the protection of nitrogen, stirring for half an hour, performing suction filtration under the protection of nitrogen, washing a filter cake with 50mL of nitrogen saturated purified water, performing suction drying to obtain pretreated aigret Z (CARBORAFIN) activated carbon, filling nitrogen, sealing and storing.
(2) Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of pretreated aigret Z (CARBORAFIN) activated carbon obtained in the step (1), stirring and adsorbing at 20-30 ℃ for 1 hour under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 400mL of ethanol into filtrate for crystallization, separating out solids, filtering and drying to obtain the sugammadex sodium with the purity of 99.735% (sugammadex sodium + monohydroxysgammadex sodium), wherein an HPLC chart is shown in figure 2.
Example 3
The purification method of sugammadex sodium comprises the following steps:
(1) adding 5g of aigret Z (CARBORAFIN) activated carbon into a three-neck flask, adding 100mL of water into the flask, vacuumizing for three times, heating to 80-85 ℃ under the protection of nitrogen, keeping the temperature and stirring for half an hour, cooling to room temperature, performing suction filtration under the protection of nitrogen, drying to obtain the pretreated aigret Z (CARBORAFIN) activated carbon, and filling nitrogen, sealing and storing.
(2) Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of pretreated aigret Z (CARBORAFIN) activated carbon obtained in the step (1), stirring and adsorbing for 1 hour at room temperature (20 ℃ -30 ℃) under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 400mL of N, N-dimethylformamide into the filtrate for crystallization, separating out solids, filtering and drying to obtain the sugammadex sodium with the purity of 99.748% (sugammadex sodium + monohydroxy sugammadex sodium), wherein an HPLC chart is shown in FIG. 3.
Comparative example 1
Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of untreated aigret Z (CARBORAFIN) activated carbon, stirring and adsorbing for 1 hour at room temperature (20-30 ℃ C., the same below) under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 720mL of methanol into filtrate for crystallization, separating out solids, filtering and drying to obtain sugammadex sodium, and detecting that the purity of the obtained sugammadex sodium is 97.804% (sugammadex sodium + monohydroxy sugammadex sodium), wherein the HPLC chart is shown in FIG. 4.
Comparative example 2
Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of pretreated specially-made aigret (TOKUSEISHIRASAGI) activated carbon prepared by the method of CN107892727A, stirring and adsorbing for 1 hour at room temperature under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 720mL of methanol into filtrate for crystallization, separating out solids, filtering and drying to obtain sugammadex sodium, and detecting that the purity of the obtained sugammadex sodium is 99.694% (sugammadex sodium + monohydroxy sugammadex sodium), wherein an HPLC chart is shown in FIG. 5.
Comparative example 3
Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of pretreated aigret A (SHIRASAGI) activated carbon prepared by the method of CN107892727A, stirring and adsorbing for 1 hour at room temperature under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 720mL of methanol into the filtrate for crystallization, separating out solids, filtering and drying to obtain sugammadex sodium, and detecting that the purity of the obtained sugammadex sodium is 99.601% (sugammadex sodium + monohydroxysgammadex sodium), wherein an HPLC chart is shown in figure 6.
Comparative example 4
Adding 20g of crude sugammadex sodium into a 250mL flask, adding 80mL of purified water for dissolving, adding 4g of medicinal activated carbon obtained in the pretreatment mode 1 (pretreatment of the same example 1) in Shanghai activated carbon plants, stirring and adsorbing at room temperature for 1 hour under the protection of nitrogen, filtering to remove the activated carbon, dropwise adding 720mL of methanol into filtrate for crystallization, separating out solids, filtering and drying to obtain sugammadex sodium, and detecting that the purity of the obtained sugammadex sodium is 97.832% (sugammadex sodium + monohydroxysgammadex sodium), wherein an HPLC chart is shown in FIG. 7.
As can be seen from the above examples and comparative examples, the adsorption impurity removal effect of the Egret Z (CARBORAFIN) activated carbon pretreated by the method on sugammadex sodium is obviously superior to that of common medicinal activated carbon, and the adsorption impurity removal effect is equivalent to that of a special Egret and Egret A, or is slightly superior to that of the special Egret and Egret A. The aigret Z without pretreatment leads to an increase in oxidation impurities, resulting in a decrease in the purity of sugammadex sodium, and failure to obtain high purity sugammadex sodium.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make many possible variations and modifications to the disclosed embodiments, or equivalent modifications, without departing from the spirit and scope of the invention, using the methods and techniques disclosed above. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention are still within the scope of the protection of the technical solution of the present invention.
Claims (10)
1. A purification method of sugammadex sodium is characterized by comprising the following steps:
(1) carrying out pretreatment on the Egret Z (CARBORAFIN) activated carbon by adopting a first method, a second method or a third method:
the main process of the first method is as follows: adding the Egret Z (CARBORAFIN) active carbon into water, stirring and dispersing, then introducing inert gas while stirring at 10-50 ℃ to replace oxygen adsorbed by the active carbon, and then filtering under the protection of the inert gas to obtain pretreated Egret Z (CARBORAFIN) active carbon;
the main process of the second method is as follows: adding the active carbon of the aigret Z (carborafin) into water, stirring and dispersing, adding a reducing agent and stirring at the temperature of 10-50 ℃ under the protection of inert gas, then filtering under the protection of inert gas, and washing with saturated inert gas water to obtain pretreated active carbon of the aigret Z (carborafin);
the main process of the third method is as follows: adding the Egret Z (CARBORAFIN) active carbon into water, stirring and dispersing, then heating to 60-95 ℃ under the protection of inert gas, preserving heat for 0.1-5 h, cooling to room temperature, and filtering under the protection of inert gas to obtain pretreated Egret Z (CARBORAFIN) active carbon;
(2) mixing and dissolving the crude sugammadex sodium product and water, adding the pretreated aigret Z (carborafin) activated carbon obtained in the step (1), adsorbing under the protection of inert gas, filtering to remove the activated carbon after adsorption, and evaporating to dryness or crystallizing to separate out the sugammadex sodium.
2. The purification method of sugammadex sodium according to claim 1, wherein in the first method in step (1), the mass ratio of the aigrette Z (CARBORAFIN) activated carbon to water is 1: 1-500, and the inert gas is introduced while stirring for 0.1-24 h; in the second method in the step (1), the mass ratio of the Egret Z (CARBORAFIN) active carbon to the water is 1: 1-500, and the stirring time is 0.1-24 h; in the third method in the step (1), the mass ratio of the Egret Z (CARBORAFIN) activated carbon to the water is 1: 1-200, and the heat preservation time is 0.5-1 hour.
3. The purification method of sugammadex sodium according to claim 1, wherein in the second method of step (1), the reducing agent is one or more of sodium thiosulfate, sodium sulfite and sodium hydrosulfite, and the amount of the reducing agent added is 0.1-20% of the mass of the aigrette Z (CARBORAFIN) activated carbon.
4. The purification method of sugammadex sodium according to claim 1, wherein in the first, second and third methods of step (1), after obtaining the pre-treated Egret Z (CARBORAFIN) activated carbon, inert gas is filled and sealed for standby.
5. The method for purifying sugammadex sodium according to any one of claims 1 to 4, wherein in the step (2), the mass ratio of the crude sugammadex sodium to water is 1: 2 to 10, and the mass of the pretreated Egret Z (CARBORAFIN) activated carbon is 2 to 100 percent of the mass of the crude sugammadex sodium.
6. The purification method of sugammadex sodium according to claim 5, wherein in the step (2), the mass of the pretreated aigret Z (CARBORAFIN) activated carbon is 10-30% of the mass of the crude sugammadex sodium.
7. The purification method of sugammadex sodium according to any one of claims 1 to 4, wherein in the step (2), the adsorption is stirred adsorption, the stirring adsorption time is 0.1h to 24h, and the stirring adsorption temperature is 0 ℃ to 50 ℃.
8. The purification process of sugammadex sodium according to claim 7, wherein in step (2), the temperature of the agitation adsorption is 20 ℃ to 30 ℃.
9. The purification process of sugammadex sodium according to any one of claims 1 to 4, wherein in step (1) and step (2), the inert gas comprises nitrogen and/or argon, and the water is purified water; in the second method in the step (1), the inert gas saturated water is nitrogen saturated water and/or argon saturated water, the nitrogen saturated water is nitrogen saturated purified water, and the argon saturated water is argon saturated purified water.
10. The purification method of sugammadex sodium according to any one of claims 1 to 4, wherein in the step (2), the evaporation to dryness comprises reduced pressure evaporation to dryness, the crystallization comprises dropwise adding a poor solvent to crystallize out, and the poor solvent comprises one or more of methanol, ethanol, acetone, acetonitrile and N, N-dimethylformamide; and/or, in the step (2), the purity of the obtained sugammadex sodium is more than 99.5%, and the single impurity is less than 0.1%.
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| CN106565858A (en) * | 2016-10-13 | 2017-04-19 | 王炳永 | Purification method for sugammadex sodium |
| CN109021147A (en) * | 2017-06-08 | 2018-12-18 | 天津科伦药物研究有限公司 | A kind of purification process for the more glucose sodium that relaxes |
| CN107892727A (en) * | 2017-11-27 | 2018-04-10 | 合肥博思科创医药科技有限公司 | A kind of purification process for the more glucose sodium that relaxes |
| CN109438591A (en) * | 2018-12-29 | 2019-03-08 | 博瑞生物医药（苏州）股份有限公司 | The preparation process of easypro more glucose sodium |
| CN109553702A (en) * | 2018-12-29 | 2019-04-02 | 博瑞生物医药（苏州）股份有限公司 | A kind of purification process for the more glucose sodium that relaxes |
| CN110482548A (en) * | 2019-09-04 | 2019-11-22 | 中国科学院山西煤炭化学研究所 | A method of removing super capacitor active carbon oxygen-containing functional group |
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