CN1080204A - A kind of technology of concentrating aqueous solution of clavulanate - Google Patents
A kind of technology of concentrating aqueous solution of clavulanate Download PDFInfo
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- CN1080204A CN1080204A CN 93103713 CN93103713A CN1080204A CN 1080204 A CN1080204 A CN 1080204A CN 93103713 CN93103713 CN 93103713 CN 93103713 A CN93103713 A CN 93103713A CN 1080204 A CN1080204 A CN 1080204A
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- clavulanic acid
- resin
- reverse osmosis
- clavulanate
- aqueous solution
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Abstract
The present invention relates to a kind of technology with the reverse osmosis unit concentrating aqueous solution of clavulanate, this technology comprises preparation, preliminary treatment, decolouring, concentrated, the drying and other steps of feed liquid; Compared with prior art, that the present invention has is easy and simple to handle, concentration time short, concentrate the yield height, can improve heat-sensitive substance stability, reduce energy resource consumption, be adapted to characteristics such as suitability for industrialized production; In addition, reverse osmosis membrane can be regenerated, and uses repeatedly.
Description
The present invention relates to the concentration technology of compound water solution, especially a kind of technology that adopts the reverse osmosis concentrating aqueous solution of clavulanate.
Clavulanic acid is a kind of beta-lactam enzyme inhibitor, and it and amoxycillin can overcome serious day by day drug resistance problem with other beta-lactam antibiotic coupling, improve the bacteriostatic activity of beta-lactam antibiotic significantly.Because clavulanic acid to thermally labile, can make the clavulanic acid inactivation with conventional concentrator is concentrated.Existing processes is with clavulanic acid ferment filtrate alkali anion resins exchange, with the ethanol liquid of NaCl, KCl, LiCl clavulanic acid eluted, and after concentrating through vacuum rotary evaporator again, crystallization, dry Clavulanate crude product; This crude product is by 732
(k+)Resin changes into the clavulanic acid aqueous solutions of potassium; Carried out carbon decoloring then, vacuum freezedrying gets the pure product of clavulanic acid sylvite.The defective of this technology is: (1) needs a large amount of ethanol liquid wash-outs; (2) to concentrate with vacuum rotary evaporator, can not be used for suitability for industrialized production; (3) the potassium clavulanate saline solution is the direct freeze-drying of low concentration, and cost is too high.
Purpose of the present invention be exactly the defective that exists at above-mentioned prior art and provide a kind of easy and simple to handle, cost is low, be applicable to the technology of the concentrating aqueous solution of clavulanate of suitability for industrialized production.
Technical solution of the present invention is: this concentration technology is to adopt reverse osmosis unit to carry out, this technology may further comprise the steps: (1) uses LiCl solution with its wash-out, concentrated, the dry clavulanic acid lithium salts that gets with weak base or strong base anion resins absorption clavulanic acid ferment filtrate then; (2) the clavulanic acid lithium salts is added by 1g 8～50ml is water-soluble to be separated, 732
(k+)Carry out ion-exchange in the resin and become the potassium clavulanate saline solution; Wherein 732
(k+)Resin demand needs 150～300ml resin for the 1g lithium salts, and elution speed is 1/100～1/300 of a per minute resin volume, and the ratio of height to diameter of resin is 8～20: 1; (3) in above-mentioned potassium clavulanate saline solution, add active carbon and decolour, through centrifugal or filtration active carbon or small molecular weight impurity are removed then; Wherein the addition of active carbon is 0.5～3.0g/100ml solution, and bleaching temperature is 0～15 ℃, and bleaching time is 10～30min; (4) the clavulanic acid aqueous solutions of potassium that will handle is cooled to 5～25 ℃, be placed in the reverse osmosis unit and concentrate, the molecular weight that dams of reverse osmosis membrane is 100～400, in concentration process, at first the cooling system in the reverse osmosis unit is opened, feed liquid is remained within the said temperature scope, suitably increase flow velocity then, pressure is slowly added to 15～40kg/cm
2; (5) feed liquid after will concentrating is directly carried out freeze drying or is carried out crystallization with acetone or isopropyl alcohol as solvent, the volume ratio of concentrate and solvent is 1: 10～30, crystallization temperature is-10 ℃～+ 5 ℃, obtains the potassium clavulanate product salt through suction filtration, drying at last.
The first step of such scheme is that the deionized water with 3～5 times of resin volumes washes down resin then with weak base anion resins absorption clavulanic acid ferment filtrate, carries out wash-out with 1.0%～2.5% the LiCl aqueous solution again and gets the clavulanic acid Aqueous Lithium Salts; This aqueous solution is that the micropore filtering film of 0.45～0.8 μ gives filtration with the aperture, be that 5000～50000 milipore filter removes albumen with the molecular weight that dams again, enter in the reverse osmosis unit at last and concentrate, concentrate is carried out freeze drying get the clavulanic acid lithium salts.
The ratio of height to diameter of above-mentioned weak base anion resins is 3～10: 1, and elution speed is 1/100～1/300 of a per minute resin volume.
Compared with prior art, the present invention have easy and simple to handle, concentration time short, concentrate the yield height, can improve heat-sensitive substance stability, reduce energy resource consumption, be adapted to advantage such as suitability for industrialized production; In addition, reverse osmosis membrane can be regenerated, and uses repeatedly.
Below in conjunction with specific embodiment, the invention will be further described:
Embodiment 1:
(1) uses 25L710
#Weak base anion resins (ratio of height to diameter is 6: 1) absorption 1000L clavulanic acid ferment filtrate, to set with the 150L deionized water then and refer to wash down, use the also available KCl of LiCl(of 75L1.0% again, NaCl) aqueous solution carries out wash-out, elution speed is per minute 0.13L, eluent filters with the micropore filtering film of 0.45 μ, be that 5000 milipore filter is removed big molecule with the molecular weight that dams again, (U.S. Millipore Corp. produces to enter reverse osmosis unit at last, type is pro-lak, membranous type R-25A, concentrate down together), concentrate is carried out freeze drying get clavulanic acid lithium salts 150g.
(2) 150g clavulanic acid lithium salts is dissolved in the 2L distilled water, uses 732 then
(k+)Resin carries out ion-exchange and becomes the potassium clavulanate saline solution; Wherein 732
(k+)The volume of resin is 40L, and ratio of height to diameter is 9: 1, and elution speed is 0.4L/min, and the collected volume of potassium clavulanate saline solution is 10L.
(3) add the 50g needle-use activated carbon in the above-mentioned sylvite aqueous solution and decolour, bleaching temperature is 3 ℃, and bleaching time is 10min, through filtering active carbon and small molecular weight impurity is removed then.
(4) the potassium clavulanate saline solution that above-mentioned process is given processing is cooled to 5 ℃, imports in the reverse osmosis unit then to concentrate, and the molecular weight that dams of reverse osmosis membrane is 100; In concentration process, at first open the cooling system of reverse osmosis unit, make it to remain on 6 ℃, suitably increase flow velocity then, pressure is slowly added to 15kg/cm
2, the potassium clavulanate saline solution is concentrated into 1.3L through reverse osmosis unit.
(5) above-mentioned concentrate convection drying in frozen vacuum dryer is got the potassium clavulanate product salt.
Embodiment 2:
(1) gets among the embodiment 1 (1) step gained clavulanic acid lithium salts 50g and be dissolved in the 2L distilled water, use 732 then
(k+)Resin carries out ion-exchange and becomes the potassium clavulanate saline solution; Wherein 732
(k+)The volume of resin is 13L, and ratio of height to diameter is 20: 1, and elution speed is 0.05L/min, and potassium clavulanate saline solution collected volume is 3.5L.
(2) add the 70g needle-use activated carbon in the above-mentioned sylvite aqueous solution and decolour, bleaching temperature is 10 ℃, and bleaching time is 20min, through centrifugal active carbon and small molecular weight impurity is removed then.
(3) the potassium clavulanate saline solution that above-mentioned process is given processing is cooled to 20 ℃, imports in the reverse osmosis unit then to concentrate, and the molecular weight that dams of reverse osmosis membrane is R75A for the 400(membranous type); In concentration process, at first open the cooling system of reverse osmosis unit, make it to remain on 15 ℃, suitably increase flow velocity then, pressure is slowly added to 40kg/cm
2, the potassium clavulanate saline solution is concentrated into 0.25L through reverse osmosis unit.
(4) the 0.25L concentrate is slowly added in the 4L isopropyl alcohol, stirring, crystallization, crystallization is carried out under 2 ℃, and crystallization time is 12hr, then suction filtration, the dry clavulanic acid sylvite finished product that gets.
Embodiment 3:
(1) gets among the embodiment 1 (1) step gained clavulanic acid lithium salts 100g and be dissolved in the 3L distilled water, use 732 then
(k+)Resin carries out ion-exchange and becomes the potassium clavulanate saline solution; Wherein 732
(k+)The volume of resin is 20L, and ratio of height to diameter is 18: 1, and elution speed is 0.3L/min, and potassium clavulanate saline solution collected volume is 7L.
(2) add the 70g needle-use activated carbon in the above-mentioned sylvite aqueous solution and decolour, bleaching temperature is 6 ℃, and bleaching time is 15min, through filtering active carbon and small molecular weight impurity is removed then.
(3) the potassium clavulanate saline solution that above-mentioned process is given processing is cooled to 10 ℃, imports in the reverse osmosis unit then to concentrate, and the molecular weight that dams of reverse osmosis membrane is 100; In concentration process, at first open the cooling system of reverse osmosis unit, make it to remain on 10 ℃, suitably increase flow velocity then, pressure is slowly added to 25kg/cm
2, the potassium clavulanate saline solution is concentrated into 0.45L through reverse osmosis unit.
(4) the 0.45L concentrate is slowly added in the 9L acetone, stirring, crystallization, crystallization is carried out under-4 ℃, crystallization time 3hr, suction filtration, the dry clavulanic acid sylvite finished product that gets then.
Above for only for adopting the example of hyperfiltration concentrating aqueous solution of clavulanate, similarly, the present invention also can be used for concentrating of the concentrating of other antibiotic aqueous solution, water purification and other water-soluble substances.
Claims (3)
1, a kind of technology of concentrating aqueous solution of clavulanate is characterized in that: this concentration technology adopts reverse osmosis unit to carry out, and this technology may further comprise the steps:
(1) with weak base or strong base anion resins absorption clavulanic acid ferment filtrate, use LiCI solution then with its wash-out, concentrated, the dry clavulanic acid lithium salts that gets;
(2) the clavulanic acid lithium salts is added by lg 8～50ml is water-soluble to be separated, 732
(k+)Carry out ion-exchange in the resin and become the potassium clavulanate saline solution; Wherein 732
(k+)Resin demand needs 150～300ml resin for the 1g lithium salts, and elution speed is 1/100～1/300 of a per minute resin volume, and the ratio of height to diameter of resin is 8～20: 1;
(3) in above-mentioned potassium clavulanate saline solution, add active carbon and decolour, through centrifugal or filtration active carbon or small molecular weight impurity are removed then; Wherein the addition of active carbon is 0.5～3.0g/100ml solution, and bleaching temperature is 0～15 ℃, and bleaching time is 10～30mln;
(4) the clavulanic acid aqueous solutions of potassium that will handle is cooled to 5～25 ℃, be placed in the reverse osmosis unit and concentrate, the molecular weight that dams of reverse osmosis membrane is 100～400, in concentration process, at first the cooling system in the reverse osmosis unit is opened, feed liquid is remained within the said temperature scope, suitably increase flow velocity then, pressure is slowly added to 15～40kg/cm
2
(5) feed liquid after will concentrating is directly carried out freeze drying or is carried out crystallization with acetone or isopropyl alcohol as solvent, the volume ratio of concentrate and solvent is 1: 10～30, crystallization temperature is-10 ℃～+ 5 ℃, obtains the potassium clavulanate product salt through suction filtration, drying at last.
2, the technology of a kind of concentrating aqueous solution of clavulanate according to claim 1, it is characterized in that: the first step is with weak base anion resins absorption clavulanic acid ferment filtrate, deionized water with 3～5 times of resin volumes washes down resin then, carries out wash-out with 1.0%～2.5% the LiCl aqueous solution again and gets the clavulanic acid Aqueous Lithium Salts; This aqueous solution is that the micropore filtering film of 0.45～0.8 μ gives filtration with the aperture, be that 5000～50000 milipore filter removes albumen with the molecular weight that dams again, enter in the reverse osmosis unit at last and concentrate, concentrate is carried out freeze drying get the clavulanic acid lithium salts.
3, the technology of a kind of concentrating aqueous solution of clavulanate according to claim 2 is characterized in that: the ratio of height to diameter of weak base anion resins is 3～10: 1, and elution speed is 1/100～1/300 of a per minute resin volume.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93103713 CN1038816C (en) | 1993-03-30 | 1993-03-30 | Process for concentrating aqueous solution of clavulanate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93103713 CN1038816C (en) | 1993-03-30 | 1993-03-30 | Process for concentrating aqueous solution of clavulanate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1080204A true CN1080204A (en) | 1994-01-05 |
| CN1038816C CN1038816C (en) | 1998-06-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93103713 Expired - Fee Related CN1038816C (en) | 1993-03-30 | 1993-03-30 | Process for concentrating aqueous solution of clavulanate |
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| CN (1) | CN1038816C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108773924A (en) * | 2018-05-03 | 2018-11-09 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in clavulanic acid extraction raffinate |
| CN109305978A (en) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | A kind of new method preparing Clavulanate |
| CN112794536A (en) * | 2020-12-21 | 2021-05-14 | 伊犁川宁生物技术股份有限公司 | Penicillin waste acid water treatment method and recycling method thereof |
-
1993
- 1993-03-30 CN CN 93103713 patent/CN1038816C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109305978A (en) * | 2017-07-26 | 2019-02-05 | 山东睿鹰先锋制药有限公司 | A kind of new method preparing Clavulanate |
| CN108773924A (en) * | 2018-05-03 | 2018-11-09 | 国药集团威奇达药业有限公司 | The comprehensive recovering process of active ingredient in clavulanic acid extraction raffinate |
| CN108773924B (en) * | 2018-05-03 | 2021-08-03 | 国药集团威奇达药业有限公司 | Comprehensive recovery method of effective components in clavulanic acid extraction raffinate |
| CN112794536A (en) * | 2020-12-21 | 2021-05-14 | 伊犁川宁生物技术股份有限公司 | Penicillin waste acid water treatment method and recycling method thereof |
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| Publication number | Publication date |
|---|---|
| CN1038816C (en) | 1998-06-24 |
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