CN104644637A - Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof - Google Patents
Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a medicine composition of piperacillin sodium tazobactam sodium and a preparation method thereof. The medicine composition is sterile powder injection, wherein the weight ratio of piperacillin sodium tazobactam sodium is (2-4):1. The piperacillin sodium tazobactam sodium sterile powder injection prepared in the invention has high stability and less impurity; by utilizing the sterile powder injection, the safety and effectiveness of clinical medication are improved greatly.
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 art.
Background technology
Piperacillin is semi-synthetic penicillins antibiotic, has broad-spectrum antibacterial action, has been widely used in clinical.Sodium-tazobactam is beta-lactamase inhibitor, belongs to the antibacterial strong synergist of the third generation, share the drug effect that can strengthen the two and extend action time with piperacillin.When avocin and sodium-tazobactam conbined usage, produce obvious synergism, be widely used in treatment serious systemic and local infection, abdominal cavity infection, lower respiratory infection, soft tissue infection, septicemia etc., than other the antibacterial complexing agent used, there is antimicrobial spectrum and indication widely, show huge advantage overcoming in drug resistance.
The current domestic existing sale of piperacillin sodium and tazobactam sodium compound preparation, is sterilized powder direct packaging and obtains, and it exists a common defect is exactly preparation stabilization difference, and impurity content is high, there is certain potential safety hazard.
In piperacillin sodium and tazobactam sodium product, because its " related substance " class impurity overwhelming majority derives from avocin, therefore the product impurity of avocin crude drug determines the impurity level of final products.Again due to after avocin adds alkali dissolution by piperacillin, after aseptic filtration, lyophilizing obtains, without purification procedures in process, so Control of Impurities also must extend to piperacillin forward.The quality of piperacillin acid plays very crucial effect at the antibacterial activity improved in medicine use procedure and safety.
Summary of the invention
The object of the invention is to provide a kind of piperacillin sodium and tazobactam sodium for injection preparation and preparation method thereof, and make piperacillin sodium and tazobactam sodium for injection preparation have purity high, impurity is few, good stability, is not easy the advantages such as irritated.
For realizing object of the present invention, the present invention by the following technical solutions:
The invention provides a kind of pharmaceutical composition of piperacillin sodium and tazobactam sodium, described pharmaceutical composition is sterile powder injection, and wherein the weight ratio of avocin and sodium-tazobactam is 2 ~ 4:1.
The present invention also provides a kind of preparation method of pharmaceutical composition of piperacillin sodium and tazobactam sodium, comprises the following steps:
(1) in dichloromethane, add 2,3-dioxy-4-ethyl piperazidine, sodium bicarbonate solution, be cooled to-10 DEG C, add solid phosgene in batches, be warming up to 30 ~ 50 DEG C, insulation reaction, filter, filtrate is for subsequent use;
(2) in dichloromethane, add ampicillin three water acid, drip triethylamine and dissolving is clarified; Add step (1) filtrate, 20 DEG C ~ 25 DEG C reactions; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 2% sodium bicarbonate, stratification; Water layer adds active carbon, agitation and filtration; Filtrate control temperature is 15 DEG C ~ 20 DEG C, stirs lower slow salt acid for adjusting pH to 4.5 ~ 5.0, adds crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 1 ~ 2 hour; Sucking filtration, wet product washes with water, and vacuum drying obtains piperacillin;
(3) in ethyl acetate, add Sodium isooctanoate., be stirred to and dissolve completely;
(4) in dehydrated alcohol, add triethylamine, stir, cool to-5 DEG C ~-10 DEG C, add piperacillin, be stirred to and dissolve completely, under rapid stirring, add micro-sodium iso-octoate solution, stir 5 ~ 10 minutes, slowly improve solution temperature to 15 DEG C ~ 20 DEG C while stirring, stir 20 ~ 30 minutes, more slowly add all the other sodium iso-octoate solution, insulation reaction, sucking filtration, filter cake ethyl acetate is washed, and vacuum drying obtains avocin;
(5) the avocin aseptic mixing in proportion Tazobactam Sodium sodium raw materials and step (4) obtained, subpackage and get final product.
Preferably, described in step (1), the mol ratio of 2,3-dioxy-4-ethyl piperazidines, sodium bicarbonate and solid phosgene is 3:3 ~ 4:1.
Preferably, the acid of ampicillin three water described in step (2) is 1:1 ~ 1.2 with the mol ratio of 2,3-dioxy-4-ethyl piperazidines described in step (1).
Preferably, crystal seed described in step (2) is 1% ~ 3% of described ampicillin three water acid weight.
Preferably, described in step (3), the weight ratio of ethyl acetate and described Sodium isooctanoate. is 3.8 ~ 4.2:1.
Preferably, the weight of Sodium isooctanoate. described in step (3) is 65 ~ 75% of piperacillin described in step (4).
Compared with prior art, the present invention has the following advantages:
1, the present invention adopts solid phosgene as chloride reagent, its chloride reagent such as the thionyl chloride relative to routine or phosgene, and have molten boiling point high, volatility is low, and toxicity is little, and safety is high, easily decomposes removing; Use sodium bicarbonate as acid binding agent, more easily remove, not easily remain;
2, exploitation induction piperacillin crystallization processes, adding opportunity, crystal seed amount etc. by controlling crystal seed, making crystal evenly regular, reducing and reunites and granularity is increased, thus decreases impurity and carry secretly, significantly reduction piperacillin impurity level;
3, reactant Sodium isooctanoate. is divided into 2 times to add, the avocin that first time Sodium isooctanoate. reaction is generated as nucleus, by how many control nucleus quantity of first time different Sodium isooctanoate. addition.The condition that first time Sodium isooctanoate. adds is controlled under two kinds of reactants almost nonreactive temperature, stirring condition simultaneously, by two kinds of reactant mix homogeneously, then slowly temperature is improved, avocin nucleus is generated gradually, substantially increase the purity of piperacillin sodium crystal, further reduce impurity content in raw material, improve the quality of product.
Accompanying drawing explanation
Fig. 1 is the piperacillin crystallographic microscope figure adopting prior art to prepare.
Fig. 2 is the piperacillin crystallographic microscope figure adopting the present invention to prepare.
Detailed description of the invention
Reference examples 1
Adopt the method for crystallising of the embodiment 1 in patent CN201310055833.3, use piperacillin crude product to prepare piperacillin crystal.
Crystallographic microscope figure as shown in Figure 1.Detect according to Chinese Pharmacopoeia version piperacillin related substance detection method in 2010, related substance 1 and related substance 2 content of impurities are 3.7%.
Embodiment 1
(1) in reaction bulb, add 30ml dichloromethane, add 2,3-dioxy-4-ethyl piperazidine 4.26g, sodium bicarbonate 2.52g (with water dissolution), be cooled to-10 DEG C, divides and add solid phosgene 2.97g three times in stirring, be warming up to 40 DEG C, insulation reaction 1.5 hours, filter, filtrate is for subsequent use;
(2) in reaction bulb, add 100ml dichloromethane, add ampicillin three water acid 10.07g, drip triethylamine and dissolving is clarified; Add step (1) filtrate, react 1 hour at 20 DEG C ~ 25 DEG C; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 200ml 2% sodium bicarbonate, stratification, and water layer adds 10g active carbon, stirs after 10 minutes and filters; Get filtrate, control temperature is 15 ~ 20 DEG C, stirs the lower salt acid for adjusting pH that slowly drips to 4.5-5.0, adds 0.2g crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 2 hours; Sucking filtration, wet product washes with water, and vacuum drying obtains piperacillin crystal.
