CN108324714A - A kind of preparation method of azlocillin sodium for injection sulbactam - Google Patents
A kind of preparation method of azlocillin sodium for injection sulbactam Download PDFInfo
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- CN108324714A CN108324714A CN201810076252.0A CN201810076252A CN108324714A CN 108324714 A CN108324714 A CN 108324714A CN 201810076252 A CN201810076252 A CN 201810076252A CN 108324714 A CN108324714 A CN 108324714A
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- sodium
- sulbactam
- azlocillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
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Abstract
The invention discloses a kind of preparation methods of azlocillin sodium for injection sulbactam.This method is：The lye of sodium hydroxide and a small amount of sodium carbonate is added dropwise, is reacted with azlocillin, Sulbactam, reaction material liquid quickly drops to 45 DEG C, stablizes 1~2 hour and carries out pre-freeze；Then after the lyophilization of three stages, parsing-desiccation, pressure cools down after rising test passes, is deflated to outlet after normal pressure.The present invention buffers sodium hydroxide by using sodium carbonate, the modes such as controlling reaction temperature, can effectively prevent sodium hydroxide vigorous reaction and sodium hydroxide concentrations cause degradation to material, also avoids using leading to the problem of a large amount of foams caused by sodium bicarbonate.The present invention by the way of quick-frozen, makes feed liquid crystallize rapidly in the pre-freeze stage, reduces the generation of impurity；Obtain that a kind of azlocillin sodium, sulbactam content meets the requirements and the azlocillin sodium for injection sulbactam of excellent storage stability eventually by the method for freeze-drying.
Description
Technical field
The present invention relates to a kind of preparation methods of azlocillin sodium for injection sulbactam, belong to pharmaceutical technology field.
Background technology
The semi-synthetic uride penicillin of azlocillin sodium system, is initiated by Britain, successively in Germany, Britain, the U.S. and Japan
Equal states obtain clinical application especially has pseudomonas aeruginosa good antibacterial action to gram positive bacteria and negative bacterium.Note
It penetrates and uses azlocillin sodium, indication is various infection and the verdigris caused by being mainly used for sensitive gram positive bacteria and negative bacterium
Pseudomonas infection, including septicemia, meningitis, endocarditis, purulent pleurisy, peritonitis and lower respiratory tract, gastrointestinal tract,
Biliary tract, the urinary tract, bone and soft tissue and the infection of genitals official rank, gynaecology, Obstetrics infection, malignant otitis externa, burn, skin and hand
Art infection etc..
Sulbactam is in addition to Neisseriaceae and acinetobacter calcoaceticus, to other bacteriums without antibacterial activity, but sulbactam pair
There is the inhibiting effect of irreversibility by most important beta-lactamases that beta-lactam antibiotic antibody-resistant bacterium generates.It relaxes
Batan sodium can prevent drug-fast bacteria from antibacterial activity has been greatly reinforced, to Portugal to the destruction of penicillins and cephalosporins
The antibacterial activity of grape coccus, micrococcus catarrhalis, Neisseria gonorrhoeae, Escherichia coli, klebsiella bacillus, haemophilus and bacteroid etc. is aobvious
Write enhancing.Sulbactam has apparent synergistic effect with penicillins and cephalosporins.
The problem of azlocillin sodium and sulbactam sodium compound preparation preparation process, has at present：1) do not have currently on the market
Azlocillin sodium and sulbactam sodium product mix, cannot be satisfied market needs；2) azlocillin sodium, sulbactam currently on the market
Preparation method be solvent method, such method and process is complicated, of high cost, is unfavorable for industrialized production.3) similar currently on the market
The blending process of product is to realize acid-base neutralization reaction by using sodium bicarbonate, will produce a large amount of titanium dioxides using sodium bicarbonate
Carbon foam is easy to cause slug phenomenon when feeding too fast, and needs to vacuumize removing carbon dioxide, and technique is cumbersome and difficult to control.
