CN103239454A - Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection - Google Patents
Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection Download PDFInfo
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Abstract
The invention discloses a production method of a piperacillin sodium tazobactam sodium freeze-drying preparation for injection and belongs to the technical field of medicines. The production method comprises the steps of reacting, prefreezing, sublimation drying, drying again and taking out of a box. According to the production method, in the step of reacting, sodium hydroxide is adopted for substituting sodium bicarbonate, so that no bubble is produced in a reaction process; and a sodium hydroxide solution is dropwise added into a turbid liquid containing piperacillin acid and tazobactam acid, reaction is carried out in a manner of adding nitrogen to the bottom of a reaction tank, and reaction speed of feed liquid can be increased while time that local concentration of sodium hydroxide is overhigh can be shortened, so that degradation effect of a high-concentration sodium hydroxide solution on piperacillin sodium tazobactam sodium is effectively avoided. According to the production method, mutual combination between quick freezing and slow cooling is realized on prefreezing of the piperacillin sodium tazobactam sodium freeze-drying preparation, so that a crystal form of the obtained piperacillin sodium tazobactam sodium freeze-drying preparation product, insoluble particles and related impurities of freeze-drying products are at the best level. The product piperacillin sodium tazobactam sodium freeze-drying preparation for injection prepared by using the production method disclosed by the invention is good in quality and low in impurity content.
Description
Technical field
The present invention relates to a kind of production method of piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation, be applicable to the lyophilized formulations of all specifications of piperacillin sodium injection sodium-tazobactam (8:1) and the lyophilized formulations of all specifications of piperacillin sodium injection sodium-tazobactam (4:1), belong to medical technical field.
Background technology
Sodium-tazobactam, molecular formula: C
10H
11N
4NaO
5S, molecular weight: 322.28, structural formula is as follows.Tazobactam Sodium is the novel penicillanic acid sulfones beta-lactamase inhibitor of Japanese roc drugmaker exploitation, is one of best beta-lactamase inhibitor of present clinical application effect, and it is high to have stability, and active low, toxicity is low, presses down characteristics such as enzymatic activity is strong.
Avocin, molecular formula: C
23H
26N
5NaO
7S, molecular weight: 539.54, structural formula is as follows.It is the improved seeds of the semi-synthetic beta-lactam antibiotic of the second filial generation, has has a broad antifungal spectrum, and antibacterial action is strong, and toxic and side effects gently and to serious gram negative bacilli infects with characteristics such as the renal function injury person particularly are suitable for, is extensive use of clinical.
The semisynthetic penicillin avocin that share powerful beta-lactamase inhibitor sodium-tazobactam and wide spectrum is the more satisfactory selection that solves fastbacteria.In piperacillin sodium injection and the sodium-tazobactam compound preparation, the proportioning of piperacillin and Tazobactam Sodium has two kinds of 8:1 and 4:1.Proportioning is that the compound preparation of 8:1 is studied by Japanese roc company (Taiho) at first, U.S. Lederle company obtains the 8:1 licence at first, at first went on the market in France in 1992, in succession in country's listings such as Britain, Spain, Germany and the U.S., be used for the treatment of being grown up and infecting due to child's zymogenic bacteria more than 12 years old after 1993.
The existing piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation of producing generally adopts piperacillin acid, Tazobactam Sodium acid and sodium bicarbonate are produced as the reaction supplementary material, but according to observing from producing practical situation, there are following 4 shortcomings in existing production technology: no matter (1) existing production method is put into sodium bicarbonate in piperacillin acid and the Tazobactam Sodium acid mixed liquor, still piperacillin acid is thrown in the sodium bicarbonate solution, all can produce the great amount of carbon dioxide foam in the course of reaction, cause dashing the material phenomenon when therefore reinforced too fast easily, and must adopt the mode that continues evacuation to remove the carbon dioxide that produces in the course of reaction, complex operation in the course of reaction; (2) owing to produce great amount of carbon dioxide in the solution, observe feed liquid and whether clarified difficulty, thereby influence the judgement of reaction end; (3) owing to there is certain error in the reaction end judgement, cause existing in the product the unreacted piperacillin acid of part, piperacillin acid is unstable, and therefore the decomposition owing to piperacillin acid can be introduced a part of impurity when doing stability test; (4) reaction usefulness sodium bicarbonate alkalescence a little less than, response speed is slower in the feed liquid course of reaction, reaction time is longer, production cost is higher.
Carrying out pre-freeze after reaction is finished again handles.Pre-freeze is exactly the solid of liquid preparation glaciation crystal formation attitude, makes it keep its shape when freezing behind sublimation drying under vacuum condition.If preparation does not have deep colling, then can be at the vial of emerging that can seethe with excitement of preparation under the vacuum state, the product of preparation will be destroyed mutually.During the solution quick-freezing (10～15 ℃ of per minute coolings), crystal grain remains on the visible size of microscopically, and it is thinner to obtain freezing crystal grain, and tiny crystal grain can not make the biological product grain growth and cause mechanical injuries.But because crystal grain is tiny, the gap that stays after the ice crystal distillation is narrow and small, and the resistance of water sublimed is big, and rate of drying is slow, and the production cycle prolongs, and the moisture absorption especially easily of dried goods, brings difficulty to preservation, and this is the shortcoming of quick-freezing.When freezing slowly on the contrary (1 ℃/minute), the crystallization naked eyes of formation as seen, crystal grain is bigger, after the ice crystal distillation, the gap that stays is also big, moisture very easily overflows during distillation, dry velocity ratio is very fast, has shortened lyophilization cycle, has improved production efficiency.Cause occurring " supercool " phenomenon easily but freeze slowly in freezing process, it is concentrated that " supercool " phenomenon can cause that the goods that are dried produce, and causes homogeneity poor, and influence the outward appearance of freeze-drying prods.
After freeze dryer will realize that quick-freezing can cool to shelf X degree below freezing (30 ℃) earlier in advance under As-Is, again the preparation that is dried is put into the freeze dryer casing and lower the temperature rapidly; Slowly freeze operate relatively easy, as long as just can realize freezing slowly with shelf cooling synchronously after preparation is put into drying baker.
Summary of the invention
In order to overcome the deficiency of above technology, the invention provides a kind of simple to operate, be easy to that suitability for industrialized production, production cost are low, the production method of the piperacillin sodium injection sodium-tazobactam of good product quality.The present invention adopts sodium hydroxide to replace sodium bicarbonate, makes and does not produce bubble in the course of reaction, realizes quick-freezing and mutually combining of freezing slowly product pre-freeze simultaneously, makes the product crystal formation that obtains, and particulate matter and freeze-drying prods relative substance are in an optimum level.
Technical scheme of the present invention is: a kind of production method of piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation, it is characterized in that,
(1) reaction: add water in the reactor, piperacillin acid monohydrate and Tazobactam Sodium acid, the sodium hydroxide solution that with concentration is 2-7wt% under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and stirring slowly is added drop-wise in the reactor with the speed of 50-200ml/min, feed temperature control is at≤5 ℃ in the dropping process, dropwise back feed temperature control at 5-10 ℃, response time, control was at 4-7 hour, PH is 5-7 during reaction end, and reactant concentration is 15-30wt%; After then reacted feed liquid being filtered through filter, pour into false add plug in the cillin bottle by filling pump again, the plate of then cillin bottle being packed into;
(2) pre-freeze: the shelf temperature of freeze dryer is cooled to-30 ℃ in advance, the plate of step (2) is put on the shelf, in 120 minutes, shelf temperature is slowly dropped to-40 ℃ then, the pre-freeze temperature is set in≤-40 ℃, stablized 4-8 hour;
(3) sublimation drying: after pre-freeze is finished, freeze dryer is evacuated to≤-0.08MPa, baffle temperature is warming up to 55 ℃, and the sublimation drying time is 6-12 hour;
(4) dry again: vacuum≤-0.05MPa, proceed drying, 6-10 hour drying time under temperature 55-70 ℃;
(5) outlet: lyophilizing finishes, and after pressure rises test passes, to the dividing plate cooling, drops to design temperature (25 ℃) beginning pregassing, feeds nitrogen in casing, when tank pressure reaches malleation 0.05MPa, stops pregassing, the beginning tamponade; Venting (nitrogen) outlet to the normal pressure after tamponade is finished.
