CN108456264A - A kind of purification process for the more glucose sodium that relaxes - Google Patents
A kind of purification process for the more glucose sodium that relaxes Download PDFInfo
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
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- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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Abstract
The present invention provides a kind of purification process for the more glucose sodium that relaxes.Specifically, the purification process includes：By easypro more glucose sodium crude product loading to using silica gel C18 to be purified on the chromatographic column of filler, obtains easypro more glucose purity and be more than 99%.The method of the invention not only can guarantee the quality of product, and be suitable for technique amplification production.
Description
Technical field
The present invention relates to a kind of purification process for the more glucose sodium that relaxes, specifically, utilizing the chromatographic column that silica gel C18 is filler
It purifies and the crude product for the more glucose sodium that relaxes is isolated and purified, to obtain the easypro more glucose sodium of high-purity.
Background technology
The more glucose sodium that relaxes is a kind of derivative of gamma-cyclodextrin, and molecule is made of lipophilic core and hydrophilic outer end, is one
The selective muscle relaxant antagonistic of kind, chemical name：Complete (2- carboxy ethyls) the thio-y-cvclodextrin sodium salts of the full deoxidation -6- of 6-
(eight sodium salts), structural formula is as follows：
More glucose sodium relax for reversing conventional use of neuromuscular blocking drug rocuronium or Vecuronium Bromide to act on, can stand
Reverse used rocuronium effect of being grown up, conventional reverse Children and teenager (2~17 years old) used rocuronium
Effect.The more glucose sodium that relaxes is first and unique selectivity relaxation bonding agent, is the great medicine in first, arcotic field over 20 years
Object is in progress, and is known as landmark flesh pine antagonist, granted in U.S.'s list marketing in 2015.
In recent years, with preparation or the development of purification technique, technical staff develops a variety of more glucose sodium purifying process that relax.
CN1402737 discloses the method that the more glucose sodium that relaxes is purified using dialysis, but uses a large amount of water when dialysis meeting, generates a large amount of useless
Liquid is unfavorable for environmental protection, and yield is relatively low, is only capable of up to 34%.
WO2012025937 is reported prepares the easypro more glucose of purifying using silica gel chromatographic column and gel column Sephadex G-25
Sodium；WO2013037994 then develops a kind of adsorbent of novel solid supporting material, and using the adsorbent as chromatographic column
Solid phase, to scheme to obtain the easypro more glucose sodium of high quality.
On the other hand, technical staff also develops purifies the more glucose sodium that relaxes in the way of solvent recrystallization, for example
WO2014125501, CN104844732A, CN105273095A, refined solvent system used have：Methanol/water, ethanol/water or N,
N- diformamides/water etc.；At the same time, CN105348412A report by easypro more glucose sodium salt switch to relax more glucammonium salts after,
It recycles ethyl alcohol recrystallization to obtain the easypro more glucammonium salts of high-purity, is then switched to sodium-salt form again.
Although above-mentioned document has provided a variety of purifying thinkings, the more glucose sodium that relaxes is complicated and includes multiple chiralitys
Center, especially gamma-cyclodextrin analogue is more, and all more or less existing defects of the above method cannot provide high-purity
Easypro more glucose sodium, while meeting the needs that produce greatly of industry.Therefore, it is necessary to develop efficiently and be suitable for the Portugals industrial production Shu Geng
Sugared sodium purifying method.
Invention content
The present invention provides a kind of purification process for the more glucose sodium that relaxes, this method includes：The more glucose sodium crude product that will relax loads
In silica gel C18 on the chromatographic column of filler, to collect sample eluent after elution, more glucose sodium purity of relaxing in the sample eluent
More than 99%, in embodiments can be 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%,
99.8%, 99.9% or higher.
Wherein, the grain size of the silica gel C18 fillers is 5~60 μm, and specific surface area is in 100~300m2/ g, the polyphenyl second
The grain size of alkene polymer is 20~100 μm, and specific surface area is in 500~1200m2/g。
In embodiments, with acetonitrile/water solution eluting silica gel C18 chromatographic columns, wherein ethane nitrile content is 10~30%, excellent
15~25% are selected as, can be 15,16,17,18,19,20,21,22,23,24,25%, more preferably 18~22%.In embodiment party
In case, water and acetonitrile can be pumped to silica gel C18 chromatographic columns respectively by A, B pipeline and eluted.
It is adsorbed on silica gel C18 to reduce the more glucose sodium that relaxes, guarantee purification effect and yield, acetonitrile of the present invention/
In aqueous solvent also contain acid, the acid is known to those skilled in the art or confirmable, be selected from but not limited to formic acid, acetic acid,
Trifluoroacetic acid, phosphoric acid, hydrochloric acid, preferably formic acid.Further, sour a concentration of 0.1 wherein in acetonitrile/water solvent~
0.5wt.%, preferably 0.12~0.2wt.%, can be 0.12,0.13,0.14,0.15,0.16,0.17,0.18,0.19,
0.20wt.%.
On the other hand, technical staff also investigates eluent flow rate, finds eluent flow rate in the purification process
Purification effect influences less, but the damage in order to avoid too fast flow velocity to silicagel column, while selected eluent flow rate also needs to examine
Consider the size (internal diameter) of pillar.In embodiments, eluent flow rate control of the present invention is in 1L/min~1.5L/min (columns
Sub- internal diameter 200mm), can be 1,1.1,1.2,1.3,1.4,1.5L/min；Preferably 1.1~1.3L/min, if pillar internal diameter
Reduce, eluent flow rate is also required to accordingly reduce.
In more glucose sodium purification process of relaxing, technical staff has found that removal impurity E (retention time 22.28min) is entire
The key point of purifying process determines the purifying max-thresholds of impurity E by lots of comparing experiments.When impurity E content is small in crude product
In or be equal to 1%, impurity E can be down to 0.5% hereinafter, meeting bulk pharmaceutical chemicals quality standard by silica gel C18 chromatographic columns.Further
, which is less than or equal to 0.6%, can be to 0.05% hereinafter, in embodiments by silica gel C18 column chromatographies
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 impurity E content is the quality that cannot be satisfied bulk pharmaceutical chemicals by silica gel C18 column chromatographies more than 1% in crude product
Standard impurities content is less than 0.1% requirement.In order to solve this technical problem, technical staff utilizes methacrylate ion
Exchanger resin removes impurity E, i.e., purification process of the present invention also includes pure through methacrylate exchange resin elution
The step of change.In embodiments, the step of being purified through methacrylate exchange resin elution can be C18 layers in silica gel
Column purification is analysed before or after silica gel C18 column chromatographies.
In some embodiments, methacrylate ion exchange resin, gained eluent are eluted with sodium chloride solution
In relax more glucose sodium purity be greater than or equal to 80%, wherein impurity E content be less than or equal to 0.1%, 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, relax more glucose sodium in the eluent
Purity is greater than or equal to 90%, can be 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, preferably greatly
In or equal to 95%.
Concentration of sodium chloride solution of the present invention be 0.1~1M (mol/L), can be 0.1,0.2,0.3,0.4,0.5,
0.6,0.7,0.8,0.9,1M, preferably 0.5M.
Methacrylate ion exchange resin of the present invention has the methacrylate backbone of surface hydrophilic characteristic,
Resin rigidity is good, including Toyopearl GigaCap S-650M, Toyopearl GigaCap CM-650M, Toyopearl
GigaCap Q-650M, Toyopearl GigaCap DEAE-650M, preferably Toyopearl GigaCap DEAE-650M
(vehicle economy AE-650M).
In embodiments, in order to avoid inorganic impurity influences chromatographic effect and elution rate, the more glucose sodium crude product that relaxes needs
Will be through membrane filtration, the filter sizes are 0.2~10 μm, preferably 0.3~5 μm, 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、5μm。
Purification process of the present invention, this method include：
A) easypro more glucose sodium crude product is carried on methacrylate ion exchange resin, is eluted with sodium chloride solution pure
Change, the methacrylate ion exchange resin preferably is selected from DEAE-650M；
B) it by eluent loading silica gel C18 chromatographic columns obtained by a) step, is eluted with acetonitrile/water solution, collects sample and wash
De- liquid；
Wherein, ethane nitrile content be 10~30%, preferably 15~25%, can be 15,16,17,18,19,20,21,22,
23,24,25%, more preferably 18~22%.In embodiments, water and acetonitrile can be pumped to silica gel respectively by A, B pipeline
C18 chromatographic columns are eluted.
Further, before b) step, eluent obtained by a) step is inorganic miscellaneous in solution to remove through membrane filtration
Matter, the filter sizes be 0.2~10 μm, preferably 0.3~5 μm, 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、5μm。
Further, by sample eluent it is concentrated obtain finished product relax more glucose sodium.
Silica gel C18 of the present invention is octadecyl silane filler, may be selected from but not limited to Hua Pu companies
ACCHROM, Shanghai great You chromatographic techniques company DYPM952, DYB71306, DYB7129, the Unisil C18 of Na Wei companies,
The welch Ultimate XB-C18 of Yue Xu companies, the preferably DYPM952 of great You chromatographies scientific ＆ technical corporation.
Capto Q ImpRes and Capto SP ImpRes of the present invention are strong the moon of high-throughput purification of recombinant proteins matter
Ion and strong cation exchanger, average particle size：40 μm, matrix：High flow capacity agarose, ligand：SP- sulfonate groups, Q- quaternary amines
Base.
Solvent content (such as ethane nitrile content) of the present invention indicates acetonitrile percentage by volume in the solution；Wt% of the present invention
(weight percent)=(quality of the quality+B of quality/A of B) × 100%.
Silica gel C18 or methacrylate ion exchange resin of the present invention are required for carrying out processing living before use,
Its activating treatment method is well known to those skilled in the art or it was determined that for example the activation process of silica gel C18 may refer to
Described in embodiment 2, the activation process of methacrylate ion exchange resin may refer to described in embodiment 4.
The mobile phase classification used of resin or silica gel C18 are eluted in the present invention, type of elution need according to respective attribute into
Row selection, on judging whether resin or silica gel C18 can purify the more grape sodium that relaxes without influence.
The more glucose sodium crude product of the present invention that relaxes is prepared according to methods known in the art, is referred to WO2012025937
Method is prepared described in embodiment processed, and silica gel C18, Source 15Q and other resins of the present invention can pass through quotient
Industry approach is bought.
Sample " purity " of the present invention or " content " are detected by HPLC to be obtained；Testing conditions are：Chromatographic column YMC
ODS-AQ C18 (150 × 3.0mm, 3 μm)；Detection wavelength 200nm；Using ammonium dibasic phosphate solution or acetonitrile as mobile phase.
The present invention is relaxed more glucose sodium retention time about 20.16min, impurity E retention time about 22.28min.It is of the present invention
Relative retention time=(impurity peaks retention time)/(main peak retention time), impurity E relative retention time=1.1.
Specific implementation mode
The present invention, the range of but do not limit the invention in any way are further described below by way of example.
Embodiment 1：The preparation of easypro more glucose sodium crude product
3.50kg gamma-cyclodextrins are placed in vacuum drying chamber I, 95 DEG C of Zhen Kong Du of temperature≤- 0.08MPa dryings 10~
12h is fitted into double-layer plastic bag, spare.
9.12kg triphenyl phosphorus and 35kg DMF are added in 100L reaction kettles, nitrogen protection, stirring and dissolving, be cooled to-
15 DEG C, the DMF solution (9.14kg is dissolved in 11kg DMF) of iodine is added dropwise, drop Bi Jixu stirs 0.5~1h, adds dry
3.00kg gamma-cyclodextrins, process control temp are no more than 0 DEG C, and heating is stirred to react.System cools down, and the methanol of sodium methoxide is added dropwise
Solution (2.18kg sodium methoxides are dissolved in 8kg methanol) drips and finishes 0.5~1h of stirring, material solution is transferred in 50L plastic barrels.
It is pumped into 300kg purified waters into 500L reaction kettles II, the material solution in plastic barrel is instilled into reaction kettle II, drop finishes
0~15min is stirred, rejection filter is washed three times with purified water 30kg*3, and acetone 24kg*3 washings are three times.It is anti-that solid is transferred to 50L
It answers in kettle III, 8kg industry DMF is added and dissolves solid, 45~55 DEG C of dropwise addition 20kg acetone are down to room temperature, are filtered naturally；Again
Repeat dissolving punching analysis filter process twice.70 DEG C of vacuum degrees drying 23~for 24 hours intermediate γ-ICD, the amount of obtaining range 3.0~
3.5kg, yield spectra 59.6~69.5%.
34kg chromatographically pure DMF are added into the reaction kettle IV of 200L, are added with stirring 0.76kgNaH, are cooled to -5 DEG C, drop
Add the DMF solution (1.53kg is dissolved in 10kg chromatographically pures DMF) of 3- mercaptopropionic acids, drop, which finishes, is stirred at room temperature 1~2h.During room temperature is added dropwise
The DMF solution (upper step gained γ-ICD are dissolved in 44kg chromatographically pures DMF) of mesosome γ-ICD, drop finishes, and is warming up to 65 DEG C of reactions.Drop
Temperature is added dropwise 26kg purified waters and reaction is quenched, is stirred at room temperature, and filtering is purified water dissolution with 30kg, is transferred in 200L reaction kettles V,
86kg industry DMF punching analysis is added, filters, dry, must relax more glucose sodium crude product, the amount of obtaining range 1.2kg, yield 34.3%, purity
90.22%, impurity E content 0.77%.
Embodiment 2：
Filling prepares column：By 1.2kg silica gel C18 fillers (20 μm of grain sizes,) with after the wetting of 2.4L isopropanols, it is filled to system
In the column tube of standby column, using dynamic axial compression so that filling pressure reaches 80~100Bar, uses 5~10 times of CV (cylinders
Product) ethyl alcohol prepare column as mobile phase flushing with spare.
The more glucose sodium crude product that relaxes in 10g embodiments 1 is taken to be dissolved in 100ml purified waters, 0.45 μm of membrane filtration, to the system
In continue to add water to 500ml, and adjust pH be acidity.
By the solution load sample to preparing on column, 0.15% aqueous formic acid and acetonitrile are pumped to chromatography respectively with A, B pipeline
Column is eluted, and it is 21% to keep ethane nitrile content.The main peak eluted is divided into several sections of different fractions, merges qualified fraction,
It is concentrated to give the more glucose sodium 3.7g that relaxes, yield 41%, purity 98.81%, impurity E content 0.21%.
Embodiment 3：
Column is prepared with spare according to 2 filling of embodiment
The 10g more glucose sodium crude products (purity 89.28%, impurity E content 0.60%) that relax are taken to be dissolved in 100ml purified waters,
0.45 μm of membrane filtration continues to add water to 500ml into the system, and it is acidity to adjust pH.
By the solution load sample to preparing on column, 0.15% aqueous formic acid and acetonitrile are pumped to chromatography respectively with A, B pipeline
Column is eluted, and it is 21% to keep ethane nitrile content.The main peak eluted is divided into several sections of different fractions, merges qualified fraction,
Be concentrated to give relax more glucose sodium 3.6g, yield 40%, purity 99.01%, impurity E content 0.05%.
Embodiment 4：
Load DEAE-650M chromatographic columns：：2kg DEAE-650M resins are poured into glass column, with purified water, 0.5M hydrogen
Sodium oxide molybdena, sodium chloride solution activate DEAE-650M resins with spare.
The easypro more glucose sodium crude products (purity 90.22%, impurity E content 0.77%) of about 1.2kg are dissolved in 30kg water, are stirred
Uniform sample solution, loading to aforementioned DEAE chromatographic columns are eluted with 0.5M sodium chloride solutions, collect eluent respectively, are detected
Merge afterwards and collect, purity 96.89%, yield 95%, impurity E is not detected.
Embodiment 5：
Load DEAE-650M chromatographic columns：2kg DEAE-650M resins are poured into glass column, with purified water, 0.5M hydrogen-oxygens
Change sodium, sodium chloride solution activates DEAE-650M with spare.
The easypro more glucose sodium crude products (purity 92.21, impurity E content 1.5%) of about 1.2kg are dissolved in 30kg water, stirring is equal
Even sample solution, loading to aforementioned DEAE-650M chromatographic columns are eluted with 0.5M sodium chloride solutions, collect eluent respectively, are received
Collection is concentrated to give sample purity 96.89%, yield 93%, impurity E content 0.03% containing the more glucose sodium solution that relaxes.
Embodiment 6：
Load DEAE-650M chromatographic columns：2kg DEAE-650M resins are poured into glass column, with purified water, 0.5M hydrogen-oxygens
Change sodium, sodium chloride solution activates DEAE-650M resins with spare.
The easypro more glucose sodium crude products (purity 92.21, impurity E content 0.92%) of about 1.2kg are dissolved in 30kg water, stirring is equal
Even sample solution, loading to aforementioned DEAE-650M chromatographic columns are eluted with 0.5M sodium chloride solutions, are collected containing the more glucose sodium that relaxes
Solution is concentrated to give sample purity 97.01%, yield 95%, impurity E content 0.02%.
Embodiment 7：
Filling prepares column：By 4.8~5.0kg silica gel C18 fillers (20 μm of grain sizes,) with after 10L ethanol wets, it is filled to
It prepares in the column tube of column, using dynamic axial compression so that filling pressure reaches 80~100Bar, uses 5~10 times of CV (cylinders
Product) ethyl alcohol prepare column as mobile phase flushing with spare.
Receiving liquid (purity 96.89%, impurity E is not detected) in embodiment 4 is adjusted with formic acid and obtains pH value to 3-4, and is added
Enter acetonitrile so that feed liquid and the proportioning of acetonitrile reach 81:After 19,0.45 μm of organic membrane filters, by the solution, load sample arrives in four times
It prepares on column, 0.15% aqueous formic acid and acetonitrile is pumped to chromatographic column respectively with A, B pipeline and eluted, keep ethane nitrile content
It is 21%.The main peak eluted is divided into several sections of different fractions, merges qualified fraction, is concentrated to give the more glucose sodium that relaxes, purity
99.07%, yield 75%, impurity E is not detected.
Embodiment 8：
Source 15Q chromatographic columns (4.6*100mm) are loaded with spare
The easypro more glucose sodium crude products (purity 92.21%, impurity E content 1.5%) of about 40mg are dissolved in 30ml water, loading is extremely
On ion exchange column, mobile phase A is used：Purified water, Mobile phase B：1M sodium-chloride water solutions carry out gradient elution, collect to contain and relax more
Glucose sodium solution is concentrated to give sample purity 94.21%, impurity E content 0.86%.
Embodiment 9：
Capto Q ImpRes ion exchange columns (4.6*100mm) are loaded with spare
The easypro more glucose sodium crude products (purity 92.21%, impurity E content 1.5%) of about 40mg are dissolved in 300ml water, loading
To ion exchange column, mobile phase A is used：Purified water, Mobile phase B：1M sodium-chloride water solutions carry out gradient elution, are examined through HPLC
It surveys and collects containing the more glucose sodium solution that relaxes, be concentrated to give sample purity 95.21%, impurity E content 0.73%.
Embodiment 10：
001*7 cation exchange columns and D001 anion-exchange columns are loaded respectively with spare
The easypro more glucose sodium crude products (purity 93.21%, impurity E content 0.21%) of about 40mg are dissolved in 300ml water, then
Aforementioned sample solution is passed through into 001*7 cation exchange columns and D001 anion-exchange columns successively, purifying water elution, warp is used in combination
HPLC detections are collected containing the more glucose sodium solution that relaxes, and sample purity 94.09%, impurity E content 0.20% are concentrated to give.
Embodiment 11：
Sephadex G-25 gel columns (4.6*100mm) are loaded with spare
By about 50mg relax more glucose sodium crude product (purity 90.21, impurity E content 1.0%) be dissolved in 30ml water, loading to from
It on sub- exchange column, is eluted with purified water, collects containing the more glucose sodium solution that relaxes, be concentrated to give sample purity 92.21%, impurity E
Content 0.76%.
Embodiment 12：
Column is prepared with spare according to 2 filling of embodiment
The 10g more glucose sodium crude products (purity 90.03%, impurity E content 1.02%) that relax are taken to be dissolved in 100ml purified waters,
0.45 μm of membrane filtration continues to add water to 500ml into the system, and it is acidity to adjust pH.
By the solution load sample to preparing on column, 0.15% aqueous formic acid and acetonitrile are pumped to chromatography respectively with A, B pipeline
Column is eluted, and it is 21% to keep ethane nitrile content.The main peak eluted is divided into several sections of different fractions, merges qualified fraction,
It is concentrated to give more glucose sodium purity 98.92% of relaxing, impurity E content 0.5%.
Table 1：Embodiment related substances data summarization
Conclusion：
1, from the point of view of purifying crude data in embodiment 2,4-11, DEAE-650M resins and silica gel C18 have impurity E
Impurity E can be down to 0.03% by good purification effect, especially DEAE-650M resins by 1.5%, the resin of other classifications or
Impurity E can only be down to 0.7% or so by gel column, cannot meet more quality standard of the glucose sodium as bulk pharmaceutical chemicals of relaxing completely；
2, silica gel C18 has certain purification effect to impurity E in the more glucose sodium crude product that relaxes, and works as impurity E in crude product and be
1.02%, silica gel C18 cannot be down to 0.05% hereinafter, meeting the quality standard of bulk pharmaceutical chemicals.
Claims (10)
1. a kind of purification process for the more glucose sodium that relaxes, including：The more glucose sodium crude product that relaxes is carried on the chromatography that silica gel C18 is filler
On column, sample eluent is collected after elution, more glucose sodium purity of relaxing in the preferably described sample eluent is more than 99%.
2. purification process according to claim 1, which is characterized in that acetonitrile/water solution eluting silica gel C18 chromatographic columns are used,
Wherein ethane nitrile content is 10~30%, preferably 15~25%, more preferably 18~22%.
3. purification process according to claim 2, it is characterised in that also contain acid, the acid in the acetonitrile/water solution
Selected from formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, hydrochloric acid, preferably formic acid；A concentration of 0.1~0.5wt.% of the acid, preferably
For 0.12~0.2wt.%.
4. purification process according to claim 1 or 2, it is characterised in that impurity E content in the more glucose sodium crude product that relaxes
Less than or equal to 1%, preferably lower than or equal to 0.6%.
5. purification process according to claim 1 or 2, it is characterised in that the purification process further includes that easypro more glucose sodium is thick
For product through membrane filtration step, the preferably described filter sizes are 0.2~10 μm, more preferably 0.3~5 μm.
6. purification process according to claim 1 or 2, it is characterised in that the eluent flow rate is 1~1.5L/min.
7. purification process according to claim 1 or 2, it is characterised in that the purification process further includes through methacrylic acid
The step of ester exchange resin elution purifies, the methacrylate ion exchange resin preferably is selected from DEAE-650M；It is described
More glucose sodium purity of relaxing in eluent is greater than or equal to 80%, and wherein impurity E content is less than or equal to 1%, preferably smaller than or waits
In 0.6%.
8. purification process according to claim 7, which is characterized in that elute polymethyl acid ion with sodium chloride solution
Exchanger resin chromatographs column, and the concentration of sodium chloride solution is 0.1~1M, preferably 0.5M.
9. purification process according to claim 7, it is characterised in that in the eluent relax more glucose sodium purity be more than or
Equal to 90%, preferably greater than or equal to 95%.
10. according to claim 1~9 any one of them purification process, including：
A) easypro more glucose sodium crude product is carried on methacrylate ion exchange resin, is purified by flash with sodium chloride solution, institute
It states methacrylate ion exchange resin and preferably is selected from DEAE-650M；
B) it by eluent loading silica gel C18 chromatographic columns obtained by a) step, is eluted with acetonitrile/water solution, collects sample eluent,
Wherein ethane nitrile content is 10~30%, preferably 15~25%, more preferably 18~22%.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109517093A (en) * | 2018-12-29 | 2019-03-26 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of the easypro more glucose sodium of high-purity |
| CN109517094A (en) * | 2019-01-18 | 2019-03-26 | 苏州纳微科技股份有限公司 | A kind of isolation and purification method for the more glucose that relaxes |
| 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 |
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|---|---|---|---|---|
| CN109517093A (en) * | 2018-12-29 | 2019-03-26 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of the easypro more glucose sodium of high-purity |
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| CN109517093B (en) * | 2018-12-29 | 2021-03-09 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of high-purity sugammadex sodium |
| CN109517094A (en) * | 2019-01-18 | 2019-03-26 | 苏州纳微科技股份有限公司 | A kind of isolation and purification method for the more glucose that relaxes |
| WO2020147421A1 (en) * | 2019-01-18 | 2020-07-23 | 苏州纳微科技股份有限公司 | Sugammadex isolation and purification method |
| CN111632582A (en) * | 2019-03-01 | 2020-09-08 | 月旭科技（上海）股份有限公司 | Silica gel reverse phase chromatographic packing and preparation method and application thereof |
| CN111632582B (en) * | 2019-03-01 | 2023-02-28 | 月旭科技（上海）股份有限公司 | Silica gel reverse phase chromatographic packing and preparation method and application thereof |
| CN111548435A (en) * | 2020-05-12 | 2020-08-18 | 杭州泽邦科技有限公司 | Separation and purification method of sugammadex |
| CN111548435B (en) * | 2020-05-12 | 2022-03-18 | 杭州泽邦科技有限公司 | Separation and purification method of sugammadex |
| CN111607019A (en) * | 2020-06-23 | 2020-09-01 | 常州制药厂有限公司 | Purification method of sugamonic acid |
| CN111607019B (en) * | 2020-06-23 | 2021-03-02 | 常州制药厂有限公司 | Purification method of sugamonic acid |
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