CN103551100A - Device and method for improving stability of crystals by using continuous and rapid reactive crystallization - Google Patents
Device and method for improving stability of crystals by using continuous and rapid reactive crystallization Download PDFInfo
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- CN103551100A CN103551100A CN201310530713.4A CN201310530713A CN103551100A CN 103551100 A CN103551100 A CN 103551100A CN 201310530713 A CN201310530713 A CN 201310530713A CN 103551100 A CN103551100 A CN 103551100A
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Abstract
The invention discloses a device and method for improving stability of crystals by using continuous and rapid reactive crystallization. The device comprises a kettle-type reactor and a tubular reactor connected with the kettle-type reactor in series, wherein the kettle-type reactor is internally provided with a liquid jet impacting feeding device; the liquid jet impacting feeding device comprises a hollow pipe and more than two feeding pipes, and the pipe wall of the hollow pipe is provided with a through hole through which the feeding pipes pass; the feeding pipes are inserted from an upper port of the hollow pipe and can go out from the through hole in the pipe wall, discharge openings of the feeding pipes are connected with nozzles, and the discharge opening and/or nozzle of each feeding pipe is fixed at the lower end part of the hollow pipe through a fixing frame; the nozzles are arranged in a specific way to ensure compacting collision, and a feeding pipe section between the through hole in the hollow pipe and the fixing frame is of an arc-shaped structure. The device and the method provided by the invention have the advantages that the average size and granularity of the crystals are uniform, and the purity and stability of a product are greatly improved.
Description
Technical field
The invention belongs to chemical pharmaceutical crystallization technique field, be specifically related to the device and method that a kind of continuous fast reaction crystallization improves crystal stability.
Background technology
Crystallization process, the basic production process as important, is widely used in the middle of various industrial fields.Therefore, the crystal mass of its generation, to downstream process, such as filtering, grind and being dried, also has transportation and storage process to have important impact.
For many medicine crystal compounds, stability is all the problem that needs emphasis to consider.As everyone knows, the medicine crystal compound that great majority obtain by reaction crystallization process all comprises crystal and noncrystal two kinds of structures.Crystal structure, because its lower internal freedom energy can be so that medicine be more stable.The change of drug crystallization form not only can affect its outward appearance, also can in the situation that not changing medicine internal structure, reduce the validity of medicine.Therefore, improve the content of crystal structure in medicine, not only can improve its stability, can also increase its validity.
Reaction crystallization process is superimposed course of reaction and crystallization process, and this makes whole process become complicated.Reaction crystallization process is except having the feature of course of reaction and crystallization process, also has many self distinctive features, and these features make traditional crystallization theory of extensive use no longer applicable.First, the steady domain tyeory that is situated between is no longer applicable, because the product that reactive crystallization produces, in order to improve productive rate, general insoluble or be slightly soluble in the organic solvent in its system, this just makes the solubility of product almost nil, the infinitely great ，Jie Wen of degree of supersaturation district also so not exists.Secondly, in the infinitely-great situation of degree of supersaturation, have a large amount of secondary nucleations and exist in system, this variation directly causes polymerism to replace the important impetus that interface growth becomes crystal growth.
Being not only traditional crystallization theory cannot be suitable for, and the traditional crystallization reactor based on this Theoretical Design also faces huge challenge.In traditional batch reactor, course of reaction and crystallization process occur simultaneously and complete in same container, and this production method has three significant shortcomings:
First, the mixed effect of traditional batch formula reactor is poor, and this just means, reach a considerable time of abundant mixing needs of reactant.For kinetics and the slower reaction crystallization process of crystallization kinetics, the length of incorporation time is not an important parameter in Process Design.But, the fast reaction crystallization process carrying out under high degree of supersaturation for those, inadequate mixing can cause final products attribute, comprises the very big decline of crystal size distribution, form and purity.
Secondly, the time of staying of reactant and product can not keep identical.The reaction zone entering in reactor in the reaction incipient stage can react fully, and has the longer time of staying to contact growth with crystal seed.But the reactant finally entering in reactor may, in the situation that also needing the more time of staying, leave reactor in advance.The time of staying that this reactant and product are not identical, except meeting reduces productive rate, also can cause inhomogeneous crystal size to distribute.The medicine that can degrade in course of reaction for some, under extreme case, the different time of staying may cause product just a large amount of degradeds in process of production.
