CN105037452B - A kind of process for purification of quick preparation high-purity Fondaparinux sodium - Google Patents
A kind of process for purification of quick preparation high-purity Fondaparinux sodium Download PDFInfo
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Abstract
A kind of process for purification of quick preparation high-purity Fondaparinux sodium, it is low that the present invention provides a kind of production cost, easy to operate and can reach high-purity and the preparation method of high-recovery.By high performance liquid chromatography the preparation method, the Fondaparinux sodium crude product that content is 50% or more can be reached 99% or more purity by primary preparation.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of process for purification of drug, and in particular to a kind of to prepare high-purity
The process for purification of Fondaparinux sodium.
Background technology
Fondaparinux sodium is a kind of anticoagulation developed by French Sai Nuofei, is artificial synthesized, first antithrombase
The indirect inhibitor of the Xa factor of dependence.Its antithrombotic acitivity is selectively pressing down to factor Xa for antithrombin Ⅲ (AT III) mediation
The result of system.By selective binding in AT III, Fondaparinux sodium enhance (about 300 times) AT III it is original to factor Xa in
And activity.And coagulation cascade reaction has been interrupted to the neutralization of factor Xa, and inhibit the formation of fibrin ferment and the increasing of thrombus
Greatly.Fondaparinux sodium cannot inactivate fibrin ferment (activation factor II), and not act on blood platelet.Succeeding in developing for it is the mankind
The new milestone in anti-bolt field.
Fondaparinux sodium is a kind of five Carbohydrate drugs of heparin, the entitled Fondaparinux sodium of English, Chinese chemistry
It is entitled：Methyl O- (2- deoxidation -6-O- sulfonic group -2- sulfoamido-α-D- glucopyranoses)-(1 → 4)-O- (β-D- pyrans
Glucuronic acid)-(1 → 4)-O- (2- deoxidation -3,6-O- disulfonic acid base -2- sulfoamido-α-D- glucopyranoses)-(1 →
4)-O- (2-O- sulfonic group-α-L- pyrans iduronic acid)-(1 → 4) -2- deoxidation -6-O- sulfonic group -2- sulfoamido-α-D-
Ten sodium salt of glucopyranoside, chemical structural formula are as follows：
Fondaparinux sodium is pure chemistry synthesis, and synthetic route is up to 50 multisteps, and synthesis difficulty is big.Obtained sulphur reaches the liver last of the ten Heavenly stems
For sodium content in crude product 60%~70%, dopant species are more.Some contaminant characteristics are closely similar with the property of Fondaparinux sodium, it is difficult to
99% or more is once purified to by common separation method.At present document report be through ion-exchange chromatography into
Row is refined.
United States Patent (USP) 20050020536 discloses a kind of using Ago-Gel as the strong anion displacement chromatography column (Q of matrix
Sepharose Fast Flow) method that isolates and purifies Fondaparinux sodium, this method carries out by mobile phase of sodium-chloride water solution
Elution, obtains 90% or more purity, reaches 98% or more purity using activated carbon adsorption.
The patent application of Publication No. CN102659859 is pointed out to be situated between with monodisperse polymethacrylates ion-exchange chromatography
Matter is that the chromatographic column of filler carries out column chromatography, also obtains 98% or more purity.
By analysis it was found that the above separation method the main problems are as follows：
It is that 1.2 rear miscellaneous is not easy to remove for relative retention time 1. being lost using activated carbon adsorption product bigger；
2. detach a large amount of Fondaparinux sodium crude product, need to use a large amount of expensive column chromatography medium, production
It is of high cost；
3. Fondaparinux sodium contaminant characteristics are close with Fondaparinux sodium property, contact plate detection can not judge, every pillar excessively
It is required to liquid phase monitoring, operation is more complicated, and preparation time is longer.
In order to effectively solve the problems, such as that the above method exists, the present invention works out one kind and quickly preparing high-purity sulphur up to the liver last of the ten Heavenly stems
The process for purification of sodium.
Invention content
The purpose of the present invention is to provide a kind of process for purification preparing high-purity Fondaparinux sodium.This method has production
Feature at low cost, easy to operate, the Fondaparinux sodium being prepared have the advantages that purity height and the rate of recovery are high.
The present invention can be passed through the Fondaparinux sodium crude product that content is 50% or more by high performance liquid chromatography the preparation method
Primary prepare reaches 99% or more purity.
