CN105037452A - Refining method for preparing high-purity fondaparinux sodium - Google Patents
Refining method for preparing high-purity fondaparinux sodium Download PDFInfo
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Abstract
A refining method for preparing high-purity fondaparinux sodium is low in production cost, simple to operate, and high in product purity and recovery rate, and adopts a high performance liquid chromatography preparation method, so as to prepare a fondaparinux sodium product of which the purity is 99 percent or higher in one step from a fondaparinux sodium crude product of which the fondaparinux sodium content is 50 percent or higher.
Description
Technical field
The invention belongs to medical art, relate to a kind of process for purification of medicine, be specifically related to a kind of process for purification preparing high purity Fondaparinux sodium.
Background technology
Fondaparinux sodium is a kind of anticoagulation developed by French Sai Nuofei, is synthetic, the indirect inhibitor of Xa factor that relies on of first antithrombin.Its antithrombotic acitivity is the result to factor Xa Selective depression that antithrombin Ⅲ (AT III) mediates.By selective binding in AT III, the Neutralization effect that Fondaparinux sodium enhances (about 300 times) AT III couple of factor Xa is original.And coagulation cascade reaction has been interrupted to the neutralizing effect of factor Xa, and inhibit the formation of zymoplasm and the increase of thrombus.Fondaparinux sodium can not deactivation zymoplasm (activation factor II), and does not act on thrombocyte.Succeeding in developing of it is the new milestone in the mankind's anti-bolt field.
Fondaparinux sodium is a kind of heparin five Carbohydrate drugs, its English Fondaparinuxsodium by name, chinesization formal name used at school is called: methyl O-(2-deoxidation-6-O-sulfonic group-2-sulfoamido-α-D-Glucopyranose)-(1 → 4)-O-(beta d glucopyranosiduronic acid)-(1 → 4)-O-(2-deoxidation-3, 6-O-disulfonic acid base-2-sulfoamido-α-D-Glucopyranose)-(1 → 4)-O-(2-O-sulfonic group-α-L-pyrans iduronic acid)-(1 → 4)-2-deoxidation-6-O-sulfonic group-2-sulfoamido-α-D-glucopyranoside ten sodium salt, chemical structural formula is as follows:
Fondaparinux sodium is pure chemistry synthesis, and synthetic route reaches 50 multisteps, and synthesis difficulty is large.The Fondaparinux sodium content in crude product obtained is 60% ~ 70%, and dopant species is many.Some contaminant characteristics is closely similar with the character of Fondaparinux sodium, is difficult to once be purified to more than 99% by common separation method.Being of current bibliographical information is refined through ion-exchange chromatography.
It take sepharose as the method for strong anion displacement chromatography post (QSepharoseFastFlow) the separation and purification Fondaparinux sodium of matrix that United States Patent (USP) 20050020536 discloses a kind of, the method is that moving phase carries out wash-out with sodium chloride aqueous solution, obtain the purity of more than 90%, then reach more than 98% purity through charcoal absorption.
Publication number is that the patent application of CN102659859 points out that the chromatographic column with single dispersing polymethacrylate ion-exchange chromatography media is filler carries out column chromatography, also obtains the purity of more than 98%.
We find by analysis, and above separation method mainly exists following problem:
1. adopt charcoal absorption product loss larger, rear assorted being not easy being 1.2 for relative retention time removes;
2., when being separated a large amount of Fondaparinux sodium crude products, need to use a large amount of expensive column chromatography media, production cost is high;
3. Fondaparinux sodium contaminant characteristics is close with Fondaparinux sodium character, and some plate detects and cannot judge, crossing every root pillar all needs liquid phase to monitor, and operate more complicated, and preparation time is longer.
In order to effectively solve aforesaid method Problems existing, the present invention works out a kind of process for purification of quick preparation high purity Fondaparinux sodium.
Summary of the invention
The object of the present invention is to provide a kind of process for purification preparing high purity Fondaparinux sodium.It is low that the method has production cost, feature simple to operate, and the Fondaparinux sodium prepared has the advantage that purity is high and the rate of recovery is high.