The 3rd, intermittent operation needs regular downtime.The taking-up that all essential factor is product of whole production process stops, this mode of operation is except losing time and labour, the operating condition in reactor, for example concentration and acid-base value, also can change along with the variation of time, thus cause batch and batch between difference be difficult to avoid.
In order to improve mixing efficiency, patent US5,314, the 506 a kind of methods that provide liquid jet to impact realize the abundant mixing of liquid before crystal nucleation.By this process, can directly obtain the crystalline product of high surface, high-purity, high stability.Patent US6,302,958B1 and US6,558,435B2 has added again ultrasonic probe on this basis, thereby has obtained stable submicron-scale crystal.These patents have been improved the mixed effect in reactor, but also have some shortcomings simultaneously.Such as course of reaction and crystallization process or generation simultaneously in same container, cannot guarantee the unified time of staying.
Summary of the invention
In order to address the above problem, the invention provides a kind of continous way crystallization reactor that is applicable to fast reaction crystallization process.This reactor carries out the course of reaction in reaction crystallization process and crystallization process separated and realizes continued operation with the reactor of two kinds of different characteristics.Thisly with the tank reactor of impact jet flow feed arrangement and the serial operation of tubular reactor, can realize the time of staying that product is identical, thereby can before production, to product quality, design control.
The object of the invention is achieved through the following technical solutions:
Continuous fast reaction crystallization improves a device for crystal stability, comprises tank reactor and the tubular reactor of connecting with it; Liquid jet is set in tank reactor and impacts feed arrangement, described liquid jet impacts feed arrangement and comprises a hollow pipe and plural feed pipe, the tube wall of hollow pipe is provided with the through hole passing for feed pipe, described feed pipe inserts from the upper port of hollow pipe, and the through hole from its tube wall passes, the discharging opening of feed pipe is all connected with nozzle, the discharging opening of each feed pipe and/or nozzle are fixed on the bottom of hollow pipe by fixed mount, with guarantee its high-velocity fluid to affect upper/lower positions constant; Described nozzle arranges to guarantee the discharging mode bumping against that liquidates; Through hole on described hollow pipe and the charging pipeline section between fixed mount are an arcuate structure.
Described hollow pipe vertically arranges, and the angle that nozzle becomes with horizontal plane is 0 °～20 °, and injector spacing is 5～15mm.
Identical with feed pipe quantity along being evenly provided with in pipe week on described fixed mount, for the fixing hole clipping of discharging opening and/or nozzle.
Described tank reactor top is cylindrical and is furnished with chuck, and bottom is conical.
In described tank reactor, be provided with a plurality of baffle plates or agitator.
Tubular reactor level, or vertically place, or be spiral placement.
Two or more reactant liquors are pumped into from the different feeds pipe of liquid jet impact feed arrangement respectively, the mode that reactant liquor bumps against to liquidate enters tank reactor from nozzle ejection, in tank reactor, in complete mixing flow mode, react nucleation, reactant liquor flows into tubular reactor afterwards, and flow and carry out crystal growth in the mode of laminar flow, then obtain stable crystal product through post processing.
In tank reactor, liquid jet impact velocity is not less than 5m/s.
Cefuroxime acid solution after sodium lactate solution and decolouring processing is pumped into from two feed pipes of liquid jet impact feed arrangement respectively, the mode that reactant liquor bumps against to liquidate enters tank reactor from nozzle ejection, in tank reactor, react at least 8min, course of reaction stirs with 50～150rpm speed; Reactant liquor flows into tubular reactor afterwards, reacts at least 22min in tubular reactor, after filtration, dry processing, finally makes Cefuroxime Sodium.
In tank reactor, it is 10m/s that described liquid jet impacts charging rate.
The present invention comprises two parts, a tank reactor and a tubular reactor.For being reacted into nuclear process, the type of flow of complete mixing flow is optimal selection, because the generation of degree of supersaturation needs the abundant mixing of reactant.Tank reactor collocation liquid jet impacts feed arrangement and can before nucleation, realize this requirement.If required tank reactor is larger, can adds paddle and baffle plate and further increase mixed effect.For crystal growing process, the type of flow of laminar flow is optimal selection, because there is no back-mixing, not only mean that crystal all growing in environment uniformly, and the time of staying of these crystal is all identical, and size is also therefore identical.
More particularly, the present invention comprises a tank reactor (reaction/nucleation district), be used in conjunction with liquid jet simultaneously and impact feed arrangement, paddle and baffle plate strengthen mixing intensity, and the tubular reactor of a suitable length (crystal vitellarium) is to avoid product back-mixing.A pair of or multipair impact feed arrangement can use simultaneously and mix two kinds or more of fluids on one side.When using jet feed arrangement, feed nozzle will keep toward each other and be uniformly distributed, and guarantees the discharging collision that can liquidate, and nozzle and horizontal plane are preferably formed as the angle of 0 °-20 °, best >=10 °, can prevent from that one charging from impacting in the nozzle that enters opposite to result in blockage like this.Above-mentioned feed arrangement can be immersed in liquid or be suspended on liquid surface and use, and the position of each feed arrangement can identically also can be adjusted according to different condition.Distance between nozzle can identically also can be adjusted according to different condition.Such as, in general, when feed arrangement is immersed in while using in liquid, the spacing between nozzle need to suitably be dwindled.In addition, according to different reactor sizes, for reaching better mixed effect, can adopt one or more agitators to be used in conjunction with.
The feed liquid of different feeds pipe can be different solvent mixture, can be anti-solvent, can be also reactant (acid/alkali, acid/salt, or alkali/salt).Selected solvent mixture preferably can be after two liquid contacts moment react, can make like this advantage of jet impulse feed arrangement perform to maximum.In tank reactor, in liquid jet impact feed arrangement different spray nozzles, the temperature of liquid can be controlled separately, and reaction temperature can loop control by water/oil.The selection of temperature will guarantee that carried liquid can adverse current not get back in jet nozzle.In the scope that the requirement of pump allows, the liquid mixture of conveying can comprise a certain amount of crystal seed, can reduce like this generation of crystal polymerism in mixed process.All the other crystal seeds can directly be invested in tank reactor.
The chamber of tank reactor is preferably cylindrical and is furnished with chuck, can control reaction temperature by water, oil circulation like this.Tank reactor need to have a downward-sloping conical lower section towards bottom centre, and angle of inclination is preferably 10 °-20 °, can conveniently be connected with tubular reactor like this.Agitator can be spiral according to concrete operations environmental selection, oar formula, anchor formula or hinging type.If the twice of the height greater than width of tank reactor, can select two or more coaxial stirrers to realize maximum mixed effect.In the situation that not affecting agitator work, in order to guarantee that the nucleus jet impulse region that speeds away removes to contact crystal seed, the position of jet impulse feed arrangement is better close to more from agitator.
How much to jet impulse feed arrangement no matter adopt, every pair of feed arrangement all will guarantee that high-speed jet charging is to produce the required high turbulent flow state of abundant mixing.Liquid jet impact velocity should be not less than 5m/s, is preferably 10m/s, can be increased to 20m/s.If feed arrangement operates more than liquid level, can suitably reduce charging rate.If the pressure of pump allows, there is no in theory speed limit.Charging rate can be adjusted by a lot of modes, such as changing jet expansion diameter, or the pressure of increasing supply.
With the tubular reactor that tank reactor conical lower section is connected, its flow rate can be controlled by discharging pump or valve.Feed rate should equate with discharging speed, to guarantee the liquid level in tank reactor, can adjust under special circumstances.For preventing that crystal from falling, the flowing velocity of liquid in pipe suspension should not be too slow, and in pipe, flowing velocity can regulate by changing caliber.In pipe, flow regime should be full-section pipe-flow laminar condition, can reduce unnecessary back-mixing like this.Need to be compared with the crystallization process of long crystal growth time for some, the length of needed tubular reactor may be longer, adopts horizontal positioned may cause being difficult in actual working environment realizing, and at this moment can adopt vertical or be spiral placement.In addition, when adopting horizontal positioned, for preventing line clogging, can downward-sloping 0-20 ° to guarantee that crystal flows out smoothly.
As continous way crystallization reactor, the time of staying of its course of reaction and crystallization process can be determined by kinetics and crystallization kinetics, then can regulate by changing the volume of tank reactor and tubular reactor.For example, for synthetic this reaction crystallization process of Cefuroxime Sodium, utilizing UV optical spectrum instrumentation can obtain its course of reaction needs to complete for 8 minutes, utilizing FBRM can obtain its crystallization process needs to complete for 22 minutes, so the time of staying of reactant in tank reactor should be not less than 8 minutes, and the time of staying of gained crystal in tubular reactor should be not less than 22 minutes.Then, according to different treating capacities, the volume of reactor can be determined.In addition, many reactor parallel operations can realize larger treating capacity.
Compared with prior art, tool of the present invention has the following advantages:
(1) adopt tank reactor (reaction/nucleation district) and the tubular reactor (crystal vitellarium) of connecting with it course of reaction is separated with crystallization process.In tank reactor, by new liquid jet impulse feed arrangement is set, realized reactant fully mixing rapidly before nucleation.
(2) compare with the crystal of producing by conventional junction crystal type, the crystal structure Du Genggao that the present invention produces, size distribution is more even, and purity and stability are better.The speed that the raising of this degree of crystallinity not only can reduce drug degradation makes it have the longer shelf-life, greatly reduces simultaneously and filters the time consuming with the grinding stage.In addition, the sizeable crystal of size uniform can improve the rate of dissolution of medicine, and this is a very important parameter for injecting drug use.
(3) the continuous mode of production of the present invention also has many good qualities.First, the continuous mode of production can realize larger output with less reactor volume, has so both saved resource and labour, can improve productive profit again.Secondly, the continuous mode of production can guarantee that all products are grown up in even environment and the time of staying is also identical, like this with regard to difference between having eliminated thoroughly batch.
Accompanying drawing explanation
Fig. 1 is the structural representation of the embodiment of the present invention 1 device, comprising: jacketed tank reactor 4, tubular reactor 5, agitator 3, liquid jet feed arrangement 6, the first feed liquid 1 and the second feed liquid 2.
Fig. 2 is the top view of Fig. 1, comprising: liquid jet feed arrangement mentioned nozzle area 7, tank reactor (reaction/nucleation district) 4 and tubular reactor (crystal vitellarium) 5.
Fig. 3 a is the structural representation of the embodiment of the present invention 2 liquid jet feed arrangements, and b is tubular structure schematic diagram, and c is a fixed rack structure schematic diagram while looking up, d, e, the structural representation of fixed mount when f is the different setting angle of nozzle.
Fig. 4 is the XRD figure of product, and a is traditional product, and b is embodiment 1 product.
Fig. 5 is the particle diameter distribution map of product, and a is traditional product, and b is embodiment 1 product.
Fig. 6 is the SEM figure of product, and a is traditional product, and b is embodiment 1 product.
Fig. 7 is the XRD figure of embodiment 2 products.
Fig. 8 is the particle diameter distribution map of embodiment 2 products.
Fig. 9 is the SEM figure of embodiment 2 products.
The specific embodiment
Below in conjunction with the drawings and specific embodiments, this use is described further, so that those skilled in the art can better understand the present invention also, can be implemented, but illustrated embodiment is not as a limitation of the invention.
Continuous fast reaction crystallization improves a device for crystal stability, as shown in Figure 1, 2, 3, comprises tank reactor 4 and the tubular reactor 5 of connecting with it; Liquid jet is set in tank reactor 4 and impacts feed arrangement 6, described liquid jet impacts feed arrangement 6 and comprises vertical hollow pipe 601 and two feed pipes 602, the tube wall of hollow pipe 601 is provided with the through hole 603 passing for feed pipe, described feed pipe 602 inserts from the upper port of hollow pipe 601, and the through hole from its tube wall 603 passes, the discharging opening of feed pipe 602 is all connected with nozzle 605, the nozzle 605 of each feed pipe is fixing by fixed mount 604, on described fixed mount, along pipe week, is evenly provided with 2 for the hole clipping 607 of fixed nozzle; Through hole 603 on described hollow pipe and the charging pipeline section between fixed mount 604 are an arcuate structure 606.Described nozzle 605 is oppositely arranged, and nozzle and horizontal plane angulation are 0 °, and spacing is 6mm, as shown in Fig. 3 (f).Described tank reactor 4 tops are cylindrical and are furnished with chuck, and bottom is conical.In described tank reactor, be provided with 1 agitator 3.Tubular reactor 5 horizontal positioned.
Liquid jet impacts feed arrangement 6 and is immersed in the liquid in tank reactor 4, coordinates a paddle 3 to use simultaneously simultaneously.The hole clipping 607 that two nozzles 605 are fixed respectively on frame is fixed, with guarantee its high-velocity fluid to affect upper/lower positions constant.The first feed liquid 1 and the second feed liquid 2 are carried out hybrid reaction nucleation in tank reactor 4, and paddle 3 takes away tank reactor 4 by these little crystal grain and contacts with crystal seed subsequently.The volume of tank reactor will be determined according to kinetics, to guarantee that reaction can complete in tank reactor.After completing in tank reactor and being reacted into nuclear process, liquid mixture leaves tank reactor and enters into tubular reactor 5, and the laminar flow liquid form in tubular reactor can guarantee that the time of staying of crystal growth is consistent.The length of tubular reactor is determined by crystal dynamics, guarantee that crystal can grow into specified size in the situation that there is no back-mixing.
The continuous fast reaction crystallization production process of Cefuroxime Sodium in laboratory scale reactor
Under 20-25 ℃ of condition, 9.0g sodium lactate (60%) is dissolved in the mixed solvent of 40ml acetone and 50ml ethanol (95%).Stir after 10 minutes, this mixed liquor is filtered, and clean with 10ml ethanol (95%), together with filtrate, put into beaker standby (the first feed liquid 1).10.0g cefuroxime acid is dissolved in the mixed solvent of 246ml acetone and 124ml ethanol (95%), and adds 0.3g active carbon under 38-42 ℃ of condition, to stir decolouring in 10-15 minute.Then, this mixed liquor is filtered, and with 30ml acetone cleaning active charcoal filter cake, together with filtrate, put into beaker standby (the second feed liquid 2).
Adjust feed pump flow velocity, under 25-28 ℃ of condition, with the charging rate of 10m/s, two bursts of liquid chargings are injected to tank reactor by jet impulse feed arrangement simultaneously, agitator speed is controlled at 80-100rpm.Adjust each valve and take and guarantee that the time of staying of liquid mixture in tank reactor is 8 minutes, mixed liquid flows into tubular reactor afterwards, and the time of staying in tubular reactor is 22 minutes.
After process finishes, mixed liquid is filtered and obtains product Cefuroxime Sodium, and reach 8.0 end by mixed liquor cleaning filter cake to the cleaning solution pH value of acetone and 95% ethanol (1.8:1).Dry through 24 hours normal-temperature vacuums again, obtain final products.
XRD, Morphologi G3 and SEM testing result show (Fig. 4～6), and the product degree of crystallinity that the product obtaining through the present invention obtains compared with conventional method is higher, and crystal size distribution is also more even.Stability of drug products experimental result shows (table 1), and the product stability obtaining through the present invention improves at least three look levels.
Table 1
The continuous fast reaction crystallization of this enforcement improves the device of crystal stability and the difference of embodiment 1 is: liquid jet impacts feed arrangement, and wherein, nozzle and horizontal plane angulation are 10 °, and spacing is 12mm, as shown in Fig. 3 (d).
The continuous fast reaction crystallization production process of Cefuroxime Sodium in pilot scale reactor
Under 20-25 ℃ of condition, 720g sodium lactate (60%) is dissolved in the mixed solvent of 3200ml acetone and 4000ml ethanol (95%).Stir after 20 minutes, this mixed liquor is filtered, and clean with 1000ml ethanol (95%), together with filtrate, put into beaker standby (the first feed liquid 1).800g cefuroxime acid is dissolved in the mixed solvent of 2000ml acetone and 1000ml ethanol (95%), and adds 100g active carbon under 38-42 ℃ of condition, to stir decolouring in 20-30 minute.Then, this mixed liquor is filtered, and with 3000ml acetone cleaning active charcoal filter cake, be communicated with filtrate and put into together beaker standby (the second feed liquid 2).
Adjust feed pump flow velocity, under 25-28 ℃ of condition, with the charging rate of 10m/s, two bursts of liquid chargings are injected to tank reactor by jet impulse feed arrangement simultaneously, agitator speed is controlled at 50-80rpm.Adjust each valve and take and guarantee that the time of staying of liquid mixture in tank reactor is 8 minutes, the time of staying in tubular reactor is 22 minutes.
After process finishes, mixed liquid is filtered and obtains product Cefuroxime Sodium, and reach 8.0 end by mixed liquor cleaning filter cake to the cleaning solution pH value of acetone and 95% ethanol (1.8:1).Dry through 24 hours normal-temperature vacuums again, obtain final products.
XRD, Morphologi G3 and SEM testing result show (Fig. 7～9), and the product degree of crystallinity that the product obtaining through the present invention obtains compared with conventional method is higher, and crystal size distribution is also more even.Stability experiment result shows (table 2), and the product stability obtaining through the present invention improves at least two look levels.
Table 2
The continuous fast reaction crystallization of this enforcement improves the device of crystal stability and the difference of embodiment 1 is:
Described nozzle and horizontal plane angulation are 15 °, and spacing is 10mm, as shown in Fig. 3 (e).
In industrial-scale reactor, the continuous fast reaction crystallization production process of Cefuroxime Sodium is calculated
The object that this suboptimization is calculated is that operating time and product treatment amount based on applied 3000L traditional batch formula reactor in current industrial production, adopt reactor of the present invention to substitute, thereby further show its commercial viability and industrial advantages.
In traditional industry production process, completing a production cycle need to approximately 10 hour.From table 3, can see, as the filtration of fruit product and process of lapping cannot be realized continued operation with production process, course of reaction need to complete in 2 hours so, by calculating, can obtain, and now only needed the reactor of the present invention of 4 50L just can replace the reactor of 3000L.As the filtration of fruit product and process of lapping can be realized continued operation with production process, so only need the reactor of the present invention of 1 50L just can replace the reactor of 3000L, realize same output.
Table 3
The above embodiment is only the preferred embodiment for absolutely proving that the present invention lifts, and protection scope of the present invention is not limited to this.Being equal to that those skilled in the art do on basis of the present invention substitutes or conversion, all within protection scope of the present invention.Protection scope of the present invention is as the criterion with claims.
Claims (10)
1. continuous fast reaction crystallization improves a device for crystal stability, it is characterized in that, comprises tank reactor and the tubular reactor of connecting with it; Liquid jet is set in tank reactor and impacts feed arrangement, described liquid jet impacts feed arrangement and comprises a hollow pipe and plural feed pipe, the tube wall of hollow pipe is provided with the through hole passing for feed pipe, described feed pipe inserts from the upper port of hollow pipe, and the through hole from its tube wall passes, the discharging opening of feed pipe is all connected with nozzle, and the discharging opening of each feed pipe and/or nozzle are fixed on the bottom of hollow pipe by fixed mount; Described nozzle arranges to guarantee the discharging mode bumping against that liquidates; Through hole on described hollow pipe and the charging pipeline section between fixed mount are an arcuate structure.
2. device according to claim 1, is characterized in that, described hollow pipe vertically arranges, and the angle that nozzle becomes with horizontal plane is 0 °～20 °, and injector spacing is 5～15mm.
3. device according to claim 2, is characterized in that, identical with feed pipe quantity along being evenly provided with in pipe week on described fixed mount, for the fixing hole clipping of discharging opening and/or nozzle.
4. according to the device described in claim 1 or 2 or 3, it is characterized in that, described tank reactor top is cylindrical and is furnished with chuck, and bottom is conical.
5. according to the device described in claim 1 or 2 or 3, it is characterized in that, in described tank reactor, be provided with a plurality of baffle plates or agitator.
6. according to the device described in claim 1 or 2 or 3, it is characterized in that, tubular reactor level, or vertically place, or be spiral placement.
7. a continuous fast reaction crystallization improves the method for crystal stability, it is characterized in that, two or more reactant liquors are pumped into from the different feeds pipe of liquid jet impact feed arrangement respectively, the mode that reactant liquor bumps against to liquidate enters tank reactor from nozzle ejection, in tank reactor, in complete mixing flow mode, react nucleation, reactant liquor flows into tubular reactor afterwards, and flows and carry out crystal growth in the mode of laminar flow, then obtains stable crystal product through post processing.
8. method according to claim 7, is characterized in that, in tank reactor, liquid jet impact velocity is not less than 5m/s.
9. according to the method described in claim 7 or 8, it is characterized in that, cefuroxime acid solution after sodium lactate solution and decolouring processing is pumped into from two feed pipes of liquid jet impact feed arrangement respectively, the mode that reactant liquor bumps against to liquidate enters tank reactor from nozzle ejection, in tank reactor, react at least 8min, course of reaction stirs with 50～150rpm speed; Reactant liquor flows into tubular reactor afterwards, reacts at least 22min in tubular reactor, after filtration, dry processing, finally makes Cefuroxime Sodium.
10. method according to claim 9, is characterized in that, in tank reactor, it is 10m/s that described liquid jet impacts charging rate.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279209A (en) * | 2016-08-24 | 2017-01-04 | 南昌立健药业有限公司 | A kind of preparation technology of cefuroxime sodium for injection |
| CN107652306A (en) * | 2017-10-24 | 2018-02-02 | 北京红太阳药业有限公司 | A kind of Cefuroxime Sodium crystal-form compound |
| CN107855088A (en) * | 2017-12-20 | 2018-03-30 | 中国科学院青岛生物能源与过程研究所 | A kind of efficient, intelligence reactive crystallization equipment |
| CN108325492A (en) * | 2018-03-14 | 2018-07-27 | 荆门市熊兴化工有限公司 | A kind of nitration processes and device preparing H acid |
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| CN1239099A (en) * | 1998-01-27 | 1999-12-22 | 株式会社林原生物化学研究所 | Method for continuous manufacture of anhydrous crystalline maltitol and manufacturing apparatus therefor |
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| CN202527151U (en) * | 2012-01-18 | 2012-11-14 | 浙江大学 | Oscillatory flow tubular reaction crystallizer |
| CN203577791U (en) * | 2013-10-31 | 2014-05-07 | 华南理工大学 | Device for improving crystal stability by continuously and rapidly reactive crystallization |
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| US5314506A (en) * | 1990-06-15 | 1994-05-24 | Merck & Co., Inc. | Crystallization method to improve crystal structure and size |
| CN1239099A (en) * | 1998-01-27 | 1999-12-22 | 株式会社林原生物化学研究所 | Method for continuous manufacture of anhydrous crystalline maltitol and manufacturing apparatus therefor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106279209A (en) * | 2016-08-24 | 2017-01-04 | 南昌立健药业有限公司 | A kind of preparation technology of cefuroxime sodium for injection |
| CN107652306A (en) * | 2017-10-24 | 2018-02-02 | 北京红太阳药业有限公司 | A kind of Cefuroxime Sodium crystal-form compound |
| CN107855088A (en) * | 2017-12-20 | 2018-03-30 | 中国科学院青岛生物能源与过程研究所 | A kind of efficient, intelligence reactive crystallization equipment |
| CN108325492A (en) * | 2018-03-14 | 2018-07-27 | 荆门市熊兴化工有限公司 | A kind of nitration processes and device preparing H acid |
| CN108325492B (en) * | 2018-03-14 | 2023-12-19 | 湖北丽康源化工有限公司 | Nitration technology and device for preparing H acid |
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