Invention content
The present invention overcomes above-mentioned the deficiencies in the prior art, provide a kind of system of azlocillin sodium for injection sulbactam
Preparation Method.This method use azlocillin, Sulbactam and sodium hydroxide for primary raw material carry out reaction generate azlocillin sodium relax
Batan sodium buffers sodium hydroxide by using sodium carbonate, and it is acutely anti-to can effectively prevent sodium hydroxide for the modes such as controlling reaction temperature
The degradation to material should be caused with sodium hydroxide concentrations, also avoided using a large amount of foams of generation caused by sodium bicarbonate
Problem.The present invention by the way of quick-frozen, makes feed liquid crystallize rapidly in the pre-freeze stage, reduces the generation of impurity；Eventually by cold
Dry method is lyophilized and obtains that a kind of azlocillin sodium, sulbactam content meets the requirements and the injection A Luo of excellent storage stability
XiLin sodium and sulbactam sodium.
The technical scheme is that：A kind of preparation method of azlocillin sodium for injection sulbactam, characterized in that
1) at salt
Azlocillin is first put into material-compound tank, and the water of naoh concentration 3-10% and concentration of sodium carbonate 1-3% is added dropwise
Solution is reacted；Sulbactam is put into after being added dropwise again, is added dropwise naoh concentration 3-10%'s and concentration of sodium carbonate 1-3%
Aqueous solution is reacted；0-5 DEG C of temperature, pH≤7.0 during control feeds intake are controlled in entire reaction process；After feeding intake
PH6.0-6.5 is adjusted, plate (or after being filled into cillin bottle, cillin bottle is packed into plate) is packed into after aseptic filtration；
2) pre-freeze
The baffle temperature of freeze dryer is cooled to -30 DEG C ± 1 DEG C in advance, the plate of step 1) is placed on partition board, it will
Baffle temperature drops to -45 DEG C in 20-30 minutes, stablizes 1~2 hour；
3) lyophilization
After the completion of pre-freeze, it is 10~28pa to be evacuated to absolute pressure, carries out lyophilization in three stages；
First stage：Freeze dryer baffle temperature is warming up to 0 DEG C from -45 DEG C, 100~150 minutes used times；
Second stage：Freeze dryer baffle temperature is warming up to 30 DEG C from 0 DEG C, 600~800 minutes used times；
Phase III：Freeze dryer baffle temperature is warming up to 45 DEG C from 30 DEG C, 120~180 minutes used times；
4) parsing-desiccation
It is evacuated to absolute pressure≤5pa, freeze dryer baffle temperature rises to 50 DEG C, 100~140 minutes used times；It maintains again
150~200 minutes；
5) outlet
After the completion of parsing-desiccation, pressure cools down after rising test passes, deflates (fill cillin bottle in the process wants tamponade)
Outlet after to normal pressure.
Preferably, the step 1) uses the aqueous solution of naoh concentration 4% and concentration of sodium carbonate 1.325%.
Preferably, the mass ratio of azlocillin sodium and sulbactam is 1 in the product：10~10：1, more preferably 8：
1；Wherein azlocillin dosage (Kg)：The ÷ of W × 8/9 (1- moisture) azlocillins ÷ content；A:It is adjusted according to technological standards and is
Number.Sulbactam dosage (Kg)：The ÷ of W × 1/9 (1- moisture) ÷ contents.W is azlocillin sodium and sulbactam quality in product
(pure).
Preferably, sodium hydroxide and the mass ratio of azlocillin are 1：14.0-15.0, more preferably 1：14.4 hydroxide
The mass ratio of sodium and Sulbactam is 1：7.0-8.0 more preferably 1：7.27；Sodium carbonate and the mass ratio of azlocillin are 1：
43.0-44.0, more preferably 1：43.47, the mass ratio of sodium carbonate and Sulbactam is 1：23.0-24.0, more preferably 1：
23.08。
The chemical reaction process of the present invention is as follows：
Azlocillin salt-forming reaction：
Sulbactam salt-forming reaction：
The blending process of similar product is to realize acid-base neutralization reaction by using sodium bicarbonate currently on the market, uses carbon
Sour hydrogen sodium generates great amount of carbon dioxide foam, slug phenomenon is easy to cause when feeding too fast, and need to vacuumize removal titanium dioxide
Carbon, technique are cumbersome and difficult to control.The generation for generating a large amount of foams is avoided instead of sodium bicarbonate using sodium hydroxide, but is used
Sodium hydroxide there may be the problem of be：Sodium hydroxide vigorous reaction and sodium hydroxide concentrations cause the degradation of material.This
Invention sodium hydroxide compounds a small amount of sodium carbonate, not only acts as the effect of buffering dispersion sodium hydroxide, sodium carbonate generate a small amount of two
Carbon oxide gas also functions to the disturbance of solution the effect of certain dispersion sodium hydroxide, can be in conjunction with (0-5 DEG C) reaction of low temperature
Prevent " degradation that sodium hydroxide vigorous reaction and sodium hydroxide concentrations cause material ".Although sodium carbonate also generates two simultaneously
Carbon oxide gas, but calculated with sodium, sodium carbonate about generate the carbon dioxide gas of half relative to sodium bicarbonate, while by
The concentration of sodium carbonate is small in the present invention, compared to all using sodium bicarbonate, about generates 10% carbon dioxide gas, will not produce
Raw a large amount of foams and slug problem, can not vacuumize completely, easy to operate.
The beneficial effects of the invention are as follows：The present invention uses azlocillin, Sulbactam and sodium hydroxide to be carried out for primary raw material
Reaction generates azlocillin sodium and sulbactam sodium, buffers sodium hydroxide by using sodium carbonate, the modes such as controlling reaction temperature can have
Effect prevents sodium hydroxide vigorous reaction and sodium hydroxide concentrations from causing the degradation to material, finally obtains a kind of azlocillin
Sodium, sulbactam content meet the requirements and the azlocillin sodium for injection sulbactam of excellent storage stability.The present invention reacted
Cheng Danyi, operation and control are simple；Baffle temperature is dropped to -45 DEG C in 20-30 minutes during pre-freeze simultaneously, keeps feed liquid rapid
Crystallization, prevents impurity from excessively generating.The present invention prepares azlocillin sodium for injection sulbactam using the method for freeze-drying, should
Method is easy to operate, high income, at low cost, is easy to industrialized production.The preparation method of the present invention is mainly for the production of injection
Azlocillin sodium and sulbactam sodium (8：1) demand of the market for such product, is met.
Specific implementation mode
Embodiment 1：
Azlocillin moisture 3.1%, content 99.0% weigh：119.54g；
Sulbactam moisture 0.1%, content 99.6% weigh：14.54g；
Sodium hydroxide：10.3g (8.3g+2.0g), sodium bicarbonate 3.38g (2.75g+0.63g), it is dense to be configured to sodium hydroxide
Degree is 4% and the aqueous solution use of concentration of sodium carbonate 1.325%).
1) at salt
1. by bottom water 100ml is added in material-compound tank, 5 DEG C are cooled to, rotational speed regulation is to 250 revs/min, by azlocillin
119.54g is slowly put into material-compound tank, while by the water of prepared naoh concentration 4% and concentration of sodium carbonate 1.325%
Solution is added drop-wise in material-compound tank, then Sulbactam 14.54g is added material-compound tank, while by 4% He of prepared naoh concentration
The aqueous solution of concentration of sodium carbonate 1.325% is added drop-wise in material-compound tank, controls 0~5 DEG C of temperature, and observation is online at any time during feeding intake
PH value, pH is not higher than 7.0 during control feeds intake.
It is finished 2. feeding intake, close observation tank temperature, tank temperature, which should control, is maintained at 0~5 DEG C, and a tank was recorded every 10 minutes
Temperature.PH is read, if pH value is higher and solution is clarified, suitable azlocillin can proportionally be added, Sulbactam is adjusted,
Until reaching required pH value；If pH opens cover less than 6.0 and naoh concentration 4% and concentration of sodium carbonate is added
1.325% aqueous solution is adjusted, and so that it is fully reacted about 30 minutes, then read pH value, if pH value is still below 6.0, again
The appropriate aqueous solution that naoh concentration 4% and concentration of sodium carbonate 1.325% is added, makes its reaction, recycles this process until molten
Liquid is clarified and pH value is between 6.0-6.5.
3. sampling and testing material liquid pH, while feed temperature is recorded, pH value 6.27 prepares punishment in advance sabot.
2) pre-freeze
The baffle temperature of freeze dryer is cooled to -30 DEG C ± 1 DEG C in advance, the plate of step 1) is placed on partition board, it will
Baffle temperature drops to -45 DEG C in 20-30 minutes, stablizes 1~2 hour；
3) lyophilization
After the completion of pre-freeze, it is 10~28pa to be evacuated to absolute pressure, carries out lyophilization in three stages；
First stage：Freeze dryer baffle temperature is warming up to 0 DEG C from -45 DEG C, 100~150 minutes used times；
Second stage：Freeze dryer baffle temperature is warming up to 30 DEG C from 0 DEG C, 600~800 minutes used times；
Phase III：Freeze dryer baffle temperature is warming up to 45 DEG C from 30 DEG C, 120~180 minutes used times.
4) parsing-desiccation
It is evacuated to absolute pressure≤5pa, freeze dryer baffle temperature rises to 50 DEG C, 100~140 minutes used times；It maintains again
150~200 minutes.
5) outlet
After the completion of parsing-desiccation, pressure cools down after rising test passes, is deflated to outlet after normal pressure.
Embodiment 2：
1) at salt
Azlocillin moisture 3.1%, content 99.0% weigh：119.54g；
Sulbactam moisture 0.1%, content 99.6% weigh：14.54g；
Sodium hydroxide：10.3g (8.3g+2.0g), sodium bicarbonate 3.38g (2.75g+0.63g), it is dense to be configured to sodium hydroxide
Degree uses for the aqueous solution of 4% and concentration of sodium carbonate 1.325%；
Step is 1.：Bottom water 110ml is cooled to 4.5 DEG C, and azlocillin 119.54g is slowly put into material-compound tank, simultaneously will
The aqueous solution of prepared naoh concentration 4% and concentration of sodium carbonate 1.325% is added drop-wise in material-compound tank, then by Sulbactam
14.54g is added in material-compound tank, while by the water-soluble drop of prepared naoh concentration 4% and concentration of sodium carbonate 1.325%
It is added in material-compound tank, controls 0~5 DEG C of temperature, observe on-line pH value during feeding intake at any time, pH should not be high during control feeds intake
In 7.0.
Remaining is the same as embodiment 1.
Embodiment 3：
1) at salt
Azlocillin moisture 3.1%, content 99.0% weigh：119.54g；
Sulbactam moisture 0.1%, content 99.6% weigh：14.54g；
Sodium hydroxide：10.3g (8.3g+2.0g), sodium bicarbonate 3.38g (2.75g+0.63g), it is dense to be configured to sodium hydroxide
Degree is 8% and the aqueous solution use of concentration of sodium carbonate 2.65%).
Step is 1.：Bottom water 100ml is cooled to 5 DEG C, and azlocillin 119.54g is slowly put into material-compound tank, while will match
The aqueous solution of the naoh concentration 8% and concentration of sodium carbonate 2.65% that make is added drop-wise in material-compound tank, then by Sulbactam
14.54g is added in material-compound tank, while by the water-soluble drop of prepared naoh concentration 8% and concentration of sodium carbonate 2.65%
It is added in material-compound tank, controls 0~5 DEG C of temperature, observe on-line pH value during feeding intake at any time, pH should not be high during control feeds intake
In 7.0.
Step 3. sampling and testing material liquid pH, while feed temperature is recorded, pH value 6.23, aseptic filtration is filled into cillin bottle
Afterwards, cillin bottle is packed into plate.
After the completion of step 5) outlet parsing-desiccation, pressure cools down after rising test passes, starts pregassing when being down to 25 DEG C, to
It is filled with nitrogen in babinet, when tank pressure reaches positive pressure 0.05Mpa, stops pregassing and starts tamponade.It deflates after the completion of tamponade
Outlet after to normal pressure.
Remaining is the same as embodiment 1.
Embodiment 1-3 product stabilities data (24 months) are relatively more as shown in table 1.
The product stability data comparison sheet of 1 embodiment 1-3 of table
It can be seen that from the correction data of table 1：Sodium and sulbactam sodium good product quality in azlocillin produced by the invention, impurity
Content is low, and stability is good.
Claims (7)
1. a kind of preparation method of azlocillin sodium for injection sulbactam, characterized in that include the following steps：
1) at salt
Azlocillin is first put into material-compound tank, and the aqueous solution of naoh concentration 3-10% and concentration of sodium carbonate 1-3% is added dropwise
It is reacted；Sulbactam is put into after being added dropwise again, the water-soluble of naoh concentration 3-10% and concentration of sodium carbonate 1-3% is added dropwise
Liquid is reacted；0-5 DEG C of temperature, pH≤7.0 during control feeds intake are controlled in entire reaction process；It is adjusted after feeding intake
Feed liquid is packed into plate by pH6.0-6.5 after aseptic filtration；
2) pre-freeze
The baffle temperature of freeze dryer is cooled to -30 DEG C ± 1 DEG C in advance, the plate of step 1) is placed on partition board, by partition board
Temperature drops to -45 DEG C in 20-30 minutes, stablizes 1~2 hour；
3) lyophilization
After the completion of pre-freeze, it is 10~28pa to be evacuated to absolute pressure, carries out lyophilization in three stages；
First stage：Freeze dryer baffle temperature is warming up to 0 DEG C from -45 DEG C, 100~150 minutes used times；
Second stage：Freeze dryer baffle temperature is warming up to 30 DEG C from 0 DEG C, 600~800 minutes used times；
Phase III：Freeze dryer baffle temperature is warming up to 45 DEG C from 30 DEG C, 120~180 minutes used times；
4) parsing-desiccation
It is evacuated to absolute pressure≤5pa, freeze dryer baffle temperature rises to 50 DEG C, 100~140 minutes used times；Maintain 150 again~
200 minutes；
5) outlet
After the completion of parsing-desiccation, pressure cools down after rising test passes, is deflated to outlet after normal pressure.
2. a kind of preparation method of azlocillin sodium for injection sulbactam as described in claim 1, characterized in that the step
The rapid aqueous solution for 1) using naoh concentration 4% and concentration of sodium carbonate 1.325%.
3. a kind of preparation method of azlocillin sodium for injection sulbactam as claimed in claim 1 or 2, characterized in that institute
It is 1 to state the mass ratio of azlocillin sodium and sulbactam in product：10~10：1.
4. a kind of preparation method of azlocillin sodium for injection sulbactam as claimed in claim 3, characterized in that the production
The mass ratio of azlocillin sodium and sulbactam is 8 in object：1.
5. a kind of preparation method of azlocillin sodium for injection sulbactam as claimed in claim 1 or 2, characterized in that institute
State after feed liquid is filled into cillin bottle by step 1), cillin bottle be packed into plate, in step 5) deflation course will to cillin bottle into
Row tamponade.
6. a kind of preparation method of azlocillin sodium for injection sulbactam as claimed in claim 1 or 2, characterized in that institute
The mass ratio for stating sodium hydroxide and azlocillin is 1：The mass ratio of 14.0-15.0, sodium hydroxide and Sulbactam is 1：7.0-
8.0。
7. a kind of preparation method of azlocillin sodium for injection sulbactam as claimed in claim 1 or 2, characterized in that carbon
Sour sodium and the mass ratio of azlocillin are 1：The mass ratio of 43.0-44.0, sodium carbonate and Sulbactam is 1：23.0-24.0.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810076252.0A CN108324714A (en) | 2018-01-26 | 2018-01-26 | A kind of preparation method of azlocillin sodium for injection sulbactam |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111362969A (en) * | 2020-04-22 | 2020-07-03 | 苏州二叶制药有限公司 | Preparation process of azlocillin sodium |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1836659A (en) * | 2005-03-21 | 2006-09-27 | 山东瑞阳制药有限公司 | Azlocillin/sulbactam antibacterial composition |
| CN103239454A (en) * | 2013-05-06 | 2013-08-14 | 齐鲁天和惠世制药有限公司 | Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection |
| CN107129507A (en) * | 2017-06-01 | 2017-09-05 | 四川制药制剂有限公司 | The high efficiency preparation method of azlocillin sodium for injection |
-
2018
- 2018-01-26 CN CN201810076252.0A patent/CN108324714A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1836659A (en) * | 2005-03-21 | 2006-09-27 | 山东瑞阳制药有限公司 | Azlocillin/sulbactam antibacterial composition |
| CN103239454A (en) * | 2013-05-06 | 2013-08-14 | 齐鲁天和惠世制药有限公司 | Production method of piperacillin sodium tazobactam sodium freeze-drying preparation for injection |
| CN107129507A (en) * | 2017-06-01 | 2017-09-05 | 四川制药制剂有限公司 | The high efficiency preparation method of azlocillin sodium for injection |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111362969A (en) * | 2020-04-22 | 2020-07-03 | 苏州二叶制药有限公司 | Preparation process of azlocillin sodium |
| 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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Application publication date: 20180727 |