Content, by high performance liquid chromatography preparation method, can be that the Fondaparinux sodium crude product of more than 50% reaches more than 99% purity through once preparing by the present invention.
Fondaparinux sodium is the many sodium salts of a kind of piperylene, is insoluble in organic solvent, can not adopt general C18 reversed-phase column preparative separation.SOURCE series strong base anion resin, belong to high resolution IEC filler, relative price is cheap, and its 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 the various biochemical substances of fine separation purifying.
Concrete, the preparation method of Fondaparinux sodium of the present invention, comprises the following steps:
(1) be dissolved in purified water by Fondaparinux sodium crude product, concentration is 0.5 ~ 1g/mL;
(2) prepare Fondaparinux sodium with highly effective liquid phase chromatographic system gradient elution, collect the product that purity is higher;
Preparation liquid phase: waters prepares purifying instrument; Flow velocity: 14mL/min; Ultraviolet wavelength: 210nm; Sample size: 5mL; Mobile phase A, B carry out gradient elution, mobile phase A: sodium chloride solution, Mobile phase B: water for injection, carry out gradient elution in the following manner, collect 46.00min ~ 49.00min target components;
(3) concentrated, desalination, drying obtains highly purified Fondaparinux sodium.
Wherein, Fondaparinux sodium crude product belongs to currently available products, can commercially buy, and its purity is greater than 50%.
Wherein, mobile phase A is 1 ~ 3mol/L sodium chloride aqueous solution, is preferably 2mol/L sodium chloride aqueous solution.
Wherein, glass (GL) chromatographic column that highly effective liquid phase chromatographic system chromatographic column used is produced for GEHealthcare company, specification is 10 × 100mm ~ 75 × 500mm; With strong base anion resin for stationary phase, preferred SOURCE series;
Highly effective liquid phase chromatographic system chromatographic column filler granularity used is 3 ~ 30 μm, and particle diameter is more little is more conducive to product separation, but particle diameter more mini system pressure will be larger, be preferably particle size range be 10 ~ 15 μm.
Wherein, concentrated described in step 3, desalination, dry detailed process is: by collected component temperature 40 ± 2 DEG C, under the condition of vacuum tightness >=0.09MPa, be evaporated to the saturated solution of sodium-chlor, direct loading is to the desalination of sephadex G-25 chromatography column, by collected product temperature 40 ± 2 DEG C, under the condition of vacuum tightness >=0.09MPa, be evaporated to dry.
Preferably, the preparation method of Fondaparinux sodium of the present invention, comprises following operation steps:
(1) get Fondaparinux sodium crude product and be dissolved in purified water, be mixed with the aqueous solution of 1g/mL,
(2) prepare Fondaparinux sodium with highly effective liquid phase chromatographic system gradient elution, chromatographic condition is as follows:
GE glass column, the specification of chromatographic column is 50 × 250mm or 10x100mm, and stationary phase is Source15Q, packing material size 15um, and mobile phase A is 1 ~ 3mol/L sodium chloride aqueous solution, and Mobile phase B is water for injection, and flow velocity is 14ml/mim, and determined wavelength is 210nm.Sample size 5mL, according to the form below wash-out, collects 46.00min ~ 49.00min target components;
(3) component collected by is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column; Collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry, obtains white solid, obtains high purity Fondaparinux sodium.
The preparation method of Fondaparinux sodium of the present invention is through that screening obtains, and screening process is as follows:
The contrast experiment of GEQ and DIONEXCarboPac two kinds of chromatographic columns is specific as follows:
Chromatographic column: GESourceQ10/100; Preparation liquid phase: waters prepares purifying instrument; Flow velocity: 3.8ml/min; Ultraviolet wavelength: 210nm; Sample size: 20mg; Mobile phase A, B carry out gradient elution (mobile phase A: 117g/L sodium chloride solution, Mobile phase B: water for injection), and gradient is as follows:
GEQ chromatographic column prepares purifying spectrogram as shown in Figure 1:
Chromatographic column: DIONEXCarboPacPA1; Preparation liquid phase: waters prepares purifying instrument; Flow velocity: 5ml/min; Ultraviolet wavelength: 210nm; Sample size: 20mg; Mobile phase A, B carry out gradient elution (mobile phase A: 117g/L sodium chloride solution, Mobile phase B: water for injection), and gradient is as follows:
DIONEXCarboPac chromatographic column prepares purifying spectrogram as shown in Figure 2:
The spectrogram being prepared N1 by contrast GEQ and DIONEXCarboPac two kinds of chromatographic columns is found, impurity ability before GEQ chromatographic column product separation peak is better than the impurity after product separation peak, and the impurity ability after DIONEXCarboPac chromatographic column product separation peak is better than the impurity before product separation peak.Because impurity a large amount of in N1 is mainly before product peak, GEQ chromatographic column is therefore selected to carry out purification effect better.
In addition, the filler specification of DIONEXCarboPac chromatographic column is more single, is difficult to realize amplifying; And the filler specification kind of GEQ chromatographic column is more, meet the demand of amplifying further and producing.Therefore, select GEQ chromatographic column more reasonable.
Noun of the present invention is further explained:
GE (GL) chromatographic column: glass (GL) chromatographic column that GEHealthcare company produces, specification is 10 × 100mm ~ 75 × 500mm;
Stationary phase is Source15Q:Source is the low back-pressure medium (filler) of high speed, and be alkaline resin anion(R.A), particle diameter is 15um
The present invention adopts preparative liquid chromatography system, obtains through preparative separation the product that purity is greater than 99%.It is simple that preparation method of the present invention has technique, and the features such as production cost is low, constant product quality, meanwhile, moving phase of the present invention selects sodium chloride aqueous solution and water, can not to environmental effects.
Figure of description
Accompanying drawing 1:GEQ chromatographic column prepares purifying spectrogram
Accompanying drawing 2:DIONEXCarboPac chromatographic column prepares purifying spectrogram
Accompanying drawing 3: embodiment 1 Fondaparinux sodium crude product liquid chromatogram
Accompanying drawing 4: gained purified product liquid chromatogram after embodiment 1 Fondaparinux sodium is separated
Accompanying drawing 5: embodiment 2 Fondaparinux sodium crude product liquid chromatogram
Accompanying drawing 6: gained purified product liquid chromatogram after embodiment 2 Fondaparinux sodium is separated
Accompanying drawing 7: embodiment 3 Fondaparinux sodium crude product liquid chromatogram
Accompanying drawing 8: gained purified product liquid chromatogram after embodiment 3 Fondaparinux sodium is separated
Accompanying drawing 9: embodiment 4 Fondaparinux sodium crude product liquid chromatogram
Accompanying drawing 10: embodiment 4 Fondaparinux sodium sepharose purified product liquid chromatogram
Accompanying drawing 11: embodiment 4 Fondaparinux sodium dextrane gel purified product liquid chromatogram
Embodiment
By following specific embodiment, the present invention is further illustrated, but not as restriction.
Embodiment 1
Get Fondaparinux sodium crude product 15g, be dissolved in 15mL purified water, be mixed with the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration, sampling HPLC analyzes, and Fondaparinux sodium crude product purity is 59.5%, and spectrogram is shown in Fig. 3.GESourceQ (GL) chromatographic column (50 × 250), stationary phase is Source15Q, and moving phase is sodium chloride aqueous solution (1mol/L) and water, and flow velocity is 14ml/mim, and determined wavelength is 210nm.Sample size 5mL, according to the form below wash-out, collects 46.00min ~ 49.00min target components;
Collected component is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column, and collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry.Obtain white solid 5.75g.The rate of recovery is 64.4%.Sampling HPLC detects, and purity is 99.7%, and spectrogram is shown in Fig. 4.Gained compound
1hNMR data are: (400MHz, CDCl
3) 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
Get Fondaparinux sodium crude product 15g, be dissolved in 15mL purified water, be mixed with the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration, sampling HPLC analyzes, and Fondaparinux sodium crude product purity is 58.5%, and spectrogram is shown in Fig. 5.GESourceQ (GL) chromatographic column (50 × 250), stationary phase is Source15Q, and moving phase is sodium chloride aqueous solution (2mol/L) and water, and flow velocity is 14ml/mim, and determined wavelength is 210nm.Sample size 5mL, according to the form below wash-out, collects 46.00min ~ 49.00min target components;
Collected component is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column, and collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry.Obtain white solid 5.57g.The rate of recovery is 63.4%.Sampling HPLC detects, and purity is 99.8%, and spectrogram is shown in Fig. 6.
Embodiment 3
Get Fondaparinux sodium crude product 15g, be dissolved in 15mL purified water, be mixed with the aqueous solution of 1g/mL, through 0.22 μm of membrane filtration, sampling HPLC analyzes, and Fondaparinux sodium crude product purity is 64.2%, and spectrogram is shown in Fig. 7.GESourceQ (GL) chromatographic column (50 × 250), stationary phase is Source15Q, and moving phase is sodium chloride aqueous solution (3mol/L) and water, and flow velocity is 14ml/mim, and determined wavelength is 210nm.Sample size 5mL, according to the form below wash-out, collects 46.00min ~ 49.00min target components;
Collected component is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column, and collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry.Obtain white solid 5.58g.The rate of recovery is 57.9%.Sampling HPLC detects, and purity is 99.8%, and spectrogram is shown in Fig. 8.
Embodiment 4, comparative experiments
Get Fondaparinux sodium crude product 5g, be dissolved in 15mL purified water, sampling HPLC analyzes, and Fondaparinux sodium crude product purity is 67.5%, and spectrogram is shown in Fig. 9.Be that strong anion displacement chromatography post (QSepharoseFastFlow) separation and purification of matrix is carried out first time and purified with sepharose, first carry out rushing post with 0.2NNaCl, carry out, except low electric charge impurity, reclaiming Fondaparinux sodium with 0.8NNaCl with 0.46NNaCl again.Obtain Fondaparinux sodium (2.8g), purity is 83.3%, and spectrogram is shown in Figure 10.
2.8g Fondaparinux sodium crude product is dissolved in 28mL water, add 0.28g gac, stirring at room temperature two hours, filters, by filtrate temperature 40 ± 2 DEG C, vacuum tightness >=0.09MPa, be evaporated to the saturated solution of sodium-chlor, direct loading is to the desalination of sephadex G-25 chromatography column, and collected product is temperature 40 ± 2 DEG C, vacuum tightness >=0.09MPa, is evaporated to dry.Obtain white solid 1.6g.The rate of recovery is 47.4%.Sampling HPLC detects, and purity is 97.7%, and spectrogram is shown in Figure 11.
Can be further illustrated by above-mentioned experiment:
Preparation method of the present invention: 1. can obtain highly purified Fondaparinux sodium, and have the higher rate of recovery; 2. production cost reduces, and avoids having used a large amount of expensive column chromatography media; 3. simple to operate, be easy to produce.
Claims (10)
1. prepare a process for purification for high purity Fondaparinux sodium, it is characterized in that, comprise the steps:
(1) be dissolved in purified water by Fondaparinux sodium crude product, concentration is 0.5 ~ 1g/mL;
(2) prepare Fondaparinux sodium with highly effective liquid phase chromatographic system gradient elution, collect the product that purity is higher;
Preparation liquid phase: waters prepares purifying instrument; Flow velocity: 14mL/min; Ultraviolet wavelength: 210nm; Sample size: 5mL; Mobile phase A, B carry out gradient elution, mobile phase A: sodium chloride solution, Mobile phase B: water for injection, collect 46.00min ~ 49.00min target components;
(3) concentrated, desalination, drying obtains highly purified Fondaparinux sodium.
2. process for purification according to claim 1, is characterized in that, gradient elution process is as follows:
3. process for purification according to claim 1, is characterized in that, Fondaparinux sodium crude product belongs to currently available products, passable
Commercially buy, its purity is greater than 50%.
4. process for purification according to claim 1, is characterized in that, mobile phase A is 1 ~ 3mol/L sodium chloride aqueous solution, excellent
Elect 2mol/L sodium chloride aqueous solution as.
5. process for purification according to claim 1, is characterized in that, highly effective liquid phase chromatographic system chromatographic column used is GEMonoQ chromatographic column, with strong base anion resin for stationary phase, preferred SOURCE series, chromatographic column filler granularity is 3 ~ 30 μm, and being preferably particle size range is 10 ~ 15 μm.
6. process for purification according to claim 1, it is characterized in that, concentrated described in step 3, desalination, dry detailed process is: by collected component temperature 40 ± 2 DEG C, under the condition of vacuum tightness >=0.09MPa, be evaporated to the saturated solution of sodium-chlor, direct loading to the desalination of sephadex G-25 chromatography column, by collected product temperature 40 ± 2 DEG C, under the condition of vacuum tightness >=0.09MPa, be evaporated to dry.
7. process for purification according to claim 1, is characterized in that, comprises the following steps:
(1) get Fondaparinux sodium crude product and be dissolved in purified water, be mixed with the aqueous solution of 1g/mL,
(2) prepare Fondaparinux sodium with highly effective liquid phase chromatographic system gradient elution, chromatographic condition is as follows:
GEMonoQ chromatographic column, the model of chromatographic column is 10 × 100mm, stationary phase is Source15Q, packing material size 10um, and mobile phase A is 1 ~ 3mol/L sodium chloride aqueous solution, Mobile phase B is water for injection, flow velocity is 14ml/mim, and determined wavelength is 210nm, sample size 5mL, according to the form below wash-out, collects 46.00min ~ 49.00min target components;
(3) component collected by is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column; Collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry, obtains white solid, obtains high purity Fondaparinux sodium.
8. process for purification according to claim 1, is characterized in that, comprises the following steps:
(1) get Fondaparinux sodium crude product and be dissolved in purified water, be mixed with 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: GEMonoQ chromatographic column, model is 50 × 250mm, stationary phase is Source15Q, packing material size 10um, and mobile phase A is 1mol/L sodium chloride aqueous solution, Mobile phase B is water, flow velocity is 14ml/mim, and determined wavelength is 210nm, sample size 5mL, collect 46.00min ~ 49.00min target components, type of elution is as follows:
(3) component collected by is temperature 40 ± 2 DEG C, vacuum tightness >=0.09MPa, be evaporated to the saturated solution of sodium-chlor, direct loading is to the desalination of sephadex G-25 chromatography column, collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry, obtain white solid.
9. process for purification according to claim 1, is characterized in that, comprises the following steps:
(1) get Fondaparinux sodium crude product and be dissolved in purified water, be mixed with 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: GEMonoQ chromatographic column, model is 50 × 250mm, stationary phase is Source15Q, packing material size 15um, and mobile phase A is 2mol/L sodium chloride aqueous solution, Mobile phase B is water, flow velocity is 14ml/mim, and determined wavelength is 210nm, sample size 5mL, collect 46.00min ~ 49.00min target components, type of elution is as follows:
(3) component collected by is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column; Collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry, obtains white solid, is high purity Fondaparinux sodium.
10. process for purification according to claim 1, is characterized in that, comprises the following steps:
(1) get Fondaparinux sodium crude product and be dissolved in purified water, be mixed with 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: GEMonoQ chromatographic column, model is 50 × 250mm, stationary phase is Source15Q, packing material size 10um, moving phase is 3mol/L sodium chloride aqueous solution and water, and flow velocity is 14ml/mim, determined wavelength is 210nm, sample size 5mL, collect 46.00min ~ 49.00min target components, type of elution is as follows:
(3) component collected by is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to the saturated solution of sodium-chlor, and direct loading is to the desalination of sephadex G-25 chromatography column; Collected product is temperature 40 ± 2 DEG C, and vacuum tightness >=0.09MPa, is evaporated to dry, obtains white solid, is high purity Fondaparinux sodium.
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| CN105037452B (en) | 2018-10-09 |
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