Fondaparinux sodium is a kind of more sodium salts of pentosan, is insoluble in organic solvent, cannot use general C18 reversed-phase column systems
Back-up from.SOURCE series strong base anion resins, belong to high-resolution IEC fillers, and relative price is cheap, and maximum feature is
The low back-pressure of high speed is suitable for using in any high, medium and low voltage chromatographic system, is very suitable for finely isolating and purifying various biochemistry
Substance.
Specifically, the preparation method of Fondaparinux sodium of the present invention, includes the following steps：
(1) Fondaparinux sodium crude product is dissolved in purified water, a concentration of 0.5~1g/mL；
(2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution, collects the higher product of purity；
Prepare liquid phase：Waters prepares purifying instrument；Flow velocity：14mL/min；Ultraviolet wavelength：210nm；Sample size：5mL；Stream
Dynamic phase A, B carries out gradient elution, mobile phase A：Sodium chloride solution, Mobile phase B：Water for injection carries out gradient in the following manner
46.00min~49.00min target components are collected in elution；
(3) it concentrates, desalination is dried to obtain the Fondaparinux sodium of high-purity.
Wherein, Fondaparinux sodium crude product belongs to existing product, can buy on the market, and purity is more than 50%.
Wherein, mobile phase A is 1~3mol/L sodium-chloride water solutions, preferably 2mol/L sodium-chloride water solutions.
Wherein, glass (GL) color that chromatographic column used in highly effective liquid phase chromatographic system is produced by GE Healthcare companies
Column is composed, specification is 10 × 100mm~75 × 500mm；Using strong base anion resin as stationary phase, preferably SOURCE series；
Chromatographic column filler granularity used in highly effective liquid phase chromatographic system is 3~30 μm, and grain size is smaller to be more conducive to product separation,
But the smaller system pressure of grain size will be bigger, and preferably particle size range is 10~15 μm.
Wherein, it is concentrated described in step 3, desalination, dry detailed process is：By collected component in 40 ± 2 DEG C of temperature,
Under conditions of vacuum degree >=0.09MPa, it is concentrated under reduced pressure into the saturated solution of sodium chloride, direct loading to -25 layers of sephadex G
Analysis column desalination is concentrated to dryness by collected product under conditions of 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa.
Preferably, the preparation method of Fondaparinux sodium of the present invention, including following operating procedure：
(1) it takes Fondaparinux sodium crude product to be dissolved in purified water, is configured to the aqueous solution of 1g/mL,
(2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution, chromatographic condition is as follows：
The specification of GE glass columns, chromatographic column is 50 × 250mm or 10x100mm, and stationary phase is Source 15Q, is filled out
Expect that grain size 15um, mobile phase A are 1~3mol/L sodium-chloride water solutions, Mobile phase B is water for injection, flow velocity 14ml/mim, inspection
Survey wavelength is 210nm.Sample size 5mL, according to the form below elution, collects 46.00min~49.00min target components；
(3) component collected by is in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, and the saturation for being concentrated under reduced pressure into sodium chloride is molten
Liquid, direct loading to -25 chromatographic column desalination of sephadex G；Collected product in 40 ± 2 DEG C of temperature, vacuum degree >=
0.09MPa is concentrated to dryness, and obtains white solid to get high-purity Fondaparinux sodium.
The preparation method of Fondaparinux sodium of the present invention is obtained by screening, and screening process is as follows：
The contrast experiment of GE Q and DIONEX two kinds of chromatographic columns of CarboPac is specific as follows：
Chromatographic column：GE Source Q 10/100；Prepare liquid phase：Waters prepares purifying instrument；Flow velocity：3.8ml/min；It is purple
Outer wavelength：210nm；Sample size：20mg；Mobile phase A, B carry out gradient elution (mobile phase A：117g/L sodium chloride solutions, flowing
Phase B：Water for injection), gradient is as follows：
It is as shown in Figure 1 that GE Q chromatographic columns prepare purifying spectrogram：
Chromatographic column：DIONEX CarboPac PA1；Prepare liquid phase：Waters prepares purifying instrument；Flow velocity：5ml/min；It is purple
Outer wavelength：210nm；Sample size：20mg；Mobile phase A, B carry out gradient elution (mobile phase A：117g/L sodium chloride solutions, flowing
Phase B：Water for injection), gradient is as follows：
It is as shown in Figure 2 that DIONEX CarboPac chromatographic columns prepare purifying spectrogram:
The spectrogram discovery of N1, GE Q chromatographic columns are prepared by comparison two kinds of chromatographic columns of GE Q and DIONEX CarboPac
Impurity ability before separation product peak is better than the impurity after separation product peak, and DIONEX CarboPac chromatography post separations
Impurity ability after product peak is better than the impurity before separation product peak.Due in N1 a large amount of impurity mainly product peak it
Before, therefore it is more preferable to select GE Q chromatographic columns to carry out purification effect.
In addition, the filler specification of DIONEX CarboPac chromatographic columns is relatively simple, it is difficult to realize amplification；And GE Q chromatographies
The filler specification type of column is more, meets the demand that production is further amplified.Therefore, selection GE Q chromatographic columns are more reasonable.
Noun of the present invention is further explained：
GE (GL) chromatographic column：Glass (GL) chromatographic column that GE Healthcare companies are produced, specification are 10 × 100mm
~75 × 500mm；
Stationary phase is Source 15Q：Source is the low back-pressure medium (filler) of high speed, is alkaline resin anion (R.A.), grain size
For 15um
The present invention uses preparative liquid chromatography system, and the product that purity is more than 99% is obtained by preparative separation.The present invention
Preparation method have it is simple for process, production cost is low, product quality stablize the features such as, meanwhile, mobile phase of the invention select
Sodium-chloride water solution and water, will not be to environmental effects.
Figure of description
Attached drawing 1：GE Q chromatographic columns prepare purifying spectrogram
Attached drawing 2：DIONEX CarboPac chromatographic columns prepare purifying spectrogram
Attached drawing 3：1 Fondaparinux sodium crude product liquid chromatogram of embodiment
Attached drawing 4：Gained purified product liquid chromatogram after the separation of 1 Fondaparinux sodium of embodiment
Attached drawing 5：2 Fondaparinux sodium crude product liquid chromatogram of embodiment
Attached drawing 6：Gained purified product liquid chromatogram after the separation of 2 Fondaparinux sodium of embodiment
Attached drawing 7：3 Fondaparinux sodium crude product liquid chromatogram of embodiment
Attached drawing 8：Gained purified product liquid chromatogram after the separation of 3 Fondaparinux sodium of embodiment
Attached drawing 9：4 Fondaparinux sodium crude product liquid chromatogram of embodiment
Attached drawing 10：4 Fondaparinux sodium Ago-Gel purified product liquid chromatogram of embodiment
Attached drawing 11：4 Fondaparinux sodium sephadex purified product liquid chromatogram of embodiment
Specific implementation mode
By following specific examples, the present invention is further illustrated, but without limitation.
Embodiment 1
Fondaparinux sodium crude product 15g is taken, 15mL purified waters are dissolved in, is configured to the aqueous solution of 1g/mL, through 0.22 μm of filter membrane mistake
Filter, sampling HPLC analyses, Fondaparinux sodium crude product purity is 59.5%, and spectrogram is shown in Fig. 3.GE Source Q (GL) chromatographic column (50
× 250), stationary phase is Source 15Q, and mobile phase is sodium-chloride water solution (1mol/L) and water, flow velocity 14ml/mim, inspection
Survey wavelength is 210nm.Sample size 5mL, according to the form below elution, collects 46.00min~49.00min target components；
Collected component is concentrated under reduced pressure into the saturated solution of sodium chloride in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa,
To -25 chromatographic column desalination of sephadex G, collected product subtracts direct loading in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Pressure is concentrated to dryness.Obtain white solid 5.75g.The rate of recovery is 64.4%.HPLC detections are sampled, purity 99.7%, spectrogram is shown in
Fig. 4.Gained compound1H NMR datas are：(400MHz, CDCl3) δ=3.17-3.25 (m, 2H, Ac-H), 3.35-3.44 (m,
5H),3.52-3.63(m,3H),3.70-3.87(m,5H),3.89-3.92(m,2H),4.09-4.11(m,4H),4.20-4.40
(m, 6H), 4.35 (d, J=4.0Hz, 1H), 4.56 (d, J=8.0Hz, 1H, E (H1)), 4.70 (d, J=2.8Hz, 1H, G
(H5)), 4.97 (d, J=3.6Hz, 1H, H (H1)), 5.12 (d, J=3.6Hz, 1H, G (H1)), 5.47 (d, J=3.2Hz, 1H,
F (H1)), 5.57 (d, J=3.6Hz, 1H, D (H1)).
Embodiment 2
Fondaparinux sodium crude product 15g is taken, 15mL purified waters are dissolved in, is configured to the aqueous solution of 1g/mL, through 0.22 μm of filter membrane mistake
Filter, sampling HPLC analyses, Fondaparinux sodium crude product purity is 58.5%, and spectrogram is shown in Fig. 5.GE Source Q (GL) chromatographic column (50
× 250), stationary phase is Source 15Q, and mobile phase is sodium-chloride water solution (2mol/L) and water, flow velocity 14ml/mim, inspection
Survey wavelength is 210nm.Sample size 5mL, according to the form below elution, collects 46.00min~49.00min target components；
Collected component is concentrated under reduced pressure into the saturated solution of sodium chloride in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa,
To -25 chromatographic column desalination of sephadex G, collected product subtracts direct loading in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Pressure is concentrated to dryness.Obtain white solid 5.57g.The rate of recovery is 63.4%.HPLC detections are sampled, purity 99.8%, spectrogram is shown in
Fig. 6.
Embodiment 3
Fondaparinux sodium crude product 15g is taken, 15mL purified waters are dissolved in, is configured to the aqueous solution of 1g/mL, through 0.22 μm of filter membrane mistake
Filter, sampling HPLC analyses, Fondaparinux sodium crude product purity is 64.2%, and spectrogram is shown in Fig. 7.GE Source Q (GL) chromatographic column (50
× 250), stationary phase is Source 15Q, and mobile phase is sodium-chloride water solution (3mol/L) and water, flow velocity 14ml/mim, inspection
Survey wavelength is 210nm.Sample size 5mL, according to the form below elution, collects 46.00min~49.00min target components；
Collected component is concentrated under reduced pressure into the saturated solution of sodium chloride in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa,
To -25 chromatographic column desalination of sephadex G, collected product subtracts direct loading in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Pressure is concentrated to dryness.Obtain white solid 5.58g.The rate of recovery is 57.9%.HPLC detections are sampled, purity 99.8%, spectrogram is shown in
Fig. 8.
Embodiment 4, comparative experiments
Fondaparinux sodium crude product 5g is taken, 15mL purified waters, sampling HPLC analyses are dissolved in, Fondaparinux sodium crude product purity is
67.5%, spectrogram is shown in Fig. 9.Using Ago-Gel as strong anion displacement chromatography column (the Q Sepharose Fast of matrix
Flow it) isolates and purifies and carries out first time purification, first carry out rushing column with 0.2N NaCl, then carry out except low charge with 0.46N NaCl
Impurity recycles Fondaparinux sodium with 0.8N NaCl.Fondaparinux sodium (2.8g) is obtained, purity 83.3%, spectrogram is shown in Figure 10.
2.8g Fondaparinux sodium crude products are dissolved in 28mL water, 0.28g activated carbons are added, two hours are stirred at room temperature, are filtered,
By filtrate in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa is concentrated under reduced pressure into the saturated solution of sodium chloride, and direct loading is poly- to Portugal
Sugared gel G-25 chromatographic column desalinations, collected product are concentrated to dryness in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa.
To white solid 1.6g.The rate of recovery is 47.4%.HPLC detections are sampled, purity 97.7%, spectrogram is shown in Figure 11.
It can be further illustrated by above-mentioned experiment：
The preparation method of the present invention：1. the Fondaparinux sodium of high-purity can be obtained, and there is the higher rate of recovery；2. life
Cost reduction is produced, avoids having used a large amount of expensive column chromatography medium；3. it is easy to operate, it is readily produced.
Claims (7)
1. a kind of process for purification preparing high-purity Fondaparinux sodium, which is characterized in that include the following steps：
1) Fondaparinux sodium crude product is dissolved in purified water, a concentration of 0.5~1g/mL；
2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution, collects the higher product of purity；
Prepare liquid phase：Waters prepares purifying instrument；Flow velocity：14mL/min；Ultraviolet wavelength：210nm；Sample size：5mL；Mobile phase
A, B carries out gradient elution, mobile phase A：Sodium chloride solution, a concentration of 1~3mol/L, Mobile phase B：Water for injection is collected
46.00min~49.00min target components；Chromatographic column is GE Mono Q chromatographic columns SOURCE series, and chromatographic column filler granularity is
10 μm~15 μm；
3) it concentrates, desalination is dried to obtain the Fondaparinux sodium of high-purity；
Gradient elution process is as follows：
2. process for purification according to claim 1, which is characterized in that Fondaparinux sodium crude product belongs to existing product, can be with
It buys on the market, purity is more than 50%.
