CN108456264B

CN108456264B - Method for purifying sugammadex sodium

Info

Publication number: CN108456264B
Application number: CN201810153493.0A
Authority: CN
Inventors: 梅杰; 姜立志; 周大勇; 田伟伟
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2017-02-22
Filing date: 2018-02-22
Publication date: 2021-10-08
Anticipated expiration: 2038-02-22
Also published as: CN108456264A

Abstract

The invention provides a purification method of sugammadex sodium. Specifically, the purification method comprises: and (3) loading the crude sugammadex sodium onto a chromatographic column with silica gel C18 as a filler for purification, wherein the purity of the obtained sugammadex is more than 99%. The method of the invention can not only ensure the quality of the product, but also is suitable for the process scale-up production.

Description

Method for purifying sugammadex sodium

Technical Field

The invention relates to a purification method of sugammadex sodium, and particularly relates to a method for separating and purifying a crude sugammadex sodium product by using a chromatographic column with silica gel C18 as a filler to obtain high-purity sugammadex sodium.

Background

Sugammadex sodium is a derivative of gamma-cyclodextrin, the molecule of which consists of a lipophilic core and a hydrophilic outer end, and is a selective muscle relaxant antagonist with the chemical name: 6-Perdeoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin sodium salt (octasodium salt) having the following structural formula:

the sugammadex sodium is used for reversing the action of a neuromuscular blocking drug rocuronium bromide or vecuronium bromide which is conventionally used, and can immediately reverse the action of rocuronium bromide which is conventionally used by adults and the action of rocuronium bromide which is conventionally used by children and teenagers (2-17 years old). Sugammadex sodium is the first and only selective relaxant binder, the first major pharmaceutical advance in the field of narcotics for 20 years, known as a milestone muscle relaxation antagonist and approved for sale in the united states in 2015.

In recent years, with the development of preparation or purification techniques, technicians developed various sugammadex sodium purification processes. CN1402737 discloses a method for purifying sugammadex sodium by dialysis, but dialysis requires a large amount of water, generates a large amount of waste liquid, is not environment-friendly, and has a low yield of only 34%.

WO2012025937 reports the preparation of purified sugammadex sodium using silica gel chromatography column and gel column Sephadex G-25; WO2013037994 develops a new adsorbent of solid support material and uses the adsorbent as the solid phase of a chromatographic column to obtain high quality sugammadex sodium.

On the other hand, the skilled person has also developed the purification of sugammadex sodium by solvent recrystallization, such as WO2014125501, CN104844732A, CN105273095A, and the solvent systems used for purification are: methanol/water, ethanol/water, or N, N-dimethylamide/water, etc.; meanwhile, CN105348412A reports that after sugammadex sodium salt is converted to sugammadex ammonium salt, high purity sugammadex ammonium salt is obtained by recrystallization with ethanol and then converted to sodium salt form.

Although the above documents already give various purification ideas, sugammadex sodium has a complex structure and contains a plurality of chiral centers, especially gamma-cyclodextrin structural analogs are more, and the above methods are more or less defective, and can not provide high-purity sugammadex sodium, and simultaneously meet the requirement of industrial mass production. Therefore, there is a need to develop a purification method that is efficient and suitable for industrial production of sugammadex sodium.

Disclosure of Invention

The invention provides a method for purifying sugammadex sodium, which comprises the following steps: the crude sugammadex sodium is loaded on a chromatographic column with silica gel C18 as a filler, and a sample eluent is collected after elution, wherein the purity of the sugammadex sodium in the sample eluent is more than 99%, and in embodiments, the purity can be 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or more.

Wherein the particle size of the silica gel C18 filler is 5-60 mu m, and the specific surface area is 100-300 m²The particle diameter of the polystyrene polymer is 20-100 mu m, and the specific surface area is 500-1200 m²/g。

In embodiments, the silica C18 chromatography column is eluted with acetonitrile/water solution, wherein the acetonitrile content is 10-30%, preferably 15-25%, and may be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25%, more preferably 18-22%. In embodiments, the elution may be performed by separately pumping water and acetonitrile through an A, B line to a silica gel C18 chromatography column.

In order to reduce the adsorption of sugammadex on the silica gel C18 and ensure the purification effect and yield, the acetonitrile/water solvent of the invention also contains acid which is known or can be determined by those skilled in the art and is selected from but not limited to formic acid, acetic acid, trifluoroacetic acid, phosphoric acid and hydrochloric acid, and preferably formic acid. Further, the concentration of the acid in the acetonitrile/water solvent is 0.1-0.5 wt.%, preferably 0.12-0.2 wt.%, and may be 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20 wt.%.

On the other hand, the skilled person also examines the eluent flow rate, and finds that the purifying effect of the eluent flow rate in the purifying process is not greatly influenced, but the size (inner diameter) of the column needs to be considered at the same time to avoid the damage of the silica gel column caused by the too fast flow rate. In the embodiment, the flow rate of the eluent is controlled to be 1L/min-1.5L/min (the inner diameter of the column is 200mm), and can be 1, 1.1, 1.2, 1.3, 1.4 or 1.5L/min; preferably 1.1-1.3L/min, if the inner diameter of the column is reduced, the flow rate of the eluent also needs to be correspondingly reduced.

During the sugammadex purification process, the skilled person found that removal of impurity E (retention time 22.28min) was the key point of the whole purification process, and the maximum threshold for purification of impurity E was determined by a number of comparative experiments. When the content of the impurity E in the crude product is less than or equal to 1 percent, the content of the impurity E can be reduced to be less than 0.5 percent through a silica gel C18 chromatographic column, thereby meeting the quality standard of the bulk drugs. Further, the impurity content is less than or equal to 0.6%, and can be less than 0.05% by purification on a silica gel C18 column, and in embodiments can be 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, or 0.

When the content of the impurity E in the crude product is more than 1 percent, the purification by a silica gel C18 chromatographic column cannot meet the requirement that the content of the impurity in the raw material medicine is less than 0.1 percent according to the quality standard. In order to solve this technical problem, the skilled person uses a methacrylate ion exchange resin to remove the impurity E, i.e. the purification method according to the present invention further comprises a step of eluting and purifying through a methacrylate ion exchange resin. In embodiments, the step of purifying by elution with a methacrylate ion exchange resin may be before purification on a silica gel C18 column or after purification on a silica gel C18 column.

In some embodiments, the methacrylate ion exchange resin is eluted with a sodium chloride solution, resulting in an eluate having a purity of greater than or equal to 80% of sugammadex sodium, wherein the impurity E content is less than or equal to 0.1%, and can be 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01%, or 0; further, the purity of sugammadex sodium in the eluent is greater than or equal to 90%, and can be greater than or equal to 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and preferably greater than or equal to 95%.

The concentration of the sodium chloride solution is 0.1-1M (mol/L), and can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1M, and preferably 0.5M.

The methacrylate ion exchange resin has a methacrylate skeleton with surface hydrophilic property, has good resin rigidity, and comprises Toyopearl GigaCap S-650M, Toyopearl GigaCap CM-650M, Toyopearl GigaCap Q-650M and Toyopearl GigaCap DEAE-650M, preferably Toyopearl GigaCap DEAE-650M (DEAE-650M for short).

In an embodiment, in order to avoid the influence of inorganic impurities on the chromatographic effect and the elution rate, the crude sugammadex sodium product needs to be filtered through a filter membrane, and the pore size of the filter membrane is 0.2 to 10 μm, preferably 0.3 to 5 μm, and can be 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 μm.

The purification method comprises the following steps:

a) loading the crude sugammadex sodium on methacrylate ion exchange resin, eluting and purifying by using sodium chloride solution, wherein the methacrylate ion exchange resin is preferably DEAE-650M;

b) loading the eluent obtained in the step a) on a silica gel C18 chromatographic column, eluting with acetonitrile/water solution, and collecting a sample eluent;

wherein the acetonitrile content is 10-30%, preferably 15-25%, and can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25%, more preferably 18-22%. In embodiments, water and acetonitrile may be pumped separately through A, B lines to a silica gel C18 chromatography column for elution.