Crystallographic microscope figure as shown in Figure 2.Detect according to Chinese Pharmacopoeia version piperacillin related substance detection method in 2010, related substance 1 and related substance 2 content of impurities are 0.3%.
Shown by the contrast of Fig. 1 and Fig. 2, piperacillin crystal grain prepared by the present invention is well-balanced, thick, and granularity is increased to more than 30 μm by 15 μm.Due to the control of crystallization and the improvement of crystal, the total impurities of preparing product of the present invention significantly reduces.
Embodiment 2
(1) in reaction bulb, add 30ml dichloromethane, add 2,3-dioxy-4-ethyl piperazidine 4.26g, sodium bicarbonate 2.52g (with water dissolution), be cooled to-10 DEG C, divides and add solid phosgene 2.97g three times in stirring, be warming up to 40 DEG C, insulation reaction 1.5 hours, filter, filtrate is for subsequent use;
(2) in reaction bulb, add 100ml dichloromethane, add ampicillin three water acid 10.07g, drip triethylamine and dissolving is clarified; Add step (1) filtrate, react 1 hour at 20 DEG C ~ 25 DEG C; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 200ml 2% sodium bicarbonate, stratification, and water layer adds 10g active carbon, stirs after 10 minutes and filters; Get filtrate, control temperature is 15 ~ 20 DEG C, stirs the lower salt acid for adjusting pH that slowly drips to 4.5-5.0, adds 0.1g crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 2 hours; Sucking filtration, wet product washes with water, and vacuum drying obtains 12.4g piperacillin crystal.
(3) in 35ml ethyl acetate, add Sodium isooctanoate. 9.3g, be stirred to and dissolve completely, make sodium iso-octoate solution;
(4) in 32ml dehydrated alcohol, add 8ml triethylamine, stir, cool to-5 DEG C ~-10 DEG C, add piperacillin, be stirred to and dissolve completely, under rapid stirring, add a small amount of sodium iso-octoate solution, stir 5 ~ 10 minutes, slowly improve solution temperature to 15 DEG C ~ 20 DEG C while stirring, stir 20 ~ 30 minutes, more slowly add all the other sodium iso-octoate solution, insulation reaction, sucking filtration, filter cake ethyl acetate is washed, and vacuum drying obtains avocin;
(5) avocin that Tazobactam Sodium sodium raw materials and step (4) obtain is placed in the aseptic Homogeneous phase mixing of solid powder mixer in 1:2 ratio, is sub-packed in cillin bottle, jumps a queue, Zha Gai, packaging, censorship.
Embodiment 3
(1) in reaction bulb, add 30ml dichloromethane, add 2,3-dioxy-4-ethyl piperazidine 4.26g, sodium bicarbonate 2.52g (with water dissolution), be cooled to-10 DEG C, divides and add solid phosgene 2.97g three times in stirring, be warming up to 50 DEG C, insulation reaction 1.5 hours, filter, filtrate is for subsequent use;
(2) in reaction bulb, add 100ml dichloromethane, add ampicillin three water acid 12.07g, drip triethylamine and dissolving is clarified; Add step (1) filtrate, react 1 hour at 20 DEG C ~ 25 DEG C; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 200ml 2% sodium bicarbonate, stratification, and water layer adds 10g active carbon, stirs after 10 minutes and filters; Get filtrate, control temperature is 15 ~ 20 DEG C, stirs the lower salt acid for adjusting pH that slowly drips to 4.5-5.0, adds 0.12g crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 2 hours; Sucking filtration, wet product washes with water, and vacuum drying obtains 13.1g piperacillin crystal.
(3) in 35ml ethyl acetate, add Sodium isooctanoate. 9.5g, be stirred to and dissolve completely, make sodium iso-octoate solution;
(4) in 32ml dehydrated alcohol, add 8ml triethylamine, stir, cool to-5 DEG C ~-10 DEG C, add piperacillin, be stirred to and dissolve completely, under rapid stirring, add a small amount of sodium iso-octoate solution, stir 5 ~ 10 minutes, slowly improve solution temperature to 15 DEG C ~ 20 DEG C while stirring, stir 20 minutes, more slowly add all the other sodium iso-octoate solution, insulation reaction, sucking filtration, filter cake ethyl acetate is washed, and vacuum drying obtains avocin;
(5) avocin that Tazobactam Sodium sodium raw materials and step (4) obtain is placed in the aseptic Homogeneous phase mixing of solid powder mixer in 1:2 ratio, is sub-packed in cillin bottle, jumps a queue, Zha Gai, packaging, censorship.
Embodiment 4
(1) in reaction bulb, add 30ml dichloromethane, add 2,3-dioxy-4-ethyl piperazidine 4.26g, sodium bicarbonate 2.52g (with water dissolution), be cooled to-10 DEG C, divide and add solid phosgene 2.97g three times, be warming up to 50 DEG C, insulation reaction 1.5 hours, filter, filtrate is for subsequent use;
(2) in reaction bulb, add 100ml dichloromethane, add ampicillin three water acid 12.07g, drip triethylamine and dissolving is clarified; Add step (1) filtrate, react 2 hours at 20 DEG C ~ 25 DEG C; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 200ml 2% sodium bicarbonate, stratification, and water layer adds 10g active carbon, stirs after 10 minutes and filters; Get filtrate, control temperature is 15 ~ 20 DEG C, stirs the lower salt acid for adjusting pH that slowly drips to 4.5-5.0, adds 0.24g crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 2 hours; Sucking filtration, wet product washes with water, and vacuum drying obtains 13.9g piperacillin crystal.
(3) in 35ml ethyl acetate, add Sodium isooctanoate. 9.5g, be stirred to and dissolve completely, make sodium iso-octoate solution;
(4) in 32ml dehydrated alcohol, add 8ml triethylamine, stir, cool to-5 DEG C ~-10 DEG C, add piperacillin, be stirred to and dissolve completely, under rapid stirring, add a small amount of sodium iso-octoate solution, stir 5 ~ 10 minutes, slowly improve solution temperature to 15 DEG C ~ 20 DEG C while stirring, stir 20 minutes, more slowly add all the other sodium iso-octoate solution, insulation reaction, sucking filtration, filter cake ethyl acetate is washed, and vacuum drying obtains avocin;
(5) avocin that Tazobactam Sodium sodium raw materials and step (4) obtain is placed in the aseptic Homogeneous phase mixing of solid powder mixer in 1:4 ratio, is sub-packed in cillin bottle, jumps a queue, Zha Gai, packaging, censorship.
Test example 1
Piperacillin sodium and tazobactam sodium sample prepared by Example 2-4 and each 1 batch of commercially available piperacillin sodium and tazobactam sodium for injection, be placed in 40 DEG C and 75% humidity light protected environment, respectively at placement after the 1st, 2,3,6 months sampling investigate, with within 0 month, investigate data and compare, related substance total amount result of the test is 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％ |
Above result shows: this product is in accelerated test, and its related substances is without significant change, and stability is high; Its related substances is far below commercially available prod, and Product Safety is higher.
Test example 2
Piperacillin sodium and tazobactam sodium sample prepared by Example 2-4 and each 1 batch of commercially available piperacillin sodium and tazobactam sodium for injection, be placed in 25 DEG C and 75% humidity light protected environment, respectively at placement after the 3rd, 6,9,12 months sampling investigate, with within 0 month, investigate data and compare, related substance total amount result of the test is 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％ |
Above result shows: this product is in long term test, and its related substances is without significant change, and stability is high; Its related substances is far below commercially available prod, and Product Safety is higher.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technical staff in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (7)
1. a pharmaceutical composition for piperacillin sodium and tazobactam sodium, is characterized in that, described pharmaceutical composition is sterile powder injection, and wherein the weight ratio of avocin and sodium-tazobactam is 2 ~ 4:1.
