CN103087079A - Crystallization method of piperacillin - Google Patents
Crystallization method of piperacillin Download PDFInfo
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- CN103087079A CN103087079A CN2013100558333A CN201310055833A CN103087079A CN 103087079 A CN103087079 A CN 103087079A CN 2013100558333 A CN2013100558333 A CN 2013100558333A CN 201310055833 A CN201310055833 A CN 201310055833A CN 103087079 A CN103087079 A CN 103087079A
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Abstract
The invention discloses a crystallization method of piperacillin, belonging to the technical field of medicine. In the method, sodium bicarbonate is used as the alkali, the piperacillin is prepared into piperacillin sodium aqueous solution with concentration of 10-50%, after absorption and removal of impurities, with absence of organic solvent, the solution is treated by pure aqueous phase fractional crystallization, thus, the piperacillin acid is obtained. In the method, the frequently-used ethyl acetate, acetone or alcohol and water mixed solvent crystallization method is replaced by the pure aqueous phase crystallization method, the phenomena, for example, the product is not easy to devitrify or is tacky in devitrification, caused by the existence of organic solvent, are avoided, and the quality and the yield of products both are improved greatly. The method has the advantages of obtaining the raw material easily, being low in cost, being less harmful for environment, being safe and reliable, and being excellent in product quality.
Description
Technical field
The present invention relates to a kind of crystallization method of piperacillin, belong to medical technical field.
Background technology
Piperacillin (piperacillin), chemistry (2S by name, 5R, 6R)-3,3-dimethyl-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine formamido group)-2-phenylacetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid monohydrate, Co., Ltd. develops by Japan folic hill chemical industry, the semi-synthetic penicillins microbiotic, the tool broad-spectrum antibacterial action.The piperacillin structural formula is as follows:
At present, all adopt lyophilization in the piperacillin use procedure, it is prepared into sodium-salt form and the beta-lactam inhibitor couplings such as sulbactam or sodium-tazobactam, to improve its anti-microbial activity.But the ability that there is no place to go impurity due to freeze-drying process, therefore, very crucial effect is played in anti-microbial activity and the security of the quality of piperacillin acid in improving the medicine use procedure.There are two major impurities to be respectively in the piperacillin finished product: the degraded product (seeing reaction formula 2) that the polymkeric substance (seeing reaction formula 1) that piperacillin and Ampicillin Trihydrate condensation produce and piperacillin and ethyl acetate produce.The former is the polymkeric substance of high molecular, and certain potential safety hazard is in use arranged; The latter is due to the residual impact of ethyl acetate, along with the prolongation meeting in storage time increases gradually, and affects the quality of medicine.
The production process of reaction formula 1 polymeric impurities
The production process of reaction formula 2 degradation impurity
At present, report is less about the refining method of piperacillin, generally piperacillin crude product and sodium bicarbonate to be prepared into the aqueous solution of piperacillin sodium, then add the organic solvents such as ethyl acetate, acetone or alcohol in system, obtain piperacillin finished product (as ES2321153A1, CN101941980A) by the hcl acidifying crystallization.The piperacillin that obtains of crystallization is due to the participation that organic solvent is arranged in this way, cause the dissolvent residual of the piperacillin finished product that obtains higher, and the polymeric impurities in product is difficult to drop to lower level.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of crystallization method of piperacillin.The method adopts the crystallization mode of pure water phase, and with low cost, environmental hazard is little, and is safe and reliable, and quality product and yield are improved significantly.
Technical scheme of the present invention is as follows: will add entry in piperacillin, control 5 ~ 10 ℃ of temperature, (mol ratio of sodium bicarbonate and piperacillin is that 1 ~ 1.01:1) to be mixed with the pH value be 4.9 ~ 5.1, and concentration is the piperacillin sodium water solution of 10-50wt% to add sodium bicarbonate; Then the piperacillin sodium water solution is by the adsorption-edulcoration of ETDA-2Na and gac; Divide at last the two-stage to obtain again piperacillin acid finished product carrying out acidizing crystal under 0-50 ℃ after suction filtration, cleaning and drying.The pH value of described fs acidizing crystal is 4.0 ~ 4.5, and the pH value of subordinate phase acidizing crystal is 1.0 ~ 1.5.Reaction equation is as follows:
The concentration of described piperacillin sodium water solution is preferably 30 ~ 35%.
Described souring temperature is preferably 40 ~ 45 ℃.
The mass ratio of described ETDA-2Na and gac is 1:5 ~ 20.
The invention has the beneficial effects as follows: the present invention is by adjusting temperature and pH value, can make that piperacillin sodium effectively adsorbs, removal of impurities and pure water acidizing crystal mutually.The present invention adopts the crystallization method of pure water phase to replace the mixed solvent crystallization method of ethyl acetate, acetone or alcohol and water commonly used, has avoided being difficult for the phenomenons such as crystallization or crystallization are clamminess because organic solvent participates in causing product.By this crystallization method to product in polymeric impurities content can be reduced to≤0.05%, the residual of ethyl acetate is reduced to below 50ppm, the stability of product obviously is better than organic solvent and participates in the product that lower crystallization obtains, crystallization yield 〉=96%.
Embodiment
The present invention will be further described below in conjunction with embodiment, but be not limited to this.
Embodiment 1:
Drop into successively piperacillin 200g in the 1000mL there-necked flask, purified water 600mL controls 5 ~ 10 ℃ of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and this moment, system pH was 4.95.Add EDTA-2Na1.0g, gac 10g, suction filtration after stirring decolouring 30min.Filtrate is transferred in clean there-necked flask, and between regulation system temperature to 40 ~ 45 ℃, slowly dripping 2mol/L hydrochloric acid to system pH is 4.0, stirring and crystallizing 60min.Continuing slowly to drip hydrochloric acid to system pH is 1.0, stirring and crystallizing 60min.With the reaction system suction filtration, wash material with purified water 100mL making beating.Drying obtains white crystalline piperacillin finished product 196.5g, crystallization yield 98.3%, HPLC content 99.9%, polymer content 0.02%, the residual 21ppm of ethyl acetate.
Embodiment 2:
Drop into successively piperacillin 200g in the 1000mL there-necked flask, purified water 1200mL controls 5 ~ 10 ℃ of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and this moment, system pH was 5.05.Add EDTA-2Na1.0g, gac 10g, suction filtration after stirring decolouring 30min.Filtrate is transferred in clean there-necked flask, and between regulation system temperature to 40 ~ 45 ℃, slowly dripping 2mol/L hydrochloric acid to system pH is 4.15, stirring and crystallizing 60min.Continuing slowly to drip hydrochloric acid to system pH is 1.05, stirring and crystallizing 60min.With the reaction system suction filtration, wash material with purified water 100mL making beating.Drying obtains white crystalline piperacillin finished product 192.3g, crystallization yield 96.2%, HPLC content 99.8%, polymer content 0.04%, the residual 39ppm of ethyl acetate.
Embodiment 3:
Drop into successively piperacillin 200g in the 1000mL there-necked flask, purified water 1800mL controls 5 ~ 10 ℃ of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and this moment, system pH was 5.10.Add EDTA-2Na1.0g, gac 10g, suction filtration after stirring decolouring 30min.Filtrate is transferred in clean there-necked flask, and between regulation system temperature to 40 ~ 45 ℃, slowly dripping 2mol/L hydrochloric acid to system pH is 4.10, stirring and crystallizing 60min.Continuing slowly to drip hydrochloric acid to system pH is 1.13, stirring and crystallizing 60min.With the reaction system suction filtration, wash material with purified water 100mL making beating.Drying obtains white crystalline piperacillin finished product 192.8g, crystallization yield 96.4%, HPLC content 99.7%, polymer content 0.05%, the residual 43ppm of ethyl acetate.
Embodiment 4:
Drop into successively piperacillin 200g in the 1000mL there-necked flask, purified water 400mL controls 5 ~ 10 ℃ of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and this moment, system pH was 4.93.Add EDTA-2Na1.0g, gac 10g, suction filtration after stirring decolouring 30min.Filtrate is transferred in clean there-necked flask, and between regulation system temperature to 40 ~ 45 ℃, slowly dripping 2mol/L hydrochloric acid to system pH is 4.13, stirring and crystallizing 60min.Continuing slowly to drip hydrochloric acid to system pH is 1.21, stirring and crystallizing 60min.With the reaction system suction filtration, wash material with purified water 100mL making beating.Drying obtains white crystalline piperacillin finished product 194.5g, crystallization yield 97.3%, HPLC content 99.9%, polymer content 0.03%, the residual 32ppm of ethyl acetate.
Embodiment 5:
Drop into successively piperacillin 200g in the 1000mL there-necked flask, purified water 700mL controls 5 ~ 10 ℃ of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and this moment, system pH was 4.97.Add EDTA-2Na1.0g, gac 10g, suction filtration after stirring decolouring 30min.Filtrate is transferred in clean there-necked flask, and between regulation system temperature to 40 ~ 45 ℃, slowly dripping 2mol/L hydrochloric acid to system pH is 4.27, stirring and crystallizing 60min.Continuing slowly to drip hydrochloric acid to system pH is 1.20, stirring and crystallizing 60min.With the reaction system suction filtration, wash material with purified water 100mL making beating.Drying obtains white crystalline piperacillin finished product 196.1g, crystallization yield 98.1%, HPLC content 99.9%, polymer content 0.02%, the residual 25ppm of ethyl acetate.
Comparative Examples:
Adopt the CN101941980A(number of patent application: 201010273253.8, denomination of invention: the crystallization method of the embodiment 2 the crystallization and purification separation method of the improvement of piperacillin acid).Its crystallization yield 86.5%, HPLC content 99.9%, polymer content 0.25%, the residual 3000ppm of ethyl acetate.
Below the more as shown in table 1 of product polymer content, the ethyl acetate of embodiment 1-5 residual and yield and prior art (CN101941980A).As can be seen from Table 1: crystallization method of the present invention has significantly reduced polymer content and ethyl acetate residual quantity, has improved product yield.
The comparison sheet of product polymer content, the ethyl acetate of table 1 embodiment 1-5 residual and yield and prior art
| Crystallization method | Polymer content | Ethyl acetate is residual | Product yield |
| CN101941980A | 0.25% | 3000ppm | 86.5% |
| Embodiment 1 | 0.02% | 21ppm | 98.3% |
| Embodiment 2 | 0.04% | 39ppm | 96.2% |
| Embodiment 3 | 0.05% | 43ppm | 96.4% |
| Embodiment 4 | 0.03% | 32ppm | 97.3% |
| Embodiment 5 | 0.02% | 25ppm | 98.1% |
Claims (4)
1. the crystallization method of a piperacillin, is characterized in that, will add entry in piperacillin, controls 5 ~ 10 ℃ of temperature, and adding sodium bicarbonate to be mixed with the pH value is 4.9 ~ 5.1, and concentration is the piperacillin sodium water solution of 10-50wt%; Then the piperacillin sodium water solution is by the adsorption-edulcoration of ETDA-2Na and gac; Divide at last the two-stage to obtain piperacillin acid finished product through suction filtration, cleaning and drying again after carrying out acidizing crystal under 0-50 ℃; The pH value of described fs acidizing crystal is 4.0 ~ 4.5, and the pH value of subordinate phase acidizing crystal is 1.0 ~ 1.5.
2. the crystallization method of piperacillin as claimed in claim 1, is characterized in that, the concentration of described piperacillin sodium water solution is 30 ~ 35wt%.
3. the crystallization method of piperacillin as claimed in claim 1 or 2, is characterized in that, described acidizing crystal temperature is 40 ~ 45 ℃.
4. the crystallization method of piperacillin as claimed in claim 1 or 2, is characterized in that, the mass ratio of described ETDA-2Na and gac is 1:5 ~ 20.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530039A (en) * | 2014-12-26 | 2015-04-22 | 江西富祥药业股份有限公司 | Method for preparing piperacillin impurity C |
| CN104644637A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof |
| CN108276399A (en) * | 2018-01-26 | 2018-07-13 | 齐鲁天和惠世制药有限公司 | A kind of Piperacillin impurity and preparation method thereof |
| CN109134497A (en) * | 2017-07-24 | 2019-01-04 | 陈立平 | A kind of 1/2 water Piperacillin sodium compound |
| CN109160918A (en) * | 2017-07-27 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/4 water Piperacillin sodium compound of one kind and its drug combination preparation |
| CN109734724A (en) * | 2019-01-30 | 2019-05-10 | 齐鲁天和惠世（乐陵）制药有限公司 | A kind of method for crystallising of Piperacillin acid |
| CN113072565A (en) * | 2021-03-17 | 2021-07-06 | 内蒙古常盛制药有限公司 | Crystallization method of piperacillin |
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| ES2321153A1 (en) * | 2007-10-11 | 2009-06-02 | Astur Pharma S.A. | Intermediate for the synthesis of piperacilina (Machine-translation by Google Translate, not legally binding) |
| CN101941980A (en) * | 2010-09-06 | 2011-01-12 | 景德镇市富祥药业有限公司 | Modified crystallization purifying and precipitating method of piperacillin acid |
| CN102807572A (en) * | 2011-05-30 | 2012-12-05 | 秦引林 | Refining method for piperacillin sodium |
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| DD295162A5 (en) * | 1990-06-15 | 1991-10-24 | Arzneimittelwerk Dresden Gmbh I. V.,De | PROCESS FOR PREPARING D-ALPHA- (4-ETHYL-2,3-DIOXO-PIPERAZINE-1-CARBONYLAMINO) -BENZYLPENICILLINE |
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| ES2321153A1 (en) * | 2007-10-11 | 2009-06-02 | Astur Pharma S.A. | Intermediate for the synthesis of piperacilina (Machine-translation by Google Translate, not legally binding) |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530039A (en) * | 2014-12-26 | 2015-04-22 | 江西富祥药业股份有限公司 | Method for preparing piperacillin impurity C |
| CN104530039B (en) * | 2014-12-26 | 2017-01-18 | 江西富祥药业股份有限公司 | Method for preparing piperacillin impurity C |
| CN104644637A (en) * | 2015-01-27 | 2015-05-27 | 华北制药股份有限公司 | Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof |
| CN104644637B (en) * | 2015-01-27 | 2017-11-10 | 华北制药股份有限公司 | A kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof |
| CN109134497A (en) * | 2017-07-24 | 2019-01-04 | 陈立平 | A kind of 1/2 water Piperacillin sodium compound |
| CN109160918A (en) * | 2017-07-27 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/4 water Piperacillin sodium compound of one kind and its drug combination preparation |
| CN108276399A (en) * | 2018-01-26 | 2018-07-13 | 齐鲁天和惠世制药有限公司 | A kind of Piperacillin impurity and preparation method thereof |
| CN109734724A (en) * | 2019-01-30 | 2019-05-10 | 齐鲁天和惠世（乐陵）制药有限公司 | A kind of method for crystallising of Piperacillin acid |
| CN109734724B (en) * | 2019-01-30 | 2021-06-29 | 山东安舜制药有限公司 | Crystallization method of piperacillin acid |
| CN113072565A (en) * | 2021-03-17 | 2021-07-06 | 内蒙古常盛制药有限公司 | Crystallization method of piperacillin |
| CN113072565B (en) * | 2021-03-17 | 2023-08-29 | 内蒙古常盛制药有限公司 | Crystallization method of piperacillin |
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