CN104644637B - A kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof - Google Patents
A kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof Download PDFInfo
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- CN104644637B CN104644637B CN201510040537.5A CN201510040537A CN104644637B CN 104644637 B CN104644637 B CN 104644637B CN 201510040537 A CN201510040537 A CN 201510040537A CN 104644637 B CN104644637 B CN 104644637B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 title claims abstract description 19
- 238000002347 injection Methods 0.000 title abstract description 10
- 239000007924 injection Substances 0.000 title abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 46
- 229910052708 sodium Inorganic materials 0.000 claims description 39
- 239000011734 sodium Substances 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 229960002292 piperacillin Drugs 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000013078 crystal Substances 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 11
- 238000001291 vacuum drying Methods 0.000 claims description 11
- 241000790917 Dioxys <bee> Species 0.000 claims description 10
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 10
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 10
- 229960000723 ampicillin Drugs 0.000 claims description 10
- 238000013517 stratification Methods 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 229960000373 tazobactam sodium Drugs 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000000843 powder Substances 0.000 abstract description 6
- 229960003865 tazobactam Drugs 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 4
- 238000005352 clarification Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
- 150000003851 azoles Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 125000005909 ethyl alcohol group Chemical group 0.000 description 3
- 229960005264 piperacillin sodium Drugs 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000007792 addition Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of pharmaceutical composition of piperacillin sodium and tazobactam sodium and preparation method thereof, the pharmaceutical composition is sterile powder injection, and wherein the weight ratio of avocin and sodium-tazobactam is 2~4:1.Piperacillin sodium and tazobactam sodium sterile powder injection produced by the present invention, stability is high, and impurity is few, substantially increases the safety and effectiveness of clinical application.
Description
Technical field
The present invention relates to a kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof, belong to medical science
Field.
Background technology
Piperacillin is semi-synthetic penicillins antibiotic, has broad-spectrum antibacterial action, is widely used to clinic.His azoles
Batan sodium is beta-lactamase inhibitor, belongs to the strong synergist of third generation antibacterial, the medicine of the two can be strengthened by being shared with Piperacillin
Effect and extension action time.When avocin is used in combination with sodium-tazobactam, obvious synergy is produced, is widely used in
Serious systemic and local infection, abdominal cavity infection, ALRI, soft tissue infection, septicemia etc. are treated, than what is used
Other antibacterial complexing agents have wider antimicrobial spectrum and indication, and huge advantage is shown in terms of drug resistance is overcome.
Piperacillin sodium and tazobactam sodium compound preparation is domestic at present have been sold, and is aseptic powdery direct packaging system
, its exist one it is common the defects of be exactly that preparation stabilization is poor, impurity content is high, certain potential safety hazard be present.
In piperacillin sodium and tazobactam sodium product, because its " relevant material " class impurity overwhelming majority is drawn from piperazine
XiLin sodium, therefore the product impurity of avocin bulk drug determines the impurity level of final products.Again due to avocin
After Piperacillin plus alkali soluble solution, after aseptic filtration freeze obtain, during without purification procedures, so Control of Impurities must also
Extend forwardly into Piperacillin.Antibacterial activity and security of the quality of Piperacillin acid during medicine use is improved play
Very crucial effect.
The content of the invention
It is an object of the present invention to provide a kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof, make injection
Have purity high with piperacillin sodium and tazobactam sodium preparation, impurity is few, and stability is good, it is not easy to the advantages that allergy.
To realize the purpose of the present invention, the present invention uses following technical scheme：
The present invention provides a kind of pharmaceutical composition of piperacillin sodium and tazobactam sodium, and described pharmaceutical composition is aseptic powder
The weight ratio of injection, wherein avocin and sodium-tazobactam is 2~4:1.
The present invention also provides a kind of preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium, including following step
Suddenly：
(1) in dichloromethane, 2,3- dioxy -4- ethyl piperazidines, sodium bicarbonate solution is added, is cooled to -10 DEG C, in batches
Solid phosgene is added, is warming up to 30~50 DEG C, insulation reaction filters, and filtrate is standby；
(2) in dichloromethane, the water of ampicillin three acid is added, triethylamine, which is added dropwise, clarifies dissolving；Add step (1) filter
Liquid, 20 DEG C~25 DEG C reactions；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, stratification, discards water layer；Dichloromethane layer is added dropwise
2% sodium acid carbonate, stratification；Water layer adds activated carbon, agitation and filtration；It is 15 DEG C~20 DEG C that filtrate, which controls temperature, under stirring
Slow salt acid for adjusting pH adds crystal seed to 4.5~5.0 immediately, be further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid to 1.0~
1.5, growing the grain 1~2 hour；Filter, wet product is washed with water, and vacuum drying obtains Piperacillin；
(3) sodium iso-octoate is added in ethyl acetate, stirring is to being completely dissolved；
(4) in absolute ethyl alcohol, triethylamine is added, is stirred, cool to -5 DEG C~-10 DEG C, added Piperacillin, stir
Mix to being completely dissolved, under quick stirring, add micro sodium iso-octoate solution, stir 5~10 minutes, slowly improve while stirring molten
Liquid temperature degree stirs 20~30 minutes to 15 DEG C~20 DEG C, is slow added into remaining sodium iso-octoate solution, insulation reaction, filters, filter
Cake is washed with ethyl acetate, and vacuum drying obtains avocin；
(5) the avocin sterile mixing in proportion for obtaining Tazobactam Sodium sodium raw materials and step (4), dispenses and produces.
Preferably, the mol ratio of 2,3- dioxy -4- ethyl piperazidines described in step (1), sodium acid carbonate and solid phosgene is
3:3~4:1.
Preferably, the acid of the water of ampicillin three described in step (2) and 2,3- dioxy -4- ethyl piperazidines described in step (1)
Mol ratio be 1:1~1.2.
Preferably, crystal seed described in step (2) is the 1%~3% of the water acid weight of ampicillin three.
Preferably, the weight ratio of ethyl acetate described in step (3) and the sodium iso-octoate is 3.8~4.2:1.
Preferably, the weight of sodium iso-octoate described in step (3) is 65~75% of Piperacillin described in step (4).
Compared with prior art, the present invention has advantages below：
1st, the present invention is using solid phosgene as chloride reagent, and it is relative to acyl chlorides such as the thionyl chloride of routine or phosgene
Change reagent, have molten boiling point high, volatility is low, small toxicity, safe, easily decomposes and removes；Using sodium acid carbonate as tiing up acid
Agent, it is easier to remove, be not easy to remain；
2nd, exploitation induction Piperacillin crystallization processes, by controlling crystal seed to add opportunity, crystal seed amount etc., make crystal uniformly advise
It is whole, reduce and reunite and increase granularity, so as to reduce impurity entrainment, Piperacillin impurity level is greatly lowered；
3rd, reactant sodium iso-octoate is divided into 2 additions, the avocin that first time sodium iso-octoate is reacted to generation is made
For nucleus, how much control nucleus quantity of different sodium iso-octoate addition for the first time passed through.First time sodium iso-octoate is added simultaneously
Condition control under two kinds of reactants almost nonreactive temperature, stirring condition, two kinds of reactants are well mixed, Ran Houhuan
It is slow to improve temperature, avocin nucleus is increasingly generated, substantially increases the purity of Piperacillin sodium crystal, is further reduced
Impurity content in raw material, improve the quality of product.
Brief description of the drawings
Fig. 1 is the Piperacillin crystallographic microscope figure prepared using prior art.
Fig. 2 is the Piperacillin crystallographic microscope figure prepared using the present invention.
Embodiment
Reference examples 1
Using the method for crystallising of the embodiment 1 in patent CN201310055833.3, piperazine is prepared using Piperacillin crude product
Draw XiLin crystal.
Crystallographic microscope figure is as shown in Figure 1.According to the relevant substance detecting method inspection of Chinese Pharmacopoeia version Piperacillin in 2010
Survey, be 3.7% about material 1 and the content of impurities of relevant material 2.
Embodiment 1
(1) in reaction bulb, 30ml dichloromethane is added, adds 2,3- dioxy -4- ethyl piperazidines 4.26g, sodium acid carbonate
2.52g (is dissolved) with water, is cooled to -10 DEG C, adds solid phosgene 2.97g in stirring in three times, is warming up to 40 DEG C, insulation reaction
1.5 hours, filter, filtrate is standby；
(2) in reaction bulb, 100ml dichloromethane is added, adds the water acid 10.07g of ampicillin three, triethylamine, which is added dropwise, to be made
Dissolving clarification；Step (1) filtrate is added, is reacted 1 hour at 20 DEG C~25 DEG C；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, it is quiet
Layering is put, discards water layer；The sodium acid carbonates of 200ml 2%, stratification is added dropwise in dichloromethane layer, and water layer adds 10g activated carbons, stirred
Filtered after mixing 10 minutes；Filtrate is taken, it is 15~20 DEG C to control temperature, and salt acid for adjusting pH is slowly added dropwise under stirring to 4.5-5.0, stands
0.2g crystal seeds are added, is further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid is to 1.0~1.5, growing the grain 2 hours；Filter, wet product
It is washed with water, vacuum drying obtains Piperacillin crystal.
Crystallographic microscope figure is as shown in Figure 2.According to the relevant substance detecting method inspection of Chinese Pharmacopoeia version Piperacillin in 2010
Survey, be 0.3% about material 1 and the content of impurities of relevant material 2.
Shown by Fig. 1 and Fig. 2 contrast, Piperacillin crystal grain prepared by the present invention is well-balanced, and thick, granularity is by 15
μm increase to more than 30 μm.Due to the control of crystallization and the improvement of crystal, the total impurities that the present invention prepares product are greatly reduced.
Embodiment 2
(1) in reaction bulb, 30ml dichloromethane is added, adds 2,3- dioxy -4- ethyl piperazidines 4.26g, sodium acid carbonate
2.52g (is dissolved) with water, is cooled to -10 DEG C, adds solid phosgene 2.97g in stirring in three times, is warming up to 40 DEG C, insulation reaction
1.5 hours, filter, filtrate is standby；
(2) in reaction bulb, 100ml dichloromethane is added, adds the water acid 10.07g of ampicillin three, triethylamine, which is added dropwise, to be made
Dissolving clarification；Step (1) filtrate is added, is reacted 1 hour at 20 DEG C~25 DEG C；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, it is quiet
Layering is put, discards water layer；The sodium acid carbonates of 200ml 2%, stratification is added dropwise in dichloromethane layer, and water layer adds 10g activated carbons, stirred
Filtered after mixing 10 minutes；Filtrate is taken, it is 15~20 DEG C to control temperature, and salt acid for adjusting pH is slowly added dropwise under stirring to 4.5-5.0, stands
0.1g crystal seeds are added, is further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid is to 1.0~1.5, growing the grain 2 hours；Filter, wet product
It is washed with water, vacuum drying obtains 12.4g Piperacillin crystal.
(3) sodium iso-octoate 9.3g is added in 35ml ethyl acetate, stirs to being completely dissolved, sodium iso-octoate solution is made；
(4) in 32ml absolute ethyl alcohols, 8ml triethylamines is added, are stirred, cool to -5 DEG C~-10 DEG C, added piperazine and draw
XiLin, stirring under quick stirring, add a small amount of sodium iso-octoate solution, stir 5~10 minutes, delay while stirring to being completely dissolved
The slow solution temperature that improves stirs 20~30 minutes to 15 DEG C~20 DEG C, is slow added into remaining sodium iso-octoate solution, and insulation is anti-
Should, filter, filter cake is washed with ethyl acetate, and vacuum drying obtains avocin；
(5) avocin for obtaining Tazobactam Sodium sodium raw materials and step (4) is by 1:2 ratios are placed in solid powder mixing
Sterile uniformly mixing, is sub-packed in cillin bottle, jumps a queue in machine, Zha Gai, packaging, censorship.
Embodiment 3
(1) in reaction bulb, 30ml dichloromethane is added, adds 2,3- dioxy -4- ethyl piperazidines 4.26g, sodium acid carbonate
2.52g (is dissolved) with water, is cooled to -10 DEG C, adds solid phosgene 2.97g in stirring in three times, is warming up to 50 DEG C, insulation reaction
1.5 hours, filter, filtrate is standby；
(2) in reaction bulb, 100ml dichloromethane is added, adds the water acid 12.07g of ampicillin three, triethylamine, which is added dropwise, to be made
Dissolving clarification；Step (1) filtrate is added, is reacted 1 hour at 20 DEG C~25 DEG C；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, it is quiet
Layering is put, discards water layer；The sodium acid carbonates of 200ml 2%, stratification is added dropwise in dichloromethane layer, and water layer adds 10g activated carbons, stirred
Filtered after mixing 10 minutes；Filtrate is taken, it is 15~20 DEG C to control temperature, and salt acid for adjusting pH is slowly added dropwise under stirring to 4.5-5.0, stands
0.12g crystal seeds are added, is further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid is to 1.0~1.5, growing the grain 2 hours；Filter, it is wet
Product are washed with water, and vacuum drying obtains 13.1g Piperacillin crystal.
(3) sodium iso-octoate 9.5g is added in 35ml ethyl acetate, stirs to being completely dissolved, sodium iso-octoate solution is made；
(4) in 32ml absolute ethyl alcohols, 8ml triethylamines is added, are stirred, cool to -5 DEG C~-10 DEG C, added piperazine and draw
XiLin, stirring under quick stirring, add a small amount of sodium iso-octoate solution, stir 5~10 minutes, delay while stirring to being completely dissolved
The slow solution temperature that improves stirs 20 minutes to 15 DEG C~20 DEG C, is slow added into remaining sodium iso-octoate solution, insulation reaction, takes out
Filter, filter cake are washed with ethyl acetate, and vacuum drying obtains avocin；
(5) avocin for obtaining Tazobactam Sodium sodium raw materials and step (4) is by 1:2 ratios are placed in solid powder mixing
Sterile uniformly mixing, is sub-packed in cillin bottle, jumps a queue in machine, Zha Gai, packaging, censorship.
Embodiment 4
(1) in reaction bulb, 30ml dichloromethane is added, adds 2,3- dioxy -4- ethyl piperazidines 4.26g, sodium acid carbonate
2.52g (is dissolved) with water, is cooled to -10 DEG C, is added solid phosgene 2.97g in three times, is warming up to 50 DEG C, insulation reaction 1.5 is small
When, filter, filtrate is standby；
(2) in reaction bulb, 100ml dichloromethane is added, adds the water acid 12.07g of ampicillin three, triethylamine, which is added dropwise, to be made
Dissolving clarification；Step (1) filtrate is added, is reacted 2 hours at 20 DEG C~25 DEG C；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, it is quiet
Layering is put, discards water layer；The sodium acid carbonates of 200ml 2%, stratification is added dropwise in dichloromethane layer, and water layer adds 10g activated carbons, stirred
Filtered after mixing 10 minutes；Filtrate is taken, it is 15~20 DEG C to control temperature, and salt acid for adjusting pH is slowly added dropwise under stirring to 4.5-5.0, stands
0.24g crystal seeds are added, is further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid is to 1.0~1.5, growing the grain 2 hours；Filter, it is wet
Product are washed with water, and vacuum drying obtains 13.9g Piperacillin crystal.
(3) sodium iso-octoate 9.5g is added in 35ml ethyl acetate, stirs to being completely dissolved, sodium iso-octoate solution is made；
(4) in 32ml absolute ethyl alcohols, 8ml triethylamines is added, are stirred, cool to -5 DEG C~-10 DEG C, added piperazine and draw
XiLin, stirring under quick stirring, add a small amount of sodium iso-octoate solution, stir 5~10 minutes, delay while stirring to being completely dissolved
The slow solution temperature that improves stirs 20 minutes to 15 DEG C~20 DEG C, is slow added into remaining sodium iso-octoate solution, insulation reaction, takes out
Filter, filter cake are washed with ethyl acetate, and vacuum drying obtains avocin；
(5) avocin for obtaining Tazobactam Sodium sodium raw materials and step (4) is by 1:4 ratios are placed in solid powder mixing
Sterile uniformly mixing, is sub-packed in cillin bottle, jumps a queue in machine, Zha Gai, packaging, censorship.
Test example 1
His azoles of piperacillin sodium and tazobactam sodium sample prepared by Example 2-4 and commercially available piperacillin sodium injection
Each 1 batch of Batan sodium, it is placed in 40 DEG C and 75% humidity light protected environment, the 1st after placement, sampling investigation in 2,3,6 months, with
Investigate data within 0 month to be compared, relevant material total amount result of the test is shown in Table 1.
Table 1
| 0 month | 1 month | 2 months | 3 months | 6 months | |
| Embodiment 2 | 0.45% | 0.47% | 0.47% | 0.47% | 0.49% |
| Embodiment 3 | 0.49% | 0.48% | 0.50% | 0.52% | 0.52% |
| Embodiment 4 | 0.81% | 0.84% | 0.81% | 0.83% | 0.84% |
| Commercially available prod | 2.6% | 2.8% | 2.8% | 2.9% | 3.0% |
Result above shows：For this product in accelerated test, relevant content of material is high without significant changes, stability；Relevant thing
Matter content is far below commercially available prod, and Product Safety is higher.
Test example 2
His azoles of piperacillin sodium and tazobactam sodium sample prepared by Example 2-4 and commercially available piperacillin sodium injection
Each 1 batch of Batan sodium, it is placed in 25 DEG C and 75% humidity light protected environment, the 3rd after placement, sampling investigation in 6,9,12 months,
Compared with 0 month investigates data, relevant material total amount result of the test is shown in Table 2.
Table 2
| 0 month | 3 months | 6 months | 9 months | 12 months | |
| Embodiment 2 | 0.45% | 0.45% | 0.44% | 0.46% | 0.46% |
| Embodiment 3 | 0.49% | 0.48% | 0.48% | 0.50% | 0.51% |
| Embodiment 4 | 0.81% | 0.83% | 0.82% | 0.82% | 0.83% |
| Commercially available prod | 2.6% | 2.6% | 2.7% | 2.6% | 2.7% |
Result above shows：For this product in long term test, relevant content of material is high without significant changes, stability；Relevant thing
Matter content is far below commercially available prod, and Product Safety is higher.
Preferred embodiment of the invention described in detail above.It should be appreciated that one of ordinary skill in the art without
Creative work can is needed to make many modifications and variations according to the design of the present invention.Therefore, all technologies in the art
Personnel are available by logical analysis, reasoning, or a limited experiment on the basis of existing technology under this invention's idea
Technical scheme, all should be in the protection domain being defined in the patent claims.
Claims (6)
1. a kind of preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium, it is characterised in that comprise the following steps：
(1) in dichloromethane, 2,3- dioxy -4- ethyl piperazidines, sodium bicarbonate solution is added, -10 DEG C is cooled to, is added portionwise
Solid phosgene, 30~50 DEG C are warming up to, insulation reaction filters, and filtrate is standby；
(2) in dichloromethane, the water of ampicillin three acid is added, triethylamine, which is added dropwise, clarifies dissolving；Step (1) filtrate is added,
20 DEG C~25 DEG C reactions；Hydrochloric acid is added dropwise, adjusts pH to 1.5~2.0, stratification, discards water layer；Dichloromethane layer is added dropwise 2%
Sodium acid carbonate, stratification；Water layer adds activated carbon, agitation and filtration；It is 15~20 DEG C that filtrate, which controls temperature, slow salt under stirring
Acid for adjusting pH adds crystal seed, is further continued for after maintaining stirring 10~20 minutes plus hydrochloric acid is to 1.0~1.5, supported immediately to 4.5-5.0
It is brilliant 1~2 hour；Filter, wet product is washed with water, and vacuum drying obtains Piperacillin；
(3) sodium iso-octoate is added in ethyl acetate, stirring is to being completely dissolved；
(4) in absolute ethyl alcohol, triethylamine is added, is stirred, cool to -5 DEG C~-10 DEG C, add Piperacillin, stirring is extremely
It is completely dissolved, under quick stirring, adds micro sodium iso-octoate solution, stirs 5~10 minutes, slowly improve solution temperature while stirring
Degree stirs 20~30 minutes to 15 DEG C~20 DEG C, is slow added into remaining sodium iso-octoate solution, insulation reaction, filters, filter cake is used
Ethyl acetate washs, and vacuum drying obtains avocin；
(5) the avocin sterile mixing in proportion for obtaining Tazobactam Sodium sodium raw materials and step (4), dispenses and produces.
2. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 1, its feature exists
In 2,3- dioxy -4- ethyl piperazidines described in step (1), sodium acid carbonate and solid phosgene mol ratio are 3~4:3~4:1.
3. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, its feature exists
In the mol ratio of the acid of the water of ampicillin three described in step (2) and 2,3- dioxy -4- ethyl piperazidines described in step (1) is 1:1
~1.2.
4. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, its feature exists
In the crystal seed is the 1%~3% of the water acid weight of ampicillin three.
5. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, its feature exists
In the weight ratio of ethyl acetate described in step (3) and the sodium iso-octoate is 3.8~4.2:1.
6. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, its feature exists
In the weight of sodium iso-octoate described in step (3) is 65~75% of Piperacillin described in step (4).
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| CN108619154A (en) * | 2018-05-28 | 2018-10-09 | 江苏海宏制药有限公司 | A kind of prescription and technique of piperacillin sodium and tazobactam sodium for injection |
| CN109438476A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The preparation method of Piperacillin acid |
| CN113209030B (en) * | 2021-04-27 | 2023-04-25 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
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| CN1732930A (en) * | 2005-08-26 | 2006-02-15 | 华北制药集团有限责任公司 | Piperacillin sodium and tazobactam sodium compound preparation for injection |
| CN101265263A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing piperacillin sodium tazobactam sodium compound injection |
| CN102807572A (en) * | 2011-05-30 | 2012-12-05 | 秦引林 | Refining method for piperacillin sodium |
| CN103087079A (en) * | 2013-02-21 | 2013-05-08 | 齐鲁天和惠世制药有限公司 | Crystallization method of piperacillin |
| 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 |
| CN103340866A (en) * | 2013-07-11 | 2013-10-09 | 四川省惠达药业有限公司 | Piperacillin sodium-tazobactam sodium medicine composition and preparation method thereof |
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| CN101265263A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing piperacillin sodium tazobactam sodium compound injection |
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