Further, before the step b), filtering the eluent obtained in the step a) by a filter membrane to remove inorganic impurities in the solution, wherein the pore diameter of the filter membrane is 0.2-10 μm, preferably 0.3-5 μm, and can be 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 μm.

Further, the sample eluent is concentrated to obtain the finished product of sugammadex sodium.

The silica gel C18 of the present invention is an octadecyl bonded silica gel filler selected from, but not limited to, ACCHROM from Hua Spectrum, DYPM952, DYB71306, DYB7129 from Shanghai Dai Spectrum technology, Unisil C18 from Nami, Welch Ultimate XB-C18 from Yuxu, and DYPM952 from Dai Spectrum technology.

The Capto Q imprmes and Capto SP imprmes described in the present invention are strong anion and strong cation exchangers for high throughput purification of recombinant proteins, average particle size: 40 μm, matrix: high flow agarose, ligand: SP-sulfonate group, Q-quaternary ammonium group.

The content of the solvent (such as acetonitrile content) in the invention represents the volume percentage of acetonitrile in the solution; in the present invention, wt% (weight percentage) is (mass of B/mass of a + mass of B) × 100%.

The silica gel C18 or methacrylate ion exchange resin of the present invention requires activation prior to use, and the activation method is well known to those skilled in the art or can be determined, for example, the activation method of silica gel C18 can be described in example 2, and the activation method of methacrylate ion exchange resin can be described in example 4.

The type and the elution mode of the mobile phase used for eluting the resin or the silica gel C18 in the invention need to be selected according to respective attributes, and the judgment on whether the resin or the silica gel C18 can purify the sugammadex sodium is not influenced.

The crude sugammadex sodium of the present invention is prepared according to methods known in the art and can be obtained by referring to the method described in the examples of WO2012025937, and the silica gel C18, Source 15Q and other resins of the present invention are commercially available.

The purity or the content of the sample is obtained by HPLC detection; the detection conditions are as follows: column YMC ODS-AQ C18 (150X 3.0mm, 3 μm); the detection wavelength is 200 nm; diammonium phosphate solution or acetonitrile is used as a mobile phase.

The retention time of the sugammadex sodium is about 20.16min, and the retention time of the impurity E is about 22.28 min. In the present invention, the relative retention time is (impurity peak retention time)/(main peak retention time), and the relative retention time of the impurity E is 1.1.

Detailed Description

The invention is further described below by way of examples, without limiting the scope of the invention in any way.

Example 1: preparation of crude sugammadex sodium

3.50kg of gamma-cyclodextrin is placed in a vacuum drying oven I, dried for 10-12 h at the temperature of 95 ℃ and the vacuum degree of less than or equal to-0.08 MPa, and filled into a double-layer plastic bag for later use.

Adding 9.12kg of triphenylphosphine and 35kg of DMF into a 100L reaction kettle, stirring and dissolving under the protection of nitrogen, cooling to-15 ℃, dropwise adding an iodine DMF solution (9.14kg of DMF is dissolved in 11kg of DMF), continuously stirring for 0.5-1 h after dropwise adding, then adding 3.00kg of dried gamma-cyclodextrin, controlling the process temperature to be not more than 0 ℃, and heating and stirring for reaction. And cooling the system, dropwise adding a methanol solution of sodium methoxide (2.18kg of sodium methoxide is dissolved in 8kg of methanol), stirring for 0.5-1 h after dropwise adding, and transferring the material solution to a 50L plastic bucket.

And pumping 300kg of purified water into a 500L reaction kettle II, dripping the material solution in the plastic barrel into the reaction kettle II, stirring for 0-15 min after dripping, performing spin filtration, washing three times with 30kg of purified water and three times with 24kg of acetone. Transferring the solid to a 50L reaction kettle III, adding 8kg of industrial DMF to dissolve the solid, dripping 20kg of acetone at 45-55 ℃, naturally cooling to room temperature, and filtering; the dissolution, elution and filtration process was repeated twice more. Drying at 70 ℃ for 23-24 h under vacuum degree to obtain the intermediate gamma-ICD, wherein the yield ranges from 3.0 kg to 3.5kg, and the yield ranges from 59.6% to 69.5%.

Adding 34kg of chromatographic pure DMF into a 200L reaction kettle IV, adding 0.76kg of NaH under stirring, cooling to-5 ℃, dropwise adding a DMF solution of 3-mercaptopropionic acid (1.53kg of DMF dissolved in 10kg of chromatographic pure DMF), and stirring for 1-2 h at room temperature after dropwise adding. And (3) dropwise adding a DMF solution of the intermediate gamma-ICD (the gamma-ICD obtained in the previous step is dissolved in 44kg of chromatographic pure DMF) at room temperature, and heating to 65 ℃ for reaction after dropwise adding. Cooling, dropwise adding 26kg of purified water to quench the reaction, stirring at room temperature, filtering, dissolving with 30kg of purified water, transferring to a 200L reaction kettle V, adding 86kg of industrial DMF to elute, filtering and drying to obtain the crude product of the sugammadex sodium, wherein the yield is 1.2kg, the yield is 34.3%, the purity is 90.22% and the content of the impurity E is 0.77%.

Example 2:

filling a preparation column: 1.2kg of silica gel C18 filler (20 μm particle size,

) Wetting with 2.4L of isopropanol, loading into a column tube of a preparation column, adopting dynamic axial compression to ensure that the loading pressure reaches 80-100 Bar, and using ethanol with 5-10 times CV (column volume) as a mobile phase to wash the preparation column for later use.

10g of the crude sugammadex sodium of example 1 are dissolved in 100ml of purified water, filtered through a 0.45 μm filter, and water is added to the system to 500ml and the pH is adjusted to acidic.

The solution was loaded onto a preparative column and 0.15% aqueous formic acid and acetonitrile were pumped separately through A, B tubing to the column for elution, maintaining the acetonitrile content at 21%. The main peak eluted is divided into different fractions, qualified fractions are combined and concentrated to obtain 3.7g of sugammadex sodium, the yield is 41%, the purity is 98.81%, and the content of impurity E is 0.21%.

Example 3:

the preparative column was packed for use according to example 2

10g of crude sugammadex sodium (purity 89.28%, content of E impurity 0.60%) was dissolved in 100ml of purified water, filtered through a 0.45 μm filter, and water was added to the system to 500ml and pH was adjusted to acidity.

The solution was loaded onto a preparative column and 0.15% aqueous formic acid and acetonitrile were pumped separately through A, B tubing to the column for elution, maintaining the acetonitrile content at 21%. The main peak eluted is divided into different fractions, the qualified fractions are combined and concentrated to obtain 3.6g of sugammadex sodium with the yield of 40 percent and the purity of 99.01 percent, and the content of the impurity E is 0.05 percent.

Example 4:

loading a DEAE-650M chromatographic column: : 2kg of DEAE-650M resin was poured into a glass column, and DEAE-650M resin was activated with purified water, 0.5M sodium hydroxide, and sodium chloride solution for use.

About 1.2kg of crude sugammadex sodium (purity 90.22%, content of impurity E is 0.77%) is dissolved in 30kg of water, and a sample solution is uniformly stirred, loaded onto the DEAE chromatographic column, eluted by 0.5M sodium chloride solution, and eluates are respectively collected, and are combined and collected after detection, the purity is 96.76%, the yield is 95%, and the impurity E is not detected.

Example 5:

loading a DEAE-650M chromatographic column: 2kg of DEAE-650M resin was poured into a glass column, and DEAE-650M was activated with purified water, 0.5M sodium hydroxide, and sodium chloride solution for use.

About 1.2kg of crude sugammadex sodium (purity 92.21, impurity E content 1.5%) is dissolved in 30kg of water, a sample solution is uniformly stirred, the sample solution is loaded to the DEAE-650M chromatographic column, 0.5M sodium chloride solution is used for elution, eluents are respectively collected, the sugammadex sodium-containing solution is collected, and the sample purity 96.89%, the yield 93% and the impurity E content 0.03% are obtained by concentration.

Example 6:

loading a DEAE-650M chromatographic column: 2kg of DEAE-650M resin was poured into a glass column, and DEAE-650M resin was activated with purified water, 0.5M sodium hydroxide, and sodium chloride solution for use.

About 1.2kg of crude sugammadex sodium (purity 92.21, impurity E content 0.92%) is dissolved in 30kg of water, and a sample solution is uniformly stirred, loaded onto the DEAE-650M chromatographic column, eluted by 0.5M sodium chloride solution, and the sugammadex sodium-containing solution is collected and concentrated to obtain a sample with purity of 97.01%, yield of 95% and impurity E content of 0.02%.

Example 7:

filling a preparation column: 4.8 to 5.0kg of silica gel C18 filler (particle size of 20 μm,

) Wetting with 10L of ethanol, loading into a column tube of a preparation column, adopting dynamic axial compression to ensure that the loading pressure reaches 80-100 Bar, and using 5-10 times CV (column volume) of ethanol as a mobile phase to wash the preparation column for later use.

The receiving solution (purity 96.89%, no impurity E detected) in example 4 was adjusted with formic acid to pH 3-4, and acetonitrile was added so that the ratio of the feed solution to acetonitrile was 81:19, after filtration through a 0.45 μm organic membrane, the solution was loaded four times onto a preparative column, and 0.15% formic acid aqueous solution and acetonitrile were pumped to a chromatographic column through a A, B line for elution, respectively, keeping the acetonitrile content at 21%. Dividing the eluted main peak into different fractions, merging qualified fractions, and concentrating to obtain sugammadex sodium with purity of 99.07%, yield of 75% and no impurity E.

Example 8:

source 15Q chromatography columns (4.6 x 100mm) were packed for future use

Approximately 40mg of crude sugammadex sodium (purity 92.21%, impurity E content 1.5%) was dissolved in 30ml of water, loaded onto an ion exchange column and purified with mobile phase a: purified water, mobile phase B: gradient elution is carried out on 1M sodium chloride aqueous solution, the sugammadex-containing solution is collected and concentrated to obtain the product with the purity of 94.21 percent and the content of impurity E of 0.86 percent.

Example 9:

capto Q Impres ion exchange columns (4.6 x 100mm) were packed for use

Approximately 40mg of crude sugammadex sodium (purity 92.21%, impurity E content 1.5%) was dissolved in 300ml of water, loaded onto an ion exchange column and purified with mobile phase a: purified water, mobile phase B: gradient elution is carried out on 1M sodium chloride aqueous solution, the sugammadex-containing solution is collected by HPLC detection, and the purity of the sample is 95.21 percent and the content of the impurity E is 0.73 percent by concentration.

Example 10:

packing 001 x 7 cation exchange column and D001 anion exchange column separately for future use

About 40mg of crude sugammadex sodium (purity 93.21%, content of impurity E is 0.21%) is dissolved in 300ml of water, then the sample solution is sequentially passed through a 001 × 7 cation exchange column and a D001 anion exchange column, and is eluted by purified water, the sugammadex sodium-containing solution is collected by HPLC detection, and is concentrated to obtain the sample purity 94.09%, and the content of impurity E is 0.20%.

Example 11:

sephadex G-25 gel column (4.6 x 100mm) was packed for future use

About 50mg of crude sugammadex sodium (purity 90.21, impurity E content 1.0%) was dissolved in 30ml of water, loaded onto an ion exchange column, eluted with purified water, the sugammadex sodium-containing solution was collected and concentrated to a sample purity of 92.21% and impurity E content of 0.76%.

Example 12:

the preparative column was packed for use according to example 2

10g of crude sugammadex sodium (purity 90.03%, content of E impurity 1.02%) was dissolved in 100ml of purified water, filtered through a 0.45 μm filter, and water was added to the system to 500ml and pH was adjusted to acidity.

The solution was loaded onto a preparative column and 0.15% aqueous formic acid and acetonitrile were pumped separately through A, B tubing to the column for elution, maintaining the acetonitrile content at 21%. Dividing the eluted main peak into different fractions, merging qualified fractions, and concentrating to obtain sugammadex sodium with purity of 98.92% and impurity E content of 0.5%.

Table 1: example correlation material data summarization

And (4) conclusion:

1. from the crude purification data in examples 2,4-11, DEAE-650M resin and silica gel C18 have good purification effect on impurity E, especially DEAE-650M resin can reduce impurity E from 1.5% to 0.03%, and other types of resin or gel column can only reduce impurity E to about 0.7%, and can not meet the quality standard of sugammadex as the raw material drug;

2. the silica gel C18 has a certain purification effect on the impurity E in the crude sugammadex sodium product, and when the impurity E in the crude product is 1.02%, the silica gel C18 cannot reduce the impurity E to below 0.05%, so that the quality standard of the raw material medicine is met.

Claims

1. A method for purifying sugammadex sodium, comprising:

a) loading the crude sugammadex sodium on methacrylate ion exchange resin, and eluting and purifying by using sodium chloride solution;

b) loading the eluent obtained in the step a) on a silica gel C18 chromatographic column, eluting with acetonitrile/water solution, and collecting the sample eluent, wherein the acetonitrile content is 10-30%; the acetonitrile/water solution also contains acid, and the acid is selected from formic acid, acetic acid, trifluoroacetic acid, phosphoric acid and hydrochloric acid; the concentration of the acid is 0.1-0.5 wt.%; the acetonitrile content is given in volume percent.

2. The purification method according to claim 1, wherein the acetonitrile content is 15 to 25%.

3. The purification method according to claim 2, wherein the acetonitrile content is 18 to 22%.

4. The purification process according to any one of claims 1 to 3, wherein the acid is selected from formic acid; the concentration of the acid is 0.12-0.2 wt.%.

5. The purification process according to any one of claims 1 to 3, further comprising a filtration step of the crude sugammadex sodium through a filter membrane.

6. The purification method according to claim 5, wherein the pore size of the filter membrane is 0.2 to 10 μm.

7. The purification method according to claim 6, wherein the pore size of the filter membrane is 0.3 to 5 μm.

8. The purification process according to any one of claims 1 to 3, wherein the flow rate of the eluate in the step a) is 1 to 1.5L/min.

9. The purification method according to claim 5, wherein the flow rate of the eluent in the step a) is 1-1.5L/min.

10. The purification process according to any one of claims 1 to 3, wherein the methacrylate ion exchange resin is selected from the group consisting of DEAE-650M; the purity of the sugammadex sodium in the eluent in the step a) is more than or equal to 80 percent.

11. The purification process according to claim 5, wherein the methacrylate ion exchange resin is selected from the group consisting of DEAE-650M; the purity of the sugammadex sodium in the eluent in the step a) is more than or equal to 80 percent.

12. The purification process according to claim 8, wherein the methacrylate ion exchange resin is selected from the group consisting of DEAE-650M; the purity of the sugammadex sodium in the eluent in the step a) is more than or equal to 80 percent.

13. The purification method according to any one of claims 1 to 3, wherein the concentration of the sodium chloride solution is 0.1 to 1M.

14. The purification method according to claim 5, wherein the concentration of the sodium chloride solution is 0.1 to 1M.

15. The purification method according to claim 8, wherein the concentration of the sodium chloride solution is 0.1 to 1M.

16. The purification method according to claim 10, wherein the concentration of the sodium chloride solution is 0.1 to 1M.

17. The purification process according to claim 13, wherein the sodium chloride solution has a concentration of 0.5M.

18. The purification process according to any one of claims 14 to 16, wherein the sodium chloride solution has a concentration of 0.5M.

19. The purification process according to any one of claims 1 to 3, wherein the purity of sugammadex sodium in the eluate of step a) is greater than or equal to 90%.

20. The purification process according to claim 5, wherein the purity of sugammadex sodium in the eluate from step a) is greater than or equal to 90%.

21. The purification process according to claim 8, wherein the purity of sugammadex sodium in the eluate from step a) is greater than or equal to 90%.

22. The purification process according to claim 10, wherein the purity of sugammadex sodium in the eluate from step a) is greater than or equal to 90%.

23. The purification process according to claim 13, wherein the purity of sugammadex sodium in the eluate from step a) is greater than or equal to 90%.

24. The purification process according to claim 19, wherein the purity of sugammadex sodium in the eluate from step a) is greater than or equal to 95%.

25. The purification process according to any one of claims 20 to 23, wherein the purity of sugammadex sodium in the eluate of step a) is greater than or equal to 95%.