3. process for purification according to claim 1, which is characterized in that concentrated described in step 3, desalination, dry specific mistake
Cheng Wei：By collected component under conditions of 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, it is concentrated under reduced pressure into the full of sodium chloride
And solution, direct loading to -25 chromatographic column desalination of sephadex G, by collected product in 40 ± 2 DEG C of temperature, vacuum degree >=
Under conditions of 0.09MPa, it is concentrated to dryness.
4. process for purification according to claim 3, which is characterized in that include the following steps：
1) it takes Fondaparinux sodium crude product to be dissolved in purified water, is configured to the aqueous solution of 1g/mL,
2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution, chromatographic condition is as follows：
GE Mono Q chromatographic columns, 10 × 100mm of model of chromatographic column, stationary phase be Source 15Q, packing material size 10um,
Mobile phase A is 1~3mol/L sodium-chloride water solutions, and Mobile phase B is water for injection, flow velocity 14ml/mim, and Detection wavelength is
210nm, sample size 5mL, according to the form below elution, collect 46.00min~49.00min target components；
3) component collected by is concentrated under reduced pressure into the saturated solution of sodium chloride, directly in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Sample is connected to -25 chromatographic column desalination of sephadex G；Collected product is in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, decompression
It is concentrated to dryness, obtains white solid to get high-purity Fondaparinux sodium.
5. process for purification according to claim 3, which is characterized in that include the following steps：
1) it takes Fondaparinux sodium crude product to be dissolved in purified water, is configured to the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration,
2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution,
Chromatographic condition is as follows：GE Mono Q chromatographic columns, 10 × 100mm of model, stationary phase are Source 15Q, packing material size
10um, mobile phase A are 1mol/L sodium-chloride water solutions, and Mobile phase B is water, flow velocity 14ml/mim, Detection wavelength 210nm,
Sample size 5mL, collects 46.00min~49.00min target components, and type of elution is as follows：
3) component collected by is concentrated under reduced pressure into the saturated solution of sodium chloride, directly in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Sample is connected to -25 chromatographic column desalination of sephadex G, collected product is in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, decompression
It is concentrated to dryness, obtains white solid, you can.
6. process for purification according to claim 3, which is characterized in that include the following steps：
1) it takes Fondaparinux sodium crude product to be dissolved in purified water, is configured to the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration,
2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution,
Chromatographic condition is as follows：GE Mono Q chromatographic columns, 10 × 100mm of model, stationary phase are Source 15Q, packing material size
15um, mobile phase A are 2mol/L sodium-chloride water solutions, and Mobile phase B is water, flow velocity 14ml/mim, Detection wavelength 210nm,
Sample size 5mL, collects 46.00min~49.00min target components, and type of elution is as follows：
3) component collected by is concentrated under reduced pressure into the saturated solution of sodium chloride, directly in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Sample is connected to -25 chromatographic column desalination of sephadex G；Collected product is in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, decompression
It is concentrated to dryness, obtains white solid, be high-purity Fondaparinux sodium.
7. process for purification according to claim 3, which is characterized in that include the following steps：
1) it takes Fondaparinux sodium crude product to be dissolved in purified water, is configured to the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration
2) Fondaparinux sodium is prepared with highly effective liquid phase chromatographic system gradient elution,
Chromatographic condition is as follows：GE Mono Q chromatographic columns, 10 × 100mm of model, stationary phase are Source 15Q, packing material size
10um, mobile phase be 3mol/L sodium-chloride water solutions and water, flow velocity 14ml/mim, Detection wavelength 210nm, sample size 5mL,
46.00min~49.00min target components are collected, type of elution is as follows：
3) component collected by is concentrated under reduced pressure into the saturated solution of sodium chloride, directly in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa
Sample is connected to -25 chromatographic column desalination of sephadex G；Collected product is in 40 ± 2 DEG C of temperature, vacuum degree >=0.09MPa, decompression
It is concentrated to dryness, obtains white solid, be high-purity Fondaparinux sodium.
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| EP1625135B1 (en) * | 2003-02-27 | 2009-04-08 | Glaxo Group Limited | Fondaparinux sodium composition of high purity |
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| EP2256139A1 (en) * | 2009-05-05 | 2010-12-01 | Sanofi-Aventis | Novel sulfated heptasaccharide and its use as antithrombotic agent |
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| CN103992364B (en) * | 2014-03-25 | 2016-08-10 | 南京天翔医药科技有限公司 | A kind of separating and extracting process of Fondaparinux sodium |
| CN103965269B (en) * | 2014-04-16 | 2018-05-04 | 杭州华东医药集团新药研究院有限公司 | Fondaparinux sodium of low moisture high-purity and preparation method thereof |
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