CN103040768B - Powder mixing technology for compound antibiotic - Google Patents
Powder mixing technology for compound antibiotic Download PDFInfo
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- CN103040768B CN103040768B CN201310031633.4A CN201310031633A CN103040768B CN 103040768 B CN103040768 B CN 103040768B CN 201310031633 A CN201310031633 A CN 201310031633A CN 103040768 B CN103040768 B CN 103040768B
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- 230000003115 biocidal effect Effects 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 239000000843 powder Substances 0.000 title abstract description 12
- 239000011812 mixed powder Substances 0.000 claims abstract description 22
- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical group [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 claims abstract description 19
- 229960000614 sulbactam sodium Drugs 0.000 claims abstract description 19
- YRMCBQLZVBXOSJ-PCFSSPOYSA-N (e)-3-[(6r,6as)-4-hydroxy-6-methoxy-3-methyl-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enamide Chemical compound CO[C@H]1NC2=C(O)C(C)=CC=C2C(=O)N2C=C(\C=C\C(N)=O)C[C@@H]12 YRMCBQLZVBXOSJ-PCFSSPOYSA-N 0.000 claims abstract description 11
- 238000004108 freeze drying Methods 0.000 claims abstract description 11
- KCVTVKMPZQSSNU-UHFFFAOYSA-N 2-pyridin-4-ylethanethioyl chloride Chemical compound ClC(=S)CC1=CC=NC=C1 KCVTVKMPZQSSNU-UHFFFAOYSA-N 0.000 claims abstract description 8
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 claims abstract description 8
- 229960002417 cefoperazone sodium Drugs 0.000 claims abstract description 8
- 229960001994 mezlocillin sodium Drugs 0.000 claims abstract description 8
- 229960002793 amoxicillin sodium Drugs 0.000 claims abstract description 4
- ILVPFTMKCHREDJ-UHFFFAOYSA-N methyl 5-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1F ILVPFTMKCHREDJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012982 microporous membrane Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000006067 antibiotic powder Substances 0.000 claims 6
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 4
- 238000001035 drying Methods 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 229960005264 piperacillin sodium Drugs 0.000 abstract 1
- 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 abstract 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000463 material Substances 0.000 description 6
- 229940027019 amoxicillin / sulbactam Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005374 membrane filtration Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a powder mixing technology for a compound antibiotic. The compound antibiotic is obtained by cold drying after uniform mixing of antibiotic A and antibiotic B in advance, wherein the antibiotic A is mezlocillin sodium, amoxicillin sodium, cefoperazone sodium, and piperacillin sodium, and the antibiotic B is sulbactam sodium. According to the powder mixing technology, organic solvent is omitted, the environment is less polluted, the freeze-drying technology has stable yield, and the cost is low; the freeze-drying mixed powder has good uniformity, fast dissolution rate, and stable chemical quality, so that the powder mixing technology is applicable to preparation of various of compound antibiotics, and is suitable for mass production.
Description
Technical field
The present invention relates to the antibiotic mixed powder technology of a kind of compound recipe class, belong to medical technical field.
Background technology
At infectious disease, continue today occurred frequently, the mankind are for antibiotic demand also at Continued, but the continuous appearance of the fastbacteria being caused by abuse of antibiotics has become a global problem.Simultaneously, the difficulty of developing new antibiotic kind is also continuing to increase, R&D cycle and funds hit new peak repeatly, and people are effective shortcuts in the urgent need to finding the method for quick, an effective and cheap antagonism Resistant strain, wherein developing antibiotic compound.
Mezlocillin sodium/sulbactam sodium, amoxicillin/sulbactam, cefoperazone sodium/sulbactam sodium and avocin/sulbactam sodium are more representational compound recipe class antibiotic at present, generally have has a broad antifungal spectrum, can be to antimicrobial agent plurality of advantages.
Above-mentioned compound recipe class antibiotic all contains lactam nucleus, its less stable, all very responsive to acid, alkali, therefore need strict production control condition, especially be developed to after compound recipe, it is also more strict to the requirement of production technology, otherwise is easy to cause impurity content exceeding index, causes the generation of side effect.
In all multiple operation of producing at compound preparation, mixed powder is very crucial processing step.No matter existing mixed powder technology, be traditional physical mixed method or spray drying method and crystallization process, do not have general applicability, can only be applicable to the production of one or both compound antibiotics, and the homogeneity of mixed powder is difficult to be protected.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of simple and there is the antibiotic mixed powder technology of compound recipe class general applicability, that can be used in suitability for industrialized production.