Preferably, the adding mole of sodium hydroxide is the total moles sum of piperacillin acid monohydrate and Tazobactam Sodium acid in the step of the present invention (1).The mass ratio of described piperacillin acid monohydrate and Tazobactam Sodium acid is 8:1 or 4:1.
The sodium hydroxide that the present invention uses is a kind of strong alkaline substance, high-concentration sodium hydroxide solution has Degradation to piperacillin sodium and tazobactam sodium, therefore the present invention takes sodium hydroxide solution to drip in the suspension of piperacillin acid and Tazobactam Sodium acid, and the logical mode that adds nitrogen is reacted at the bottom of retort.Can accelerate the response speed of feed liquid, shorten the too high time of sodium hydroxide local concentration simultaneously.Thereby effectively avoided the generation of degraded.
Effect of the present invention is:
(1) the present invention uses the alkali that sodium hydroxide solution uses as reaction, does not produce bubble in the course of reaction, and reaction end judges that easily response speed is fast, and is with short production cycle, simple to operate, and production cost is low.
(2) make the crystal formation of final freeze-drying prods and related substance obtain a better level by the quick-freezing that realizes the pre-freeze stage and effective combination of freezing slowly.
(3) adopt the into mode of nitrogen in the multiple pressure stage of freeze-drying process, the product that this method makes, the whole of filling are nitrogen in the bottle, nitrogen is as a kind of noble gas, can be effectively that goods and oxygen are isolated, prevent oxygen to the oxidation of goods, improve the stability of goods, be conducive to the long term storage of product.
(4) the piperacillin sodium injection sodium-tazobactam good product quality of the present invention's preparation, impurity content is low.
The specific embodiment
Embodiment 1:
In the reactor of 1L, add 150ml water, (molecular weight is 80g piperacillin acid sulfuric monohydrate: 535.54, be equivalent to 14.94cMol), (molecular weight is the acid of 10g Tazobactam Sodium: 300.28, be equivalent to 3.33cMol), 7.308g sodium hydroxide (being equivalent to 18.27cMol) being dissolved in the 350ml water slowly under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and good stirring, stream is added in the reactor.The control of reaction solution temperature feeds intake and finishes feed temperature control later between 5-10 ℃ at≤5 ℃ when throwing the alkali process.PH regulator is set to shelf temperature-30 ℃ between the 5.0-7.0 the most at last, shelf temperature is dropped to-40 ℃ in 120 minutes, and the pre-freeze temperature is set in below-40 ℃, stablizes 4-8 hour.Be evacuated to≤-0.08MPa, flaggy is warming up to 55 ℃, and the sublimation drying time is 6-12 hour.The second stage of dry vacuum of product reaches≤-0.05MPa, temperature is controlled at 55-70 ℃, 6-10 hour drying time.Lyophilizing finishes pressure and rises test passes (behind the pressure lift-off value per minute≤5Pa), compressor is lowered the temperature to flaggy, drops to design temperature (25 ℃) and begins pregassing, in casing, feed nitrogen, when tank pressure reaches malleation 0.05MPa, stop pregassing, the beginning tamponade.To casing and cold-trap venting (nitrogen) outlet to the normal pressure, the index of product was as shown in table 1 after tamponade was finished.
Embodiment 2:
In the reactor of 2L, add 200ml water, 160g piperacillin acid sulfuric monohydrate (being equivalent to 29.88cMol), 20g Tazobactam Sodium acid (being equivalent to 6.66cMol), under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and good stirring, the 14.62g dissolution of sodium hydroxide (is equivalent to 36.54cMol) in 400ml water slowly stream be added in the reactor.The control of reaction solution temperature feeds intake and finishes feed temperature control later between 5-10 ℃ at≤5 ℃ when throwing the alkali process.PH regulator is set to shelf temperature-30 ℃ between the 5.0-7.0 the most at last, shelf temperature is dropped to-40 ℃ in 120 minutes, and the pre-freeze temperature is set in below-40 ℃, stablizes 4-8 hour; Be evacuated to≤-0.08MPa, flaggy is by being warming up to 55 ℃ below-45 ℃.The sublimation drying time is 6-12 hour, the second stage of dry vacuum of product reaches≤-0.05MPa, 55-70 ℃ of temperature control, 6-10 hour drying time.Lyophilizing finishes pressure and rises test passes (behind the pressure lift-off value per minute≤5Pa), compressor is lowered the temperature to flaggy, drops to design temperature (25 ℃) and begins pregassing, in casing, feed nitrogen, when tank pressure reaches malleation 0.05MPa, stop pregassing, the beginning tamponade.To casing and cold-trap venting (nitrogen) outlet to the normal pressure, the index of product was as shown in table 1 after tamponade was finished.
Embodiment 3:
In the reactor of 2L, add 300ml water, 200g piperacillin acid sulfuric monohydrate (being equivalent to 37.35cMol), 25g Tazobactam Sodium acid (being equivalent to 8.33cMol), under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and good stirring, the 18.272g dissolution of sodium hydroxide (is equivalent to 45.68cMol) in 350ml water slowly stream be added in the reactor.The control of reaction solution temperature feeds intake and finishes feed temperature control later between 5-10 ℃ at≤5 ℃ when throwing the alkali process.PH regulator is set to shelf temperature-30 ℃ between the 5.0-7.0 the most at last, shelf temperature is dropped to-40 ℃ in 120 minutes, and the pre-freeze temperature is set in below-40 ℃, stablizes 4-8 hour; Be evacuated to≤-0.08MPa, flaggy is by being warming up to 55 ℃ below-45 ℃.The sublimation drying time is 6-12 hour, the second stage of dry vacuum of product reaches≤-0.05MPa, 55-70 ℃ of temperature control, 6-10 hour drying time.Lyophilizing finishes pressure and rises test passes (behind the pressure lift-off value per minute≤5Pa), compressor is lowered the temperature to flaggy, drops to design temperature (25 ℃) and begins pregassing, in casing, feed nitrogen, when tank pressure reaches malleation 0.05MPa, stop pregassing, the beginning tamponade.To casing and cold-trap venting (nitrogen) outlet to the normal pressure, the index of product was as shown in table 1 after tamponade was finished.
Comparative Examples: with sodium bicarbonate as supplementary material and adopt to produce and to use freeze-drying process
In the reactor of 2L, add 200ml water, 160g piperacillin acid sulfuric monohydrate (being equivalent to 29.88cMol), the acid of 20g Tazobactam Sodium (is equivalent to 6.66cMol, the ratio of piperacillin and Tazobactam Sodium is 8:1), under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and good stirring, the 14.616g sodium bicarbonate is dissolved into (be equivalent to 36.54cMol) in the 400ml water slowly stream be added in the reactor.The control of the process that feeds intake feed temperature is between 5-10 ℃.PH regulator is set to 5 ℃ between the 5.0-7.0 with shelf temperature the most at last, shelf temperature is dropped to-40 ℃ in 120 minutes, and the pre-freeze temperature is set in below-40 ℃, stablizes 4-8 hour; Be evacuated to below the 800 μ bar, flaggy is by being warming up to 55 ℃ below-45 ℃.The sublimation drying time is 6-12 hour, and the second stage of dry vacuum of product reaches below the 500 μ bar, and temperature control is no more than 70 ℃, 6-10 hour drying time.Lyophilizing finishes the pressure liter, and (after the test passes of pressure lift-off value per minute≤5Pa), compressor is lowered the temperature to flaggy, drops to design temperature (25 ℃) beginning pregassing, in casing, feed nitrogen, when tank pressure reaches 0.50bar, stop pregassing, the beginning tamponade.To casing and cold-trap venting (nitrogen) outlet to the normal pressure, the index of product was as shown in table 1 after tamponade was finished.
The product stability data (24 months) of table 1 embodiment 1-4 and the comparison sheet of prior art
As can be seen from Table 1: the piperacillin sodium injection sodium-tazobactam good product quality that the present invention produces, impurity content is low.
