CN103087079B - Crystallization method of piperacillin - Google Patents
Crystallization method of piperacillin Download PDFInfo
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- CN103087079B CN103087079B CN201310055833.3A CN201310055833A CN103087079B CN 103087079 B CN103087079 B CN 103087079B CN 201310055833 A CN201310055833 A CN 201310055833A CN 103087079 B CN103087079 B CN 103087079B
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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, by Japan folic hill chemical industry, Co., Ltd. develops, semi-synthetic penicillins microbiotic, tool broad-spectrum antibacterial action.Piperacillin structural formula is as follows:
At present, in piperacillin use procedure, all adopt lyophilization, be prepared into the beta-lactam inhibitor couplings such as sodium-salt form and sulbactam or sodium-tazobactam, to improve its anti-microbial activity.But because freeze-drying process does not have the ability of place to go impurity, therefore, the quality of piperacillin acid plays very crucial effect in the anti-microbial activity and the security that improve in medicine use procedure.In piperacillin finished product, there are two major impurities respectively: 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, in use has certain potential safety hazard; The latter, 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 less about the refining method of piperacillin, generally the aqueous solution that piperacillin crude product and sodium bicarbonate is prepared into piperacillin sodium, then in system, add the organic solvent such as ethyl acetate, acetone or alcohol, obtain piperacillin finished product (as ES2321153A1, CN101941980A) by hcl acidifying crystallization.The piperacillin that crystallization obtains in this way, owing to there being the participation of organic solvent, causes the dissolvent residual of the piperacillin finished product obtaining higher, and 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, safe and reliable, and quality product and yield are improved significantly.
Technical scheme of the present invention is as follows: will in piperacillin, add water, control 5 ~ 10 DEG C of temperature, adding sodium bicarbonate (mol ratio of sodium bicarbonate and piperacillin is 1 ~ 1.01:1) to be mixed with pH value is 4.9 ~ 5.1, the piperacillin sodium water solution that concentration is 10-50wt%; Then piperacillin sodium water solution is by the adsorption-edulcoration of ETDA-2Na and gac; Finally divide the two-stage at 0-50 DEG C, to carry out acidizing crystal and obtain again piperacillin acid finished product through suction filtration, cleaning with after being dried.The pH value of described first stage 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 DEG C.
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, the acidizing crystal of removal of impurities and pure water phase.The present invention adopts the crystallization method of pure water phase to replace the mixed solvent crystallization method of conventional ethyl acetate, acetone or alcohol and water, 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 is obviously better than organic solvent and participates in the product that lower crystallization obtains, crystallization yield >=96%.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, but be not limited to this.
Embodiment 1:
In 1000mL there-necked flask, drop into successively piperacillin 200g, purified water 600mL, controls 5 ~ 10 DEG C of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and now system pH is 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 DEG C, 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.By reaction system suction filtration, pull an oar and wash material with purified water 100mL.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:
In 1000mL there-necked flask, drop into successively piperacillin 200g, purified water 1200mL, controls 5 ~ 10 DEG C of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and now system pH is 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 DEG C, 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.By reaction system suction filtration, pull an oar and wash material with purified water 100mL.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:
In 1000mL there-necked flask, drop into successively piperacillin 200g, purified water 1800mL, controls 5 ~ 10 DEG C of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and now system pH is 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 DEG C, 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.By reaction system suction filtration, pull an oar and wash material with purified water 100mL.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:
In 1000mL there-necked flask, drop into successively piperacillin 200g, purified water 400mL, controls 5 ~ 10 DEG C of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and now system pH is 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 DEG C, 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.By reaction system suction filtration, pull an oar and wash material with purified water 100mL.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:
In 1000mL there-necked flask, drop into successively piperacillin 200g, purified water 700mL, controls 5 ~ 10 DEG C of temperature, slowly adds sodium bicarbonate solid 31.5g, adds rear continuation and stirs 60min to system dissolving clarification, and now system pH is 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 DEG C, 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.By reaction system suction filtration, pull an oar and wash material with purified water 100mL.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 example:
Adopt CN101941980A(number of patent application: 201010273253.8, denomination of invention: the crystallization and purification separation method of the improvement of piperacillin acid) in the crystallization method of embodiment 2.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.
Residual and the yield of product polymer content, the ethyl acetate of table 1 embodiment 1-5 is shown compared with the 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 (3)
1. a crystallization method for piperacillin, is characterized in that, will in piperacillin, add water, controls 5 ~ 10 DEG C of temperature, and adding sodium bicarbonate to be mixed with pH value is 4.9 ~ 5.1, the piperacillin sodium water solution that concentration is 10-50wt%; Then piperacillin sodium water solution is by the adsorption-edulcoration of ETDA-2Na and gac; Finally divide the two-stage at 40 ~ 45 DEG C, to carry out after acidizing crystal again through suction filtration, cleaning and the dry piperacillin acid finished product that obtains; The pH value of described first stage 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 ~ 35 wt %.
3. 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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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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 |
| CN109734724B (en) * | 2019-01-30 | 2021-06-29 | 山东安舜制药有限公司 | Crystallization method of piperacillin acid |
| CN113072565B (en) * | 2021-03-17 | 2023-08-29 | 内蒙古常盛制药有限公司 | Crystallization method of piperacillin |
Citations (4)
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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 |
| 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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2013
- 2013-02-21 CN CN201310055833.3A patent/CN103087079B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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| 哌拉西林钠的合成工艺改进;陆晨阳;《山西化工》;20090630;第29卷(第3期);第19-21页 * |
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Effective date of registration: 20181210 Address after: 250105 Dongjia Town 849, Licheng District, Jinan City, Shandong Province Co-patentee after: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. Patentee after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Address before: 250105 Dongjia Town 849, Licheng District, Jinan City, Shandong Province Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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Address after: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20200319 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: Shandong Anxin Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |