CN117946294B - Preparation method of energy-saving and environment-friendly enoxaparin sodium - Google Patents
Preparation method of energy-saving and environment-friendly enoxaparin sodium Download PDFInfo
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- CN117946294B CN117946294B CN202311505389.0A CN202311505389A CN117946294B CN 117946294 B CN117946294 B CN 117946294B CN 202311505389 A CN202311505389 A CN 202311505389A CN 117946294 B CN117946294 B CN 117946294B
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- 229960005153 enoxaparin sodium Drugs 0.000 title claims abstract description 53
- CIJQTPFWFXOSEO-NDMITSJXSA-J tetrasodium;(2r,3r,4s)-2-[(2r,3s,4r,5r,6s)-5-acetamido-6-[(1r,2r,3r,4r)-4-[(2r,3s,4r,5r,6r)-5-acetamido-6-[(4r,5r,6r)-2-carboxylato-4,5-dihydroxy-6-[[(1r,3r,4r,5r)-3-hydroxy-4-(sulfonatoamino)-6,8-dioxabicyclo[3.2.1]octan-2-yl]oxy]oxan-3-yl]oxy-2-(hydroxy Chemical compound [Na+].[Na+].[Na+].[Na+].O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1O)NC(C)=O)O[C@@H]1C(C[C@H]([C@@H]([C@H]1O)O)O[C@@H]1[C@@H](CO)O[C@H](OC2C(O[C@@H](OC3[C@@H]([C@@H](NS([O-])(=O)=O)[C@@H]4OC[C@H]3O4)O)[C@H](O)[C@H]2O)C([O-])=O)[C@H](NC(C)=O)[C@H]1C)C([O-])=O)[C@@H]1OC(C([O-])=O)=C[C@H](O)[C@H]1O CIJQTPFWFXOSEO-NDMITSJXSA-J 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229920002683 Glycosaminoglycan Polymers 0.000 claims abstract description 41
- 238000006731 degradation reaction Methods 0.000 claims abstract description 25
- 229920000669 heparin Polymers 0.000 claims abstract description 25
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000000108 ultra-filtration Methods 0.000 claims abstract description 16
- 229960002897 heparin Drugs 0.000 claims abstract description 14
- 238000004108 freeze drying Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 13
- 238000001556 precipitation Methods 0.000 claims description 13
- 230000015556 catabolic process Effects 0.000 claims description 12
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 11
- 229960001008 heparin sodium Drugs 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 8
- 229940073608 benzyl chloride Drugs 0.000 claims description 8
- 239000002244 precipitate Substances 0.000 claims description 8
- VIGBIBDAVDHOTP-UHFFFAOYSA-M sodium;ethanol;acetate Chemical compound [Na+].CCO.CC([O-])=O VIGBIBDAVDHOTP-UHFFFAOYSA-M 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 229960001950 benzethonium chloride Drugs 0.000 claims description 6
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000004042 decolorization Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 27
- 238000000034 method Methods 0.000 abstract description 14
- 229960000610 enoxaparin Drugs 0.000 abstract description 7
- 238000007068 beta-elimination reaction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000013557 residual solvent Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- 230000001276 controlling effect Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 241001494479 Pecora Species 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- -1 amino hexose Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000013256 coordination polymer Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003055 low molecular weight heparin Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000000787 affinity precipitation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000010808 liquid waste Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
Abstract
The invention relates to the technical field of medical biology, and provides a preparation method of energy-saving and environment-friendly enoxaparin sodium, which comprises the following steps: s1, preparing glycosaminoglycan salified compounds; s2, preparing a glycosaminoglycan esterified substance; s3, preparing enoxaparin solution; s4, freeze-drying. After heparin is subjected to salinization and esterified matter preparation, beta elimination and decoloration are achieved for the first time in the degradation process, the solution is directly subjected to ultrafiltration purification to obtain enoxaparin sodium solution, and the enoxaparin sodium raw material is obtained after the degradation process is finished and is directly subjected to freeze-drying. The enoxaparin sodium product prepared by the method has the advantages of short process route, high product yield, no use of a large amount of sodium chloride, ethanol and methanol, almost no residual solvents such as methanol or ethanol, and high environmental friendliness. By the technical scheme, the problems of more preparation process procedures, large use amount of organic reagent, high solvent residue and lower yield of enoxaparin sodium in the related technology are solved.
Description
Technical Field
The invention relates to the technical field of medical biology, in particular to a preparation method of energy-saving and environment-friendly enoxaparin sodium.
Background
Heparin is a glycosaminoglycan composed of uronic acid and amino hexose and derivatives thereof, and has an average molecular weight of 16000Da. Low molecular weight heparin is generally prepared from heparin by chemical degradation and has an average molecular weight of 4000-6500Da. Enoxaparin sodium is low molecular heparin with weight average 3800-5000, and is mainly used for preventing venous thromboembolic diseases and thrombosis of hemodialysis extracorporeal circulation, especially thrombosis related to orthopedics or general surgery.
Patent CN103554305B discloses a method for preparing enoxaparin by using an affinity precipitation medium, wherein heparin benzyl ester is degraded by sodium hydroxide in a high-temperature water bath, then pH is regulated, filtration is carried out, and ethanol with the concentration of 2-4 times is added for precipitation and fractionation, thus obtaining a crude enoxaparin sodium product. And (3) after drying, dissolving again, adding hydrogen peroxide, controlling the temperature to be 25-30 ℃, performing oxidization at pH of 8.5-10.5, adding sodium chloride after the oxidization is finished, and adding 2-3 times of ethanol for precipitation. Patent CN100582123C discloses enoxaparin and its preparation method, in which heparin benzyl ester is degraded in sodium hydroxide high-temperature water solution, cooled to room temperature, diluted hydrochloric acid is added to adjust pH to neutrality, 15% sodium chloride is added, and 2 times of methanol is used for fractional precipitation. And (3) drying the precipitate to obtain a crude enox product, then dissolving again, controlling the temperature to be 30-55 ℃, performing oxidation at pH of 8.0-11.0, adjusting the solution to be neutral after the oxidation is finished, and adding 10% sodium chloride and 2 times of methanol for precipitation. Patent CN102603925B discloses a method for directly producing enoxaparin sodium from crude heparin sodium, wherein heparin benzyl ester is degraded at high temperature by sodium hydroxide, then the pH is adjusted to be neutral, 2-3 times of ethanol is added for precipitation and fractionation, and the precipitate is separated to obtain the enoxaparin sodium crude product. Dissolving enoxaparin sodium crude product in water, adsorbing free sulfate radical in the solution, adding hydrogen peroxide for oxidation, adding 2 times of ethanol, and grading and precipitating again.
In the preparation process of enoxaparin sodium, after the degradation step and the oxidation step are finished, a large amount of sodium chloride is needed to be supplemented for auxiliary sedimentation, a large amount of external impurities are introduced to influence the ionization balance of heparin, then an organic reagent with the volume of at least 2 times of the solution is added for fractional sedimentation, and the production cost and the subsequent waste liquid post-treatment process are increased due to the use of a large amount of organic reagent. The degradation process and the oxidation process are carried out step by step, then the intermediate enoxaparin sodium crude product is required to be dried, and the oxidation process has harsh process conditions, finally, the yield of enoxaparin sodium is lower, and the industrial production is not facilitated. Thus, a process for preparing enoxaparin sodium in high yield is of great importance.
Disclosure of Invention
The invention provides an energy-saving and environment-friendly preparation method of enoxaparin sodium, which solves the problems of more preparation process procedures, large use amount of organic reagent and lower yield of enoxaparin sodium in the related technology.
The technical scheme of the invention is as follows:
the invention provides a preparation method of energy-saving and environment-friendly enoxaparin sodium, which comprises the following steps:
s1, adding water into a heparin sodium raw material to dissolve, and adding a benzethonium chloride solution to prepare a glycosaminoglycan salified compound;
S2, adding the glycosaminoglycan salt into N, N-dimethylformamide for dissolution, adding benzyl chloride for reaction, adding sodium acetate ethanol solution for precipitation, and washing and drying the precipitate to obtain glycosaminoglycan esterified substance;
s3, adding water into the glycosaminoglycan esterified substance to dissolve, adding a degradation agent at 50-60 ℃ to carry out degradation reaction, adding an oxidant to carry out decolorization and purification, adjusting the pH value to 6.5-7.0, filtering, and ultrafiltering to obtain enoxaparin sodium solution;
and S4, sterilizing and freeze-drying the enoxaparin sodium solution to obtain enoxaparin sodium.
As a further technical scheme, the degradation agent comprises sodium hydroxide and/or sodium carbonate, and the oxidant comprises hydrogen peroxide and/or peracetic acid.
As a further technical scheme, the heparin sodium raw material comprises porcine-derived mucosal heparin or sheep-derived mucosal heparin.
As a further technical scheme, the mass-volume ratio of the glycosaminoglycan salt to the N, N-dimethylformamide is 1:5-10 g/mL.
As a further technical scheme, the mass-volume ratio of the glycosaminoglycan salified compound to the benzyl chloride is 1:0.2-2 g/mL.
As a further technical scheme, in the step S2, the reaction temperature is 30-45 ℃ and the reaction time is 5-24 hours.
As a further technical scheme, the mass concentration of the sodium acetate ethanol solution is 8% -10%.
As a further technical scheme, in the step S3, the degradation reaction time is 1-3 hours; the decolorizing and purifying time is 3-6 hours.
As a further technical scheme, the mass ratio of the glycosaminoglycan esterified substance to the degradation agent is 1:0.05-0.1.
As a further technical scheme, the addition volume of the oxidant is 0.3% -1.0% of the volume of the degradation liquid obtained by the degradation reaction.
As a further technical scheme, in the step S3, ultrafiltration is performed by using a 1KD ultrafiltration membrane, the water supplementing amount in the ultrafiltration process is 1-2 times of the volume of the solution, and the volume of the enoxaparin sodium solution is 1/3-1/2 of the volume of the liquid medicine before ultrafiltration.
The working principle and the beneficial effects of the invention are as follows:
1. According to the invention, the heparin sodium raw material sequentially undergoes salinization and esterification and then enters a degradation process, sodium chloride and an organic reagent are not required to be added in the degradation process and a decoloration purification process for fractional precipitation, beta elimination and decoloration are realized in the degradation process for the first time, and the solution after decoloration purification is directly subjected to ultrafiltration purification and freeze-drying to obtain enoxaparin sodium, so that a large amount of sodium chloride, ethanol and methanol are omitted, the product almost has no solvent residues such as methanol or ethanol, the environment friendliness is high, no subsequent waste organic liquid waste methanol and waste ethanol treatment burden is caused, the production process has no explosion-proof requirement, and operators have no special protection requirements.
2. In the invention, the temperature and the pH are not required to be controlled in the decoloring and purifying process, the equipment requirement is low, the application range is wide, and the method is suitable for industrial application.
3. In the invention, the process route for producing enoxaparin sodium is short, the intermediate is accurately controlled, repeated operation and adjustment of control indexes are not needed, and the quality of the prepared enoxaparin sodium product is far better than the current enoxaparin sodium CP/EP/USP pharmacopoeia standard, and the yield is up to more than 72%.
4. In the invention, the pig-source mucosal heparin and the sheep-source mucosal heparin are used as heparin sodium raw materials, so that the source of the initial raw materials is expanded, and meanwhile, the sheep-source mucosal heparin is used as the initial raw materials, thereby realizing the effective utilization of sheep intestine resources and being suitable for industrial production.
Drawings
The invention will be described in further detail with reference to the drawings and the detailed description.
Fig. 1 is a process flow diagram of example 1 of the present invention.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
S1, preparation of glycosaminoglycan salified compound
100G of swine heparin sodium is taken, 1000mL of purified water is added for stirring and dissolution, and the other 250g of benzethonium chloride is added into 1500mL of purified water for dissolving, and the mixture is mixed, stirred for reaction for 2h, filtered by suction and dried to obtain 305g of glycosaminoglycan salified compound.
S2, preparation of glycosaminoglycan esterified product
Adding the glycosaminoglycan salt into 2.4L of N, N-dimethylformamide, stirring and dissolving, adding 180mL of benzyl chloride, stirring and reacting for 8 hours at 39-41 ℃, stopping, adding 7.7L of 8wt% sodium acetate ethanol solution for precipitation, washing the obtained precipitate with ethanol, dehydrating, and drying to obtain 103g of glycosaminoglycan esterified substance.
S3, preparation of enoxaparin solution
Adding 2L of purified water into the glycosaminoglycan esterified substance, stirring and dissolving, heating to 50-60 ℃, adding 7.8g of sodium hydroxide for degradation, controlling the temperature to 57-59 ℃, stopping controlling the temperature after reacting for 1.5h, adding 12mL of hydrogen peroxide, continuously stirring for 4.5h, adjusting the pH to 6.8, filtering, ultrafiltering the filtrate by using a 1KD ultrafiltration membrane, supplementing water for 3L, ultrafiltering the filtrate to 800mL, and stopping to obtain enoxaparin sodium solution.
S4, freeze-drying
And (3) filtering the enoxaparin sodium solution through a 0.2 mu m filter element, and freeze-drying to obtain 72.5g of sheep-derived enoxaparin sodium refined product, wherein the weight yield of the enoxaparin sodium refined product is 72.5%.
Example 2
S1, preparation of glycosaminoglycan salified compound
Adding 2kg of sheep-derived heparin sodium into 20L of purified water, stirring and dissolving, adding 30L of purified water into 5.6kg of benzethonium chloride, dissolving, mixing, stirring and reacting for 2h, filtering, and drying to obtain 6.081kg of glycosaminoglycan salified substance.
S2, preparation of glycosaminoglycan esterified product
Adding 30L of N, N-dimethylformamide into the obtained glycosaminoglycan salt, stirring and dissolving, adding 6L of benzyl chloride, stirring and reacting for 20 hours at 34-36 ℃, stopping, adding 90L of 8wt% sodium acetate ethanol solution for precipitation, washing the obtained precipitate with ethanol, dehydrating, and drying to obtain 2.012kg of glycosaminoglycan esterified substance.
S3, preparation of enoxaparin solution
Adding 40L of purified water into the glycosaminoglycan esterified substance, stirring and dissolving, heating to 50-60 ℃, adding 144g of sodium hydroxide for degradation, controlling the temperature to 55-57 ℃, stopping controlling the temperature after reacting for 2 hours, adding 160mL of hydrogen peroxide, continuously stirring for 4 hours, adjusting the pH to 6.8, filtering, ultrafiltering the filtrate by using a 1KD ultrafiltration membrane, supplementing water for 50L during the ultrafiltration, and stopping ultrafiltering the filtrate to 15L to obtain enoxaparin sodium solution.
S4, freeze-drying
And (3) filtering the enoxaparin sodium solution through a 0.2 mu m filter element, and freeze-drying to obtain 1.460kg of enoxaparin sodium refined product, wherein the weight yield of the enoxaparin sodium refined product is 73%.
Example 3
S1, preparation of glycosaminoglycan salified compound
Adding 2kg of sheep-derived heparin sodium into 20L of purified water, stirring and dissolving, adding 30L of purified water into 5.6kg of benzethonium chloride, dissolving, mixing, stirring and reacting for 2h, filtering, and drying to obtain 6.108kg of glycosaminoglycan salified substance.
S2, preparation of glycosaminoglycan esterified product
Adding 60L of N, N-dimethylformamide into the obtained glycosaminoglycan salt, stirring and dissolving, adding 1.3L of benzyl chloride, stirring and reacting for 5 hours at the temperature of 43-45 ℃, stopping, adding 90L of 8wt% sodium acetate ethanol solution for precipitation, washing the obtained precipitate with ethanol, dehydrating, and drying to obtain 2.095kg of glycosaminoglycan esterified substance.
S3, preparation of enoxaparin solution
Adding 40L of purified water into the glycosaminoglycan esterified substance, stirring and dissolving, heating to 50-60 ℃, adding 200g of sodium carbonate for degradation, controlling the temperature to 51-53 ℃, stopping controlling the temperature after reacting for 3 hours, adding 400mL of peracetic acid, continuously stirring for 3 hours and 10 minutes, adjusting the pH to 6.8, filtering, ultrafiltering the filtrate by using a 1KD ultrafiltration membrane, supplementing 80L of water during the ultrafiltration, and stopping ultrafiltering the filtrate to 20L to obtain enoxaparin sodium solution.
S4, freeze-drying
And (3) filtering the enoxaparin sodium solution through a 0.2 mu m filter element, and freeze-drying to obtain 1.456kg of enoxaparin sodium refined product, wherein the weight yield of the enoxaparin sodium refined product is 72.8%.
Example 4
S1, preparation of glycosaminoglycan salified compound
2Kg of sheep-derived heparin sodium is taken, 20L of purified water is added for stirring and dissolution, and another 5.6kg of benzethonium chloride is added into 30L of purified water for dissolution, and the mixture is mixed, stirred and reacted for 2 hours, filtered by suction, and dried to obtain 6.019kg of glycosaminoglycan salified compound.
S2, preparation of glycosaminoglycan esterified product
Adding 48L of N, N-dimethylformamide into the obtained glycosaminoglycan salt, stirring and dissolving, adding 12L of benzyl chloride, stirring and reacting for 24 hours at 30-32 ℃, stopping, adding 90L of 8wt% sodium acetate ethanol solution for precipitation, washing the obtained precipitate with ethanol, dehydrating, and drying to obtain 2.069kg of glycosaminoglycan esterified substance.
S3, preparation of enoxaparin solution
Adding 40L of purified water into the glycosaminoglycan esterified substance, stirring and dissolving, heating to 50-60 ℃, adding 105g of sodium hydroxide for degradation, controlling the temperature to 54-56 ℃, stopping controlling the temperature after reacting for 1h, adding 120 mL of hydrogen peroxide, continuously stirring for 5h and 50min, adjusting the pH to 6.8, filtering, ultrafiltering the filtrate by using a 1KD ultrafiltration membrane, supplementing water for 40L, ultrafiltering the filtrate to 14L, and obtaining enoxaparin sodium solution.
S4, freeze-drying
And (3) filtering the enoxaparin sodium solution through a 0.2 mu m filter element, and freeze-drying to obtain a refined enoxaparin sodium 1.511 kg, wherein the weight yield of the refined enoxaparin sodium is 75.6%.
The enoxaparin sodium refined products prepared in examples 1-4 are subjected to 1.6-dehydration derivative, molecular weight and distribution, potency, ethanol and methanol detection according to European pharmacopoeia EP10.5, and the detection results are shown in Table 1:
Table 1 results of the detection of enoxaparin sodium fine products prepared in examples 1 to 4
From the data of examples 1-4 in Table 1, it can be known that the enoxaparin sodium essence prepared by the invention meets the enoxaparin sodium CP/EP/USP pharmacopoeia standard, the quality is far higher than the current pharmacopoeia standard, the yield is up to more than 72%, and the ethanol and methanol contents are far lower than the current CP/EP/USP pharmacopoeia standard.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (1)
1. The preparation method of the energy-saving and environment-friendly enoxaparin sodium is characterized by comprising the following steps of:
s1, adding water into a heparin sodium raw material to dissolve, and adding a benzethonium chloride solution to prepare a glycosaminoglycan salified compound;
S2, adding the glycosaminoglycan salt into N, N-dimethylformamide for dissolution, adding benzyl chloride for reaction, adding sodium acetate ethanol solution for precipitation, and washing and drying the precipitate to obtain glycosaminoglycan esterified substance;
s3, adding water into the glycosaminoglycan esterified substance to dissolve, adding a degradation agent at 50-60 ℃ to carry out degradation reaction, adding an oxidant to carry out decolorization and purification, adjusting the pH value to 6.5-7.0, filtering, and ultrafiltering to obtain enoxaparin sodium solution;
s4, sterilizing the enoxaparin sodium solution, and freeze-drying to obtain enoxaparin sodium;
Sodium chloride and organic reagents are not required to be added in the degradation process and the decoloration and purification process for fractional precipitation;
The heparin sodium raw material comprises porcine-source mucosal heparin or sheep-source mucosal heparin;
The mass volume ratio of the glycosaminoglycan salified compound to the N, N-dimethylformamide is 1:5-10 g/mL;
the mass volume ratio of the glycosaminoglycan salified compound to the benzyl chloride is 1:0.2-2 g/mL;
in the step S2, the reaction temperature is 30-45 ℃ and the reaction time is 5-24 hours;
The mass concentration of the sodium acetate ethanol solution is 8% -10%;
in the step S3, the degradation reaction time is 1-3 hours; the decolorizing and purifying time is 3-6 hours;
the mass ratio of the glycosaminoglycan esterified substance to the degradation agent is 1:0.05-0.1;
the added volume of the oxidant is 0.3% -1.0% of the volume of the degradation liquid obtained by the degradation reaction;
in the step S3, ultrafiltration is performed by using a 1KD ultrafiltration membrane, the water supplementing amount in the ultrafiltration process is 1-2 times of the volume of the solution, and the volume of the enoxaparin sodium solution is 1/3-1/2 of the volume of the liquid medicine before ultrafiltration.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311505389.0A CN117946294B (en) | 2023-11-13 | Preparation method of energy-saving and environment-friendly enoxaparin sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311505389.0A CN117946294B (en) | 2023-11-13 | Preparation method of energy-saving and environment-friendly enoxaparin sodium |
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| Publication Number | Publication Date |
|---|---|
| CN117946294A CN117946294A (en) | 2024-04-30 |
| CN117946294B true CN117946294B (en) | 2024-11-19 |
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