2. a preparation method for the pharmaceutical composition of piperacillin sodium and tazobactam sodium, is characterized in that, comprises the following steps:
(1) in dichloromethane, add 2,3-dioxy-4-ethyl piperazidine, sodium bicarbonate solution, be cooled to-10 DEG C, add solid phosgene in batches, be warming up to 30 ~ 50 DEG C, insulation reaction, filter, filtrate is for subsequent use;
(2) in dichloromethane, add ampicillin three water acid, drip triethylamine and dissolving is clarified; Add step (1) filtrate, 20 DEG C ~ 25 DEG C reactions; Drip hydrochloric acid, regulate pH to 1.5 ~ 2.0, stratification, discards water layer; Dichloromethane layer drips 2% sodium bicarbonate, stratification; Water layer adds active carbon, agitation and filtration; Filtrate control temperature is 15 ~ 20 DEG C, stirs lower slow salt acid for adjusting pH to 4.5-5.0, adds crystal seed immediately, maintain stirring and continue to add hydrochloric acid to 1.0 ~ 1.5 after 10 ~ 20 minutes again, growing the grain 1 ~ 2 hour; Sucking filtration, wet product washes with water, and vacuum drying obtains piperacillin;
(3) in ethyl acetate, add Sodium isooctanoate., be stirred to and dissolve completely;
(4) in dehydrated alcohol, add triethylamine, stir, cool to-5 DEG C ~-10 DEG C, add piperacillin, be stirred to and dissolve completely, under rapid stirring, add micro-sodium iso-octoate solution, stir 5 ~ 10 minutes, slowly improve solution temperature to 15 DEG C ~ 20 DEG C while stirring, stir 20 ~ 30 minutes, more slowly add all the other sodium iso-octoate solution, insulation reaction, sucking filtration, filter cake ethyl acetate is washed, and vacuum drying obtains avocin;
(5) the avocin aseptic mixing in proportion Tazobactam Sodium sodium raw materials and step (4) obtained, subpackage and get final product.
3. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, is characterized in that, described in step 1, the mol ratio of 2,3-dioxy-4-ethyl piperazidines, sodium bicarbonate and solid phosgene is 3 ~ 4:3 ~ 4:1.
4. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, it is characterized in that, the acid of ampicillin three water described in step (2) is 1:1 ~ 1.2 with the mol ratio of 2,3-dioxy-4-ethyl piperazidines described in step (1).
5. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, is characterized in that, described crystal seed is 1% ~ 3% of described ampicillin three water acid weight.
6. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, is characterized in that, described in step (3), the weight ratio of ethyl acetate and described Sodium isooctanoate. is 3.8 ~ 4.2:1.
7. the preparation method of the pharmaceutical composition of piperacillin sodium and tazobactam sodium according to claim 2, is characterized in that, the weight of Sodium isooctanoate. 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 |
| CN113209030A (en) * | 2021-04-27 | 2021-08-06 | 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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Effective date of registration: 20210930 Address after: 050015 No. 388 Pingdong Road, Chang'an District, Shijiazhuang City, Hebei Province Patentee after: NORTH CHINA PHARMACEUTICAL Co.,Ltd. Patentee after: NORTH CHINA PHARMACEUTICAL GROUP XIANTAI PHARMACEUTICAL Co.,Ltd. Patentee after: GUANGDONG JINCHENG JINSU PHARMACY Co.,Ltd. Address before: 050015 No. 388 Pingdong Road, Chang'an District, Shijiazhuang City, Hebei Province Patentee before: NORTH CHINA PHARMACEUTICAL Co.,Ltd. Patentee before: NORTH CHINA PHARMACEUTICAL GROUP XIANTAI PHARMACEUTICAL Co.,Ltd. Patentee before: ZHEJIANG CHANGDIAN PHARMACEUTICAL Co.,Ltd. |