The present invention adopts lyophilization to prepare the antibiotic mixed powder of compound recipe class.Lyophilizing is hydrous matter to be first frozen into solid-state, then makes moisture wherein become gaseous state from solid state sublimation, keeps the method for material to remove moisture.Lyophilization is widely used in the production of antibiotic and other medicine, and its advantage is not destroy to heat-labile material, and freeze-drying prods dissolution velocity is fast.
Technical scheme of the present invention is as follows:
The antibiotic mixed powder technology of compound recipe class, is dissolved in the water after it is characterized in that antibiotic A and antibiotic B to be pre-mixed, and obtains the product of homogeneous by freeze-dry process, and concrete steps are as follows:
(1) under room temperature, antibiotic A and antibiotic B is even by the mixed in molar ratio of 0.5 ~ 2:1;
(2) temperature control is 0～10 ℃, and said mixture is dissolved in the water, and is mixed with the aqueous solution of 20-40%wt, and regulator solution pH to 6.0-6.5, with putting into freeze drying box after 0.22 μ m filtering with microporous membrane;
(3) in 2-3 hour, be cooled to-40～-50 ℃, keep 2～3 hours;
(4) open vacuum, pressure is adjusted to 0.10mbar～0.30mbar, maintain at least 2 hours, then temperature is elevated to 5～15 ℃, maintain at least 2 hours, and then temperature is risen to 30～40 ℃, maintain at least 10 hours;
(5) being warming up to 50～55 ℃ is dried to moisture and is less than 2.0%wt;
(6) be naturally cooled to room temperature, obtain the mixed powder of antibiotic A and antibiotic B.
Preferably, the antibiotic A in above-mentioned mixed powder technology is mezlocillin sodium, Amoxicillin Sodium, cefoperazone sodium, avocin, and antibiotic B is sulbactam sodium.
Preferably, in step (1), the mol ratio of antibiotic A and antibiotic B is 1: 1 or 2:1.
Preferably, the aqueous solution configuring in step (2) is 30%wt.
Preferably, the temperature in step (3) is-45 ℃.
Preferably, the pressure in step (4) is 0.20 mbar.
Preferably, the temperature in step (5) is 55 ℃.
Adopt the method for the invention not need with an organic solvent, very low to the pollution of environment, freeze-dry process stable yield, cost is lower; And the mixed powder product homogeneity of the lyophilizing making is good, and dissolution velocity is fast, and chemical quality is stable, and is applicable to the antibiotic preparation of multiple compound recipe class, is applicable to large-scale production needs.
The specific embodiment
Below in conjunction with embodiment, the present invention is further described, but do not limit the present invention.
Embodiment 1
The preparation of the mixed powder of mezlocillin sodium/sulbactam sodium
Under room temperature, the powder mix homogeneously by mezlocillin sodium (56.1g, 0.1mol) with sulbactam sodium (25.5g, 0.1mol).0～5 ℃ of temperature control adds above-mentioned mixed mezlocillin sodium/sulbactam sodium powder in 220mL water for injection, adds sodium bicarbonate to regulate material liquid pH to 6.37, and passes through 0.22 μ m membrane filtration to freeze drying box.Within 2-3 hour, be cooled to-45 ℃, keep 2 hours.Open vacuum and reach 0.10～0.30mbar and carry out vacuum drying, maintain 2 hours, then design temperature is risen to 10 ℃, maintain 3 hours, design temperature is risen to 40 ℃, maintain 12 hours and make water sublimed thorough.Be warming up to 55 ℃ and be dried 10 hours, detecting moisture is 0.76%.Naturally be cooled to room temperature, obtain product.The indexs such as the homogeneity of the mixed powder of mezlocillin sodium/sulbactam sodium preparing after testing, and stability all reach standards of pharmacopoeia.
Embodiment 2
The preparation of the mixed powder of amoxicillin/sulbactam
Under room temperature, the powder mix homogeneously by Amoxicillin Sodium (38.7g, 0.1mol) with sulbactam sodium (25.5g, 0.1mol).0～5 ℃ of temperature control adds above-mentioned mixed amoxicillin/sulbactam powder in 180mL water for injection, adds sodium bicarbonate to regulate material liquid pH to 6.32, and passes through 0.22 μ m membrane filtration to freeze drying box.Within 2-3 hour, be cooled to-45 ℃, keep 2 hours.Open vacuum and reach 0.10～0.30mbar and carry out vacuum drying, maintain 2 hours, then design temperature is risen to 10 ℃, maintain 3 hours, design temperature is risen to 40 ℃, maintain 12 hours and make water sublimed thorough.Be warming up to 55 ℃ and be dried 10 hours, detecting moisture is 0.73%.Naturally be cooled to room temperature, obtain product.The indexs such as the homogeneity of the mixed powder of amoxicillin/sulbactam preparing after testing, and stability all reach standards of pharmacopoeia.
Embodiment 3
The preparation of the mixