CN116217752A - Drying method of enoxaparin sodium intermediate - Google Patents
Drying method of enoxaparin sodium intermediate Download PDFInfo
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- CN116217752A CN116217752A CN202310211946.1A CN202310211946A CN116217752A CN 116217752 A CN116217752 A CN 116217752A CN 202310211946 A CN202310211946 A CN 202310211946A CN 116217752 A CN116217752 A CN 116217752A
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- stirring
- benzethonium chloride
- heparin
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- 238000001035 drying Methods 0.000 title claims abstract description 46
- 229960005153 enoxaparin sodium Drugs 0.000 title claims abstract description 29
- 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 29
- 238000001914 filtration Methods 0.000 claims abstract description 60
- 229920000669 heparin Polymers 0.000 claims abstract description 59
- 238000001291 vacuum drying Methods 0.000 claims abstract description 55
- 229960002897 heparin Drugs 0.000 claims abstract description 49
- 238000005406 washing Methods 0.000 claims abstract description 41
- 230000007306 turnover Effects 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 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 abstract description 35
- 229960001950 benzethonium chloride Drugs 0.000 claims abstract description 35
- -1 heparin benzethonium chloride salt Chemical class 0.000 claims abstract description 29
- 239000012065 filter cake Substances 0.000 claims abstract description 18
- 239000000725 suspension Substances 0.000 claims abstract description 15
- 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 abstract description 10
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 85
- 238000000034 method Methods 0.000 claims 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 description 19
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000002441 reversible effect Effects 0.000 claims description 5
- 238000007599 discharging Methods 0.000 claims description 4
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical class C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 description 13
- 230000008569 process Effects 0.000 description 10
- 238000005886 esterification reaction Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000032050 esterification Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 4
- 238000007664 blowing Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- OHJKXVLJWUPWQG-PNRHKHKDSA-N Heparinsodiumsalt Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](O)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O)[C@H](C(O)=O)O1 OHJKXVLJWUPWQG-PNRHKHKDSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012691 depolymerization reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B25/00—Details of general application not covered by group F26B21/00 or F26B23/00
- F26B25/04—Agitating, stirring, or scraping devices
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
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- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mechanical Engineering (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, and provides a drying method of enoxaparin sodium intermediate, which comprises the following steps: s1, preparation: dissolving heparin sodium and benzethonium chloride respectively with water, and mixing to generate benzethonium chloride suspension; s2, standing and settling: delivering the benzethonium chloride suspension to a turnover type filtering, washing and drying machine, and standing for 1-10 hours; s3, filtering: filtering under 0.1-0.7 MPa to obtain a filter cake; s4, crushing a filter cake: heating to 40-70 ℃, controlling the vacuum degree of the cavity to-0.7 to-1.0 Mpa, and tilting to enable filter cakes on the filter plates to fall and be crushed; s5, rotary vacuum drying: rotating the turnover type filtering washing dryer at 40-70 ℃ and-0.7 to-1.0 Mpa, and drying the filter cake; s6, repeating the step S5 until the total rotary vacuum drying time is 24-72 hours, and obtaining the dried heparin benzethonium chloride salt. Through the technical scheme, the problems that the operation of the drying method of the enoxaparin sodium intermediate in the related technology is time-consuming and labor-consuming and the water content of the dried product is high are solved.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a drying method of enoxaparin sodium intermediate.
Background
Enoxaparin sodium is used as sodium salt of low molecular heparin for preventing venous thromboembolic diseases, treating deep venous embolism, preventing thrombosis in extracorporeal circulation of blood, etc. and has high bioavailability, long half life, less platelet reduction, less adverse reaction, etc. and is one safe and effective antithrombotic medicine. As an anticoagulant, enoxaparin sodium is one of the most commonly used preventive and therapeutic drugs for venous and arterial thromboembolism.
Enoxaparin sodium is prepared by taking heparin sodium as a raw material and performing the steps of salt preparation, esterification, depolymerization, decoloration, drying and the like. The salt preparation step adopts the steps of respectively dissolving heparin sodium and benzethonium chloride, mixing the heparin sodium and the benzethonium chloride to generate a water-insoluble compound salt-heparin benzethonium chloride salt, separating the heparin benzethonium chloride salt from water, and drying the salt to obtain a heparin benzethonium chloride salt dry product. In the process, different manufacturers have different methods, and a method for separating salt from water by using a centrifugal machine or nylon filter cloth is widely adopted, salt wet products are collected, and then the salt wet products are manually transferred into a vacuum drying oven or a freeze dryer for drying, wherein the lower the water content of the dried salt is, the better. The reason is that the water content of the heparin benzethonium chloride directly determines the esterification rate, and the existence of water can participate in side reactions in the esterification reaction of the next procedure, so that the esterification rate is lower, the depolymerization reaction of the next procedure is affected, and the molecular weight of enoxaparin sodium is further affected, namely a key quality index, see Jin Fei, the synthesis and purification of enoxaparin sodium [ D ] Zhejiang university, 2007.
In the prior art, the process of transferring the generated mixture of the heparin benzethonium chloride and the water to a centrifugal machine or nylon filter cloth for separation and the process of transferring the salt wet product to a vacuum drying oven or a freeze dryer are both manually operated, a great amount of time is required for manual operation, and the condition of scattering occurs in the process of transferring the salt by a tool by the manual operation, so that the waste of products is caused; the drying mode is adopted by the vacuum drying oven, and due to the fact that the viscosity of the heparin benzethonium chloride salt is high, in the drying process, the viscosity can be increased along with the reduction of moisture when the specific water content is achieved, the heparin benzethonium chloride salt is easy to harden into blocks during drying, internal moisture cannot volatilize, and further the problems that the product moisture exceeds standard, is not easy to dissolve, and is yellow in color are caused. The freeze dryer is adopted for drying, so that the input cost and the running cost are high, and the commercial production is not facilitated.
Disclosure of Invention
The invention provides a drying method of enoxaparin sodium intermediate, which solves the problems that the operation of the drying method of enoxaparin sodium intermediate in the related technology is time-consuming and labor-consuming and the water content of the dried product is higher.
The technical scheme of the invention is as follows:
a method for drying enoxaparin sodium intermediate, comprising the steps of:
s1, preparation: dissolving heparin sodium and benzethonium chloride respectively with water, and mixing to generate benzethonium chloride suspension;
s2, standing and settling: delivering the benzethonium chloride suspension to a turnover type filtering, washing and drying machine, and standing for 1-10 hours;
s3, filtering: filtering under 0.1-0.7 MPa to obtain a filter cake;
s4, crushing a filter plate: heating to 60-70 deg.c, pressurizing to-0.7 to-1.0 MPa, and tilting the filter washing drier to make the filter cake fall and break;
s5, rotary vacuum drying: rotating the turnover type filtering washing dryer at 40-70 ℃ and-0.7 to-1.0 Mpa, and drying the filter cake;
s6, repeating the step S5 until the total rotary vacuum drying time is 24-72 hours, and obtaining the dried heparin benzethonium chloride salt.
As a further technical scheme, in step S3, the filtration is followed by further reducing the pressure to 0.1MPa and continuing the pressurization for 1-10 hours.
As a further technical scheme, in step S4, the inclination angle is 100-160 ° when the tilt-turn type filtering, washing and drying machine is used.
According to the invention, the turnover type filtering washing dryer is inclined to 100-160 degrees, the height of the stirring paddle is raised to the highest, the filter cake on the filter plate falls and is broken under the drive of gravity and stirring, the height of the stirring paddle is lowered to the lowest, and the stirring is carried out for 1 circle, so that the heparin benzethonium chloride salt attached to the filter plate falls, the broken state is ensured, the exposed surface area is increased, and the dissipation of water vapor is facilitated.
As a further technical solution, in step S4, the filter plate has a pore size of 10 μm.
As a further technical scheme, in the step S5, the rotary vacuum drying comprises primary rotary vacuum drying and secondary rotary vacuum drying,
the primary rotary vacuum drying is to rotate the turnover type filtering washing dryer to 0 degree, raise the height of the stirring paddle to the highest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 100-160 degrees, continue to rotate to 40-70 degrees, continue to rotate to 80-100 degrees, and keep the angle dry for 30-60 minutes after the stirring is finished;
the secondary rotary vacuum drying is to rotate the turnover type filtering washing dryer to 0 degree, raise the height of the stirring paddle to the highest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 100-160 degrees after stirring is finished, lower the height of the stirring paddle to the lowest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 40-70 degrees, continue to rotate to 80-100 degrees, and keep the angle for 30-60 minutes for drying.
In the invention, after the surface of the material is slightly dried every 30-60 minutes, the equipment performs regular overturning and low-speed stirring to overturn and stir the material, so that the phenomenon of hardening and blocking formed by the increase of the viscosity of the water in the drying process is avoided, the material receives heat more uniformly, and the water is volatilized better.
As a further technical solution, in step S5, the rotary vacuum drying includes the following steps: and performing primary rotary vacuum drying, repeating for 1-4 times after the primary rotary vacuum drying is completed, and then performing secondary rotary vacuum drying, and repeating for 1-2 times after the secondary rotary vacuum drying is completed.
As a further technical scheme, step S6 further includes step S7 of stirring and crushing: and sequentially carrying out reverse stirring and forward stirring on the dried heparin benzethonium chloride salt, and discharging to obtain the powdered heparin benzethonium chloride salt.
According to the invention, the dried heparin benzethonium chloride salt is crushed through reverse stirring and forward stirring, so that on one hand, water embedded in the massive heparin benzethonium chloride salt is dissipated, the water content is further reduced, and on the other hand, the material is changed into powder, and the material is conveniently discharged and is subjected to esterification reaction after subsequent dissolution.
As a further technical scheme, in step S7, the rotational speed of the reverse rotation stirring is 5-10 rpm for 2-6 hours, and the rotational speed of the forward rotation stirring is 5-10 rpm for 2-6 hours.
The invention also provides the heparin benzethonium chloride salt, which is prepared by the drying method.
The invention also provides application of the heparin benzethonium chloride salt in the production of enoxaparin sodium.
The working principle and the beneficial effects of the invention are as follows:
1. according to the invention, the heparin benzethonium chloride suspension is conveyed into a turnover type filtering, washing and drying machine, and the steps of standing, sedimentation, filtering, filter cake crushing, rotary vacuum drying and the like are sequentially carried out, so that the water separation of heparin benzethonium chloride and the drying of heparin benzethonium chloride are simultaneously satisfied, the water content of the dried heparin benzethonium chloride is lower than 0.5%, the process can realize complete automation, the operation is convenient and fast, the process is suitable for commercial production, and the problems that the operation of a drying method of enoxaparin sodium intermediates in the related technology is time-consuming and labor-consuming and the water content of the dried product is higher are solved.
2. According to the invention, the heparin benzethonium chloride suspension generated by the reaction is firstly conveyed into a turnover filtering washing dryer, and is kept stand for 1-10 hours, natural sedimentation of heparin benzethonium chloride in water is realized by means of gravity in the process, and according to different molecular weights, the sedimentation rate is different, and the salt with larger molecular weight is firstly sedimentated to a filter plate and then is sedimentated, so that the salt can form a loose structure, and the salt with larger molecular weight is formed on the surface layer of the filter plate, so that the phenomenon of filter plate blockage caused by preferential entry of the salt with smaller molecular weight into the aperture of the filter plate is avoided in the filtering process, and the filtering effect is improved.
3. According to the invention, parameters such as vacuum degree, temperature, stirring frequency, equipment overturning frequency and angle are optimized in the steps of filtering, filter plate crushing, rotary vacuum drying and the like, so that the problem that the product viscosity is increased along with the decrease of moisture in the drying process is solved, the processes of heparin benzethonium chloride and water separation and heparin benzethonium chloride drying can be carried out in a turnover type filtering, washing and drying machine, the whole process is completely automatic, the operation is simple and convenient, the method is suitable for commercial production, and the practicability is high.
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: respectively dissolving and mixing heparin sodium and benzethonium chloride with water to generate heparin benzethonium chloride suspension;
s2, standing and settling: the height of the stirring paddle is reduced to the minimum, after the stirring paddle is close to a filter plate, the benzethonium chloride suspension is conveyed into a turnover type filtering, washing and drying machine, and the mixture is kept stand for 1 hour;
s3, filtering: pressurizing the top of the turnover type filtering washing dryer, vacuumizing the lower part of the turnover type filtering washing dryer to maintain the integral pressure of the tank body at 0.3Mpa, filtering liquid through a filter plate, and filtering residual solids;
s4, crushing a filter cake: when the pressure of the tank body is reduced to 0.1Mpa, continuously pressurizing and blowing for 10 hours, heating the jacket of the turnover type filtering and washing dryer, heating to 40 ℃, tilting the turnover type filtering and washing dryer to 100 ℃ and to-0.7 Mpa in vacuum, lifting the height of the stirring paddles to the highest, so that filter cakes on the filter plates fall and break, reducing the height of the stirring paddles to the lowest, stirring for 1 circle, and enabling heparin benzethonium chloride salts attached to the filter plates to fall; wherein the aperture of the filter plate is 10 mu m;
s5, rotary vacuum drying: the temperature is maintained at 40 ℃, the vacuum degree is controlled at-0.7 Mpa, the primary vacuum drying is carried out, and the secondary vacuum drying is carried out, specifically as follows:
first, carrying out vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of a stirring paddle to the highest, stirring for 5 circles at the rotating speed of 1rpm, continuing to rotate the equipment to 100 degrees, continuing to rotate the equipment to 40 degrees, continuing to rotate the equipment to 80 degrees, and keeping the angle for drying for 60 minutes;
repeating the vacuum drying step for 2 times;
and then carrying out secondary vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of a stirring paddle to the highest, stirring for 5 circles at a rotating speed of 1rpm, continuing to rotate to 100 degrees after stirring, reducing the height of the stirring paddle to the lowest, stirring for 5 circles at a rotating speed of 1rpm, continuing to rotate to 40 degrees, continuing to rotate to 80 degrees, and keeping the angle dry for 60 minutes;
repeating the secondary vacuum drying step for 1 time;
s6, repeating the step S5 until the total rotary vacuum drying time is 48 hours, and sampling and detecting the water content of the heparin benzethonium chloride salt, wherein the water content is 0.4%.
Example 2
S1, preparation: respectively dissolving and mixing heparin sodium and benzethonium chloride with water to generate heparin benzethonium chloride suspension;
s2, standing and settling: the height of the stirring paddle is reduced to the minimum, after the stirring paddle is close to a filter plate, the benzethonium chloride suspension is conveyed into a turnover type filtering, washing and drying machine, and the mixture is kept stand for 4 hours;
s3, filtering: pressurizing the top of the turnover type filtering washing dryer, vacuumizing the lower part of the turnover type filtering washing dryer to maintain the integral pressure of the tank body at 0.1Mpa, filtering liquid through a filter plate, and filtering residual solids;
s4, crushing a filter cake: when the pressure of the tank body is reduced to 0.1Mpa, continuously pressurizing and blowing for 6 hours, heating the jacket of the turnover type filtering and washing dryer, heating to 50 ℃, tilting the turnover type filtering and washing dryer to 140 ℃ and-0.8 Mpa in vacuum, lifting the height of the stirring paddle to the highest, so that the filter cake on the filter plate falls and breaks, reducing the height of the stirring paddle to the lowest, stirring for 1 circle, and enabling heparin benzethonium chloride salt attached to the filter plate to fall; wherein the aperture of the filter plate is 10 mu m;
s5, rotary vacuum drying: the temperature is maintained at 50 ℃, the vacuum degree is controlled at-0.8 Mpa, the primary vacuum drying is carried out, and the secondary vacuum drying is carried out, specifically as follows:
first, carrying out vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of the stirring paddle to the highest, stirring for 3 circles at the rotating speed of 2rpm, continuing to rotate the equipment to 140 degrees, continuing to rotate the equipment to 60 degrees, continuing to rotate the equipment to 90 degrees, and keeping the angle for drying for 30 minutes;
repeating the vacuum drying step for 4 times;
and then carrying out secondary vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of a stirring paddle to the highest, stirring for 3 circles at a rotating speed of 2rpm, continuing to rotate to 130 degrees after stirring, reducing the height of the stirring paddle to the lowest, stirring for 3 circles at the rotating speed of 2rpm, continuing to rotate to 60 degrees, continuing to rotate to 90 degrees, and keeping the angle dry for 30 minutes;
repeating the vacuum drying step for 2 times;
s6, repeating the step S5 until the total rotary vacuum drying time is 72 hours, and sampling and detecting the water content of the heparin benzethonium chloride salt, wherein the water content is 0.3%.
Example 3
S1, preparation: respectively dissolving and mixing heparin sodium and benzethonium chloride with water to generate heparin benzethonium chloride suspension;
s2, standing and settling: reducing the height of the stirring paddle to the minimum, and after the stirring paddle is close to a filter plate, conveying the benzethonium chloride suspension to a turnover type filtering, washing and drying machine, and standing for 10 hours;
s3, filtering: pressurizing the top of the turnover type filtering washing dryer, vacuumizing the lower part of the turnover type filtering washing dryer to maintain the integral pressure of the tank body at 0.7Mpa, filtering liquid through a filter plate, and filtering residual solids;
s4, crushing a filter plate: when the pressure of the tank body is reduced to 0.1Mpa, continuously pressurizing and blowing for 1 hour, heating the jacket of the turnover type filtering and washing dryer, heating to 70 ℃, tilting the turnover type filtering and washing dryer to 160 ℃ under the vacuum degree of-1.0 Mpa, lifting the height of the stirring paddle to the highest, so that the filter cake on the filter plate falls and breaks, reducing the height of the stirring paddle to the lowest, stirring for 1 circle, and enabling heparin benzethonium chloride salt attached to the filter plate to fall; wherein the aperture of the filter plate is 10 mu m;
s5, rotary vacuum drying: the temperature is maintained at 70 ℃, the vacuum degree is controlled at-1.0 Mpa, primary vacuum drying is carried out, and secondary vacuum drying is carried out, specifically as follows:
first, carrying out vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of a stirring paddle to the highest, stirring for 1 circle at the rotating speed of 5rpm, continuing to rotate the equipment to 160 degrees, continuing to rotate the equipment to 70 degrees, continuing to rotate the equipment to 100 degrees, and keeping the angle for drying for 60 minutes;
repeating the vacuum drying step for 1 time;
and then carrying out secondary vacuum drying: rotating the turnover type filtering washing dryer to 0 degrees, increasing the height of a stirring paddle to the highest, stirring for 1 circle at the rotating speed of 5rpm, continuing to rotate to 160 degrees after stirring, reducing the height of the stirring paddle to the lowest, stirring for 1 circle at the rotating speed of 5rpm, continuing to rotate to 70 degrees, continuing to rotate to 100 degrees, and keeping the angle dry for 60 minutes;
repeating the secondary vacuum drying step for 1 time;
s6, repeating the step S5 until the total rotary vacuum drying time is 24 hours, and sampling and detecting the water content of the heparin benzethonium chloride salt, wherein the water content is 0.5%.
Example 4
Steps S1-S6, as in example 1;
s7, stirring and crushing: setting the stirring rotating speed of the turnover type filtering washing dryer to 10rpm, starting a stirring reversing mode, and stirring for 2 hours; and setting the stirring rotation speed to 10rpm, starting a stirring forward rotation mode, stirring for 2 hours, stopping, and discharging to obtain the powdery heparin benzethonium chloride salt. The water content of the heparin benzethonium chloride salt is detected by sampling and is 0.3%.
Example 5
Steps S1-S6, as in example 1;
s7, stirring and crushing: setting the stirring rotating speed of the turnover type filtering washing dryer to 5rpm, starting a stirring reversing mode, and stirring for 6 hours; and setting the stirring rotation speed to 5rpm, starting a stirring forward rotation mode, stirring for 6 hours, stopping, and discharging to obtain the powdery heparin benzethonium chloride salt. The water content of the heparin benzethonium chloride salt is detected by sampling and is 0.2%.
Example 6
Enoxaparin sodium is produced using the benzethonium salt of heparin of example 1 as a starting material.
Example 7
Enoxaparin sodium is produced using the powdered heparin sodium salt of example 4 as a starting material.
Comparative example 1
And respectively dissolving and mixing heparin sodium and benzethonium chloride with water to generate heparin benzethonium chloride suspension, transferring to a centrifuge for separation to obtain a heparin benzethonium chloride wet product, and carrying out hot air circulation drying at 60 ℃ for 24 hours to obtain dried heparin benzethonium chloride, wherein the water content is 3.4% through detection, and the enoxaparin sodium is produced by taking the heparin benzethonium chloride as a raw material.
Examples 6 to 7 and comparative example 1, the production method of enoxaparin sodium was carried out according to the method disclosed in example 1 of the specification of the patent application of application No. 201310295978.0, and the molecular weight and molecular weight distribution of the enoxaparin sodium produced were as shown in the following table:
TABLE 1 molecular weight and molecular weight distribution of enoxaparin sodium produced in examples 6-7 and comparative example 1
As can be seen from the data in Table 1, when enoxaparin sodium is produced by using the heparin benzethonium chloride salt obtained by the drying method of the embodiment of the invention, the water content of the heparin benzethonium chloride salt prepared in the embodiment 6 and the embodiment 7 is lower, the degree of side reaction is low during esterification, the esterification rate is high, and the ratio of the molecular weight 2000-8000 of the prepared enoxaparin sodium is correspondingly higher, and the ratio of the part less than 2000 is more central.
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 (10)
1. A method for drying enoxaparin sodium intermediate, comprising the steps of:
s1, preparation: dissolving heparin sodium and benzethonium chloride respectively with water, and mixing to generate benzethonium chloride suspension;
s2, standing and settling: delivering the benzethonium chloride suspension to a turnover type filtering, washing and drying machine, and standing for 1-10 hours;
s3, filtering: filtering under 0.1-0.7 MPa to obtain a filter cake;
s4, crushing a filter cake: heating to 40-70 deg.c, controlling the vacuum degree of the cavity to-0.7 to-1.0 MPa, and tilting the filter washing drier to make the filter cake fall and break;
s5, rotary vacuum drying: rotating the turnover type filtering washing dryer at 40-70 ℃ and-0.7 to-1.0 Mpa, and drying the filter cake;
s6, repeating the step S5 until the total rotary vacuum drying time is 24-72 hours, and obtaining the dried heparin benzethonium chloride salt.
2. The method according to claim 1, wherein in step S3, the filtration is followed by further reducing the pressure to 0.1MPa and further pressurizing for 1 to 10 hours.
3. The method for drying enoxaparin sodium intermediate according to claim 1, wherein in step S4, the inclination angle is 100 ° to 160 ° in the inclined turnover type filtering washing dryer.
4. The method according to claim 1, wherein in step S4, the pore size of the filter plate is 10 μm.
5. The method for drying enoxaparin sodium intermediate according to claim 1, wherein in step S5, the spin vacuum drying comprises a primary spin vacuum drying and a secondary spin vacuum drying,
the primary rotary vacuum drying is to rotate the turnover type filtering washing dryer to 0 degree, raise the height of the stirring paddle to the highest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 100-160 degrees, continue to rotate to 40-70 degrees, continue to rotate to 80-100 degrees, and keep the angle dry for 30-60 minutes after the stirring is finished;
the secondary rotary vacuum drying is to rotate the turnover type filtering washing dryer to 0 degree, raise the height of the stirring paddle to the highest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 100-160 degrees after stirring is finished, lower the height of the stirring paddle to the lowest, stir for 1-5 circles at a rotating speed of 1-5 rpm, continue to rotate to 40-70 degrees, continue to rotate to 80-100 degrees, and keep the angle for 30-60 minutes for drying.
6. The method for drying enoxaparin sodium intermediate according to claim 5, wherein in step S5, the rotary vacuum drying comprises the steps of: and performing primary rotary vacuum drying, repeating for 1-4 times after the primary rotary vacuum drying is completed, and then performing secondary rotary vacuum drying, and repeating for 1-2 times after the secondary rotary vacuum drying is completed.
7. The method for drying enoxaparin sodium intermediate according to claim 1, wherein step S6 is followed by step S7 of stirring and crushing: and sequentially carrying out reverse stirring and forward stirring on the dried heparin benzethonium chloride salt, and discharging to obtain the powdered heparin benzethonium chloride salt.
8. The method according to claim 7, wherein in step S7, the rotational speed of the reverse rotation stirring is 5 to 10rpm for 2 to 6 hours, and the rotational speed of the forward rotation stirring is 5 to 10rpm for 2 to 6 hours.
9. A benzethonium salt of heparin, characterized by being produced by the drying process according to any one of claims 1 to 8.
10. Use of heparin benzethonium salts according to claim 9 for the production of enoxaparin sodium.
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