CN113004437A - Method for reducing solvent residue in sugammadex sodium - Google Patents
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Abstract
The invention relates to a method for reducing solvent residues in sugammadex sodium. The method adopts mild conditions to remove the excessive and uncontrollable solvent residues in the product, thereby achieving the purpose of controlling the product quality. Through technical improvement, in a closed container filled with an aqueous medium, residual solvent in the product is replaced by moisture in the closed environment, so that the aim of removing the residual solvent is fulfilled. By adopting the technical scheme of the invention, the high-temperature material drying condition (more than 100 ℃) can be avoided, and the product degradation under the high-temperature condition can be prevented; the instability of the high-temperature material drying process control on the dissolution residue can be avoided; the technical scheme is simple to operate, and the solvent residue is removed completely.
Description
Technical Field
The invention relates to a method for reducing solvent residue in sugammadex sodium, belonging to the field of medicinal chemistry.
Background
Sugammadex Sodium (trade name BRIDION, Sugammadex Sodium, english) chemically named 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin Sodium. The sugammadex sodium is an improved gamma-cyclodextrin, is the first selective relaxation antagonist for reversing neuromuscular blocking agents, is clinically used for reversing the neuromuscular blocking effect of rocuronium or vecuronium, and has good curative effect and safety. The drug was approved for marketing in the European Union in 2008, and has been marketed in Japan, Korea, United states, and other countries, and has been declared for production and marketing in China.
The sugammadex sodium is in a large cyclic molecular structure and is provided with a cavity, a plurality of exposed hydroxyl groups are arranged in the molecule, hydrogen bonds can be formed with solvent molecules or the solvent molecules are directly wrapped in the cavity, and the conventional reduced pressure distillation drying method is difficult to control the residual solvent to be below the standard limit of ICH (International conference on harmonization for registration of human medicines).
Disclosure of Invention
The invention aims to provide a method for reducing solvent residues in sugammadex sodium, which adopts mild conditions to remove excessive and uncontrollable solvent residues (higher than ICH limit) in products, thereby achieving the purpose of controlling the product quality.
The inventor finds that by adopting a direct volatilization method, under the condition of high air humidity in the environment (the relative humidity is more than 75%), the sugammadex sodium is placed in the air for a certain time in an open mode, so that the solvent residue is reduced more, but the time when the sugammadex sodium is reduced to meet the requirement is difficult to determine, and when the air humidity is low, the solvent residue is reduced a little, but the solvent residue quality requirement is difficult to achieve; in addition, in the direct volatilization method, the environmental humidity is difficult to control, and the operation and the control are not facilitated.
Through technical improvement, the invention replaces residual solvent in the product by moisture in the closed environment in a closed container filled with aqueous medium, thereby achieving the purpose of removing the residual solvent. By adopting the technical scheme of the invention, the high-temperature material drying condition (more than 100 ℃) can be avoided, and the product degradation under the high-temperature condition can be prevented; the instability of the dissolved residue can be prevented from being controlled by a high-temperature material drying process or a direct volatilization method and the like; the technical scheme is simple to operate, and the solvent residue is removed completely.
The invention provides a method for reducing solvent residues in sugammadex sodium, which comprises the following steps: placing the sugammadex sodium in a closed container containing an aqueous medium, and replacing residual solvent in the sugammadex sodium by using moisture in a closed environment. The method is simple to operate, avoids high-temperature conditions, and can effectively prevent the sugammadex sodium from degrading.
The residual solvent capable of being reduced comprises one or more of methanol, ethanol, isopropanol, n-butanol, acetonitrile and acetone. In some embodiments, the residual solvent that can be reduced includes methanol; in some embodiments, the reducible residual solvent comprises ethanol; in some embodiments, the residual solvent that can be reduced includes acetonitrile; in some embodiments, the residual solvent that can be reduced comprises acetone.
In some embodiments, the aqueous medium comprises water, a brine solution, or an inert gas containing water. In some embodiments, the aqueous medium is water. In some embodiments, the aqueous medium is a saline solution. In some embodiments, the aqueous medium is wet nitrogen containing water. In some embodiments, the aqueous medium is wet carbon dioxide containing water. In some embodiments, the aqueous medium is aqueous wet argon.
In some embodiments, the aqueous medium is water, and the water is at a temperature of 20 ℃ to 100 ℃, or 20 ℃ to 75 ℃, or 75 ℃ to 100 ℃. In some embodiments, the water is at a temperature of 20 ℃ to 45 ℃; in some embodiments, the water is at a temperature of 45 ℃ to 75 ℃; in some embodiments, the temperature of the water is from 45 ℃ to 100 ℃. In some embodiments, the water is at a temperature of 20 ℃, 45 ℃, 75 ℃, or 100 ℃.
In some embodiments, sugammadex sodium is spread open in a tray of material and the moisture in the system is slowly displaced by the moisture in the air. The moisture content in the environment ranges from 20% to 100%. In some embodiments, the ambient moisture is in the range of 70% to 95%.
In some embodiments, sugammadex sodium is mixed with an amount of water (1% -500%), and the solvent in sugammadex sodium is replaced by the added water.
In some embodiments, the replacement of residual solvent in the product is accomplished by continuously feeding an aqueous inert gas into a dryer containing sugammadex sodium.
In some embodiments, the replacement of residual solvent in the product is accomplished by continuously introducing wet nitrogen or wet carbon dioxide or wet argon into a dryer containing sugammadex sodium.
In some embodiments, the saline solution comprises a saturated saline solution or an unsaturated saline solution. In some embodiments, the saline solution is a saturated saline solution. In some embodiments, the brine solution is an unsaturated brine solution.
In some embodiments, the aqueous salt solution comprises at least one selected from the group consisting of aqueous potassium chloride solution, aqueous potassium bromide solution, aqueous sodium chloride solution, aqueous sodium nitrate solution, aqueous potassium nitrate solution, aqueous sodium bromide solution, aqueous lithium acetate solution, aqueous ammonium sulfate solution, aqueous sodium benzoate solution, aqueous potassium sulfate solution, and aqueous disodium hydrogen phosphate solution. In some embodiments, the brine solution is an aqueous potassium chloride solution. In some embodiments, the brine solution is an aqueous potassium bromide solution. In some embodiments, the brine solution is an aqueous sodium chloride solution.
In some embodiments, the saturated aqueous salt solution includes at least one selected from the group consisting of a saturated aqueous solution of potassium chloride, a saturated aqueous solution of potassium bromide, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium nitrate, a saturated aqueous solution of potassium nitrate, a saturated aqueous solution of sodium bromide, a saturated aqueous solution of lithium acetate, a saturated aqueous solution of ammonium sulfate, a saturated aqueous solution of sodium benzoate, a saturated aqueous solution of potassium sulfate, and a saturated aqueous solution of disodium hydrogen phosphate. In some embodiments, the brine solution is a saturated aqueous solution of potassium chloride. In some embodiments, the brine solution is a saturated aqueous solution of potassium bromide. In some embodiments, the brine solution is a saturated aqueous solution of sodium chloride.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing saturated potassium chloride aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container filled with saturated potassium bromide aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing saturated sodium chloride aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing saturated aqueous solution of sodium nitrate, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing a saturated potassium nitrate aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container filled with saturated aqueous solution of sodium bromide, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container filled with lithium acetate saturated aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing saturated aqueous solution of ammonium sulfate, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container filled with saturated sodium benzoate aqueous solution, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container containing saturated aqueous solution of disodium hydrogen phosphate, and replacing ethanol or methanol residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing sugammadex sodium in a closed container filled with saturated potassium sulfate aqueous solution, and replacing ethanol, methanol, acetonitrile or acetone residue in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing the sugammadex sodium in a closed container containing hot water at 75 ℃, and replacing residual ethanol or residual methanol in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing the sugammadex sodium in a closed container containing water at 20 ℃, and replacing residual ethanol or residual methanol in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing the sugammadex sodium in a closed container containing hot water at 45 ℃, and replacing residual ethanol or residual methanol in the sugammadex sodium by using moisture in a closed environment.
In some embodiments, a method of reducing solvent residue in sugammadex sodium, comprising: placing the sugammadex sodium in a closed container containing hot water at 100 ℃, and replacing residual ethanol or residual methanol in the sugammadex sodium by using moisture in a closed environment.
The method for reducing the solvent residue in the sugammadex sodium is used for reducing the dissolved residue of the sugammadex sodium per 1g, and the dosage of the aqueous medium is 80-250 ml.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
In the invention, the DEG C is centigrade degree; m is rice; mm means millimeter; cm means centimeter; μ m means micron; mg means mg; mL means mL; (ii) a h means hours; min means minutes; hz means Hz; ppm refers to parts per million (1 ppm-parts per million); DMSO refers to dimethyl sulfoxide.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
Instrument parameters, test conditions and characterization results
Instrument information:
gas chromatograph-Agilent 7890A-7697A
Solvent residue determination method
TABLE 1 Shugammadex sodium solvent residue test chromatography method
In the following examples, the same batch of crude sugammadex sodium was used. The loss on drying by reduced pressure drying is less than 10%, and the residual moisture can be as high as 10% according to the properties of the product.
Example 1
Preparing saturated aqueous solution of potassium chloride, placing 1000-1700ml of the saturated aqueous solution of potassium chloride in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. And (3) placing 10g of crude sugammadex sodium into a dryer for 48h, transferring the sample into a reduced pressure drying oven, and drying for 24h at 75 ℃ under reduced pressure until the drying weight loss is below 10%.
Example 2
Preparing a saturated potassium bromide aqueous solution, placing 1000-1700ml of the saturated potassium bromide aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. 10g of sugammadex sodium is put into a dryer and placed for 48h, and then a sample is transferred into a reduced pressure drying oven and dried for 24h under the reduced pressure at the temperature of 75 ℃ until the drying weight loss is below 10 percent.
Example 3
Preparing a saturated sodium chloride aqueous solution, placing 1000-1700ml of the saturated sodium chloride aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. 10g of sugammadex sodium is put into a dryer and placed for 48h, and then a sample is transferred into a reduced pressure drying oven and dried for 24h under the reduced pressure at the temperature of 75 ℃ until the drying weight loss is below 10 percent.
Example 4
Preparing a saturated sodium bromide aqueous solution, placing 1000-1700ml of the saturated sodium bromide aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 5 days, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 5
Preparing a saturated lithium acetate aqueous solution, placing 1000-1700ml of the saturated lithium acetate aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 3 days, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 6
Preparing saturated aqueous solution of ammonium sulfate, placing 1000-1700ml of the saturated aqueous solution of ammonium sulfate in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 24 hours, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 7
Preparing saturated aqueous solution of sodium benzoate, placing 1000-1700ml of saturated aqueous solution of sodium benzoate in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 24 hours, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 8
Preparing a saturated potassium nitrate aqueous solution, placing 1000-1700ml of the saturated potassium nitrate aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 24 hours, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 9
Preparing saturated aqueous solution of disodium hydrogen phosphate, placing 1000-1700ml of the saturated aqueous solution of disodium hydrogen phosphate in a drier with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 24 hours, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 10
Preparing saturated potassium sulfate aqueous solution, placing 1000-1700ml of the saturated potassium sulfate aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. After 10g of sugammadex sodium is put into a dryer and placed for 24 hours, a sample is transferred into a reduced pressure drying oven and dried for 24 hours under reduced pressure at 75 ℃ until the drying weight loss is below 10%.
Example 11
Preparing saturated potassium sulfate aqueous solution, placing 1000-1700ml of the saturated potassium sulfate aqueous solution in a dryer with the diameter of 25-30cm (ensuring that the liquid level of the solution is not higher than the sample), and balancing for 5-16h until the humidity is constant. 10g of sugammadex sodium is put into a dryer and placed for 48h, and then a sample is transferred into a reduced pressure drying oven and dried for 24h under the reduced pressure at the temperature of 75 ℃ until the drying weight loss is below 10 percent.
Example 12
Adding 800-1000ml of hot water at 75 ℃ into a dryer of 25-30cm (ensuring that the liquid level of the hot water is not higher than that of the sample), paving 10g of sugammadex sample in a material tray in the dryer, sealing, placing for 9h, transferring the sample into a reduced-pressure drying box, and drying at 75 ℃ for 24h under reduced pressure until the loss on drying is below 10%.
Example 13
Adding 800-1000ml of water with the temperature of 20 ℃ into a dryer with the length of 25-30cm (ensuring that the liquid level of the water is not higher than that of the sample), paving 5g of a sugammadex sample in a material tray in the dryer, sealing, placing for 7 days, transferring the sample into a reduced-pressure drying box, and drying for 24 hours at the temperature of 75 ℃ under reduced pressure until the loss on drying is below 10%.
Example 14
Adding 800-1000ml of hot water at 45 ℃ into a dryer of 25-30cm (ensuring that the liquid level of the hot water is not higher than that of the sample), paving 5g of the sugammadex sample in a material tray in the dryer, sealing, placing the dryer in an oil bath at 45 ℃, standing for 16h, transferring the sample into a reduced-pressure drying box, and drying at 75 ℃ for 24h under reduced pressure until the drying weight loss is below 10%.
Example 15
Adding 1000ml of hot water at 100 ℃ of 800-30 cm into a dryer (the liquid level of the hot water is ensured not to be higher than that of the sample), paving 5g of sodium sugammadex sample in a material tray in the dryer, sealing, changing the hot water every 15min, placing for 3h, transferring the sample into a reduced pressure drying box, and drying under reduced pressure at 75 ℃ for 24h until the drying weight loss is below 10%.
The results of the determination of solvent residue for the crude sugammadex sodium and the product of examples 1-15 are shown in tables 2-4.
Table 2 in the examples ethanol residue determination results for sugammadex sodium product
Table 3 results of acetonitrile and acetone residue measurements of crude sugammadex sodium and product in examples
Table 4 results of methanol residue measurement of crude sugammadex sodium and product in examples
As can be seen from tables 2-4, the sugammadex bulk drug is placed in a closed container filled with an aqueous medium, and the residual solvent in the sugammadex bulk drug is replaced by moisture in a closed environment, so that the effect of effectively reducing the residual solvent can be achieved.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method for reducing solvent residue in sugammadex sodium, comprising: placing the sugammadex sodium in a closed container containing an aqueous medium, and replacing residual solvent in the sugammadex sodium by using moisture in a closed environment.
2. The method of claim 1, wherein the solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, acetonitrile, acetone.
3. The method of claim 1, wherein the aqueous medium comprises water, a brine solution, or an aqueous inert gas.
4. A method according to claim 1 or 3, wherein the aqueous medium is water, and the temperature of the water is 20 ℃ to 100 ℃, or 75 ℃, or 45 ℃.
5. A method according to claim 1 or 3, characterized in that the aqueous medium is wet nitrogen containing water.
6. The method of claim 3, wherein the saline solution comprises a saturated saline solution or an unsaturated saline solution.
7. The method according to claim 3 or 6, wherein the aqueous salt solution comprises at least one selected from the group consisting of an aqueous potassium chloride solution, an aqueous potassium bromide solution, an aqueous sodium chloride solution, an aqueous sodium nitrate solution, an aqueous potassium nitrate solution, an aqueous sodium bromide solution, an aqueous lithium acetate solution, an aqueous ammonium sulfate solution, an aqueous sodium benzoate solution, an aqueous potassium sulfate solution, and an aqueous disodium hydrogen phosphate solution.
8. The method according to claim 6, wherein the saturated aqueous salt solution comprises at least one selected from the group consisting of a saturated aqueous solution of potassium chloride, a saturated aqueous solution of potassium bromide, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium nitrate, a saturated aqueous solution of potassium nitrate, a saturated aqueous solution of sodium bromide, a saturated aqueous solution of lithium acetate, a saturated aqueous solution of ammonium sulfate, a saturated aqueous solution of sodium benzoate, a saturated aqueous solution of potassium sulfate, and a saturated aqueous solution of disodium hydrogen phosphate.
9. The method of claim 1, comprising: placing the sugammadex sodium in a closed container containing a potassium chloride saturated aqueous solution or a sodium chloride saturated aqueous solution, and replacing residual ethanol or residual methanol in the sugammadex sodium by using moisture in a closed environment; or comprises the following steps: placing the sugammadex sodium in a closed container containing hot water at 45 ℃, and replacing residual methanol in the sugammadex sodium by using moisture in a closed environment; or comprises the following steps: placing the sugammadex sodium in a closed container containing saturated potassium sulfate aqueous solution, and replacing residual acetonitrile or residual acetone in the sugammadex sodium by using moisture in a closed environment; or comprises the following steps: placing the sugammadex sodium in a closed container containing hot water at 75 ℃, and replacing residual ethanol in the sugammadex sodium by using moisture in a closed environment.
10. The method according to any one of claims 1 to 9, wherein the aqueous medium is water or an aqueous salt solution, the amount of the aqueous medium being 80 to 250ml per 1g of sugammadex sodium required to reduce the solvent residue.
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CN105348412A (en) * | 2014-08-22 | 2016-02-24 | 江苏恩华药业股份有限公司 | Method for purifying sugammadex sodium |
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CN103145875A (en) * | 2012-12-07 | 2013-06-12 | 青岛九龙生物医药有限公司 | Technique of reducing organic solvent residue in heparin sodium |
CN105348412A (en) * | 2014-08-22 | 2016-02-24 | 江苏恩华药业股份有限公司 | Method for purifying sugammadex sodium |
CN108929389A (en) * | 2017-05-23 | 2018-12-04 | 合肥博思科创医药科技有限公司 | A kind of environmentally protective easypro more glucose sodium preparation method |
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 |
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