Claims (3)
1. the production method of a piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation is characterized in that,
(1) reaction: add water in the reactor, piperacillin acid monohydrate and Tazobactam Sodium acid, the sodium hydroxide solution that with concentration is 2-7wt% under the logical nitrogen of Polycondensation Reactor and Esterification Reactor and stirring slowly is added drop-wise in the reactor with the speed of 50-200ml/min, feed temperature control is at≤5 ℃ in the dropping process, dropwise back feed temperature control at 5-10 ℃, response time, control was at 4-7 hour, PH is 5-7 during reaction end, and reactant concentration is 15-30wt%; After then reacted feed liquid being filtered through filter, pour into false add plug in the cillin bottle by filling pump again, the plate of then cillin bottle being packed into;
(2) pre-freeze: the shelf temperature of freeze dryer is cooled to-30 ℃ in advance, the plate of step (2) is put on the shelf, in 120 minutes, shelf temperature is slowly dropped to-40 ℃ then, the pre-freeze temperature is set in≤-40 ℃, stablized 4-8 hour;
(3) sublimation drying: after pre-freeze is finished, freeze dryer is evacuated to≤-0.08MPa, baffle temperature is warming up to 55 ℃, and the sublimation drying time is 6-12 hour;
(4) dry again: vacuum≤-0.05MPa, proceed drying, 6-10 hour drying time under temperature 55-70 ℃;
(5) outlet: lyophilizing finishes, and after pressure rises test passes, to the dividing plate cooling, drops to 25 ℃ of beginning pregassings, feeds nitrogen in casing, when tank pressure reaches malleation 0.05MPa, stops pregassing, the beginning tamponade; The outlet to the normal pressure of exitting after tamponade is finished.
2. the production method of a kind of piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation as claimed in claim 1, it is characterized in that the adding mole of sodium hydroxide is the total moles sum of piperacillin acid monohydrate and Tazobactam Sodium acid in the described step (1).
3. the production method of a kind of piperacillin sodium injection Tazobactam Sodium sodium freeze-dried preparation as claimed in claim 1 or 2 is characterized in that, the mass ratio of described piperacillin acid monohydrate and Tazobactam Sodium acid is 8:1 or 4:1.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105616415A (en) * | 2016-01-15 | 2016-06-01 | 齐鲁天和惠世制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium for injection |
| CN106714799A (en) * | 2014-10-08 | 2017-05-24 | 泽井制药株式会社 | Method for producing freeze-dried preparation |
| CN108096197A (en) * | 2017-12-26 | 2018-06-01 | 齐鲁天和惠世制药有限公司 | A kind of production method of injection sodium-tazobactam |
| CN108324714A (en) * | 2018-01-26 | 2018-07-27 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of azlocillin sodium for injection sulbactam |
| CN112057426A (en) * | 2020-10-21 | 2020-12-11 | 山东安信制药有限公司 | Method for preparing piperacillin sodium and tazobactam sodium freeze-dried powder by microreactor |
| CN112409381A (en) * | 2020-12-03 | 2021-02-26 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101299995A (en) * | 2005-12-05 | 2008-11-05 | 桑多斯股份公司 | Process for the preparation of lyophilized piperacilline sodium with improved stability after reconstitution |
| CN102382123A (en) * | 2011-03-10 | 2012-03-21 | 海南美好西林生物制药有限公司 | Preparation method of tazobactam sodium |
-
2013
- 2013-05-06 CN CN201310163081.2A patent/CN103239454B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101299995A (en) * | 2005-12-05 | 2008-11-05 | 桑多斯股份公司 | Process for the preparation of lyophilized piperacilline sodium with improved stability after reconstitution |
| CN102382123A (en) * | 2011-03-10 | 2012-03-21 | 海南美好西林生物制药有限公司 | Preparation method of tazobactam sodium |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106714799A (en) * | 2014-10-08 | 2017-05-24 | 泽井制药株式会社 | Method for producing freeze-dried preparation |
| 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 |
| CN105616415A (en) * | 2016-01-15 | 2016-06-01 | 齐鲁天和惠世制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium for injection |
| CN108096197A (en) * | 2017-12-26 | 2018-06-01 | 齐鲁天和惠世制药有限公司 | A kind of production method of injection sodium-tazobactam |
| CN108324714A (en) * | 2018-01-26 | 2018-07-27 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of azlocillin sodium for injection sulbactam |
| CN112057426A (en) * | 2020-10-21 | 2020-12-11 | 山东安信制药有限公司 | Method for preparing piperacillin sodium and tazobactam sodium freeze-dried powder by microreactor |
| CN112409381A (en) * | 2020-12-03 | 2021-02-26 | 山东安信制药有限公司 | Piperacillin sodium and tazobactam sodium co-amorphous substance and preparation method thereof |
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Effective date of registration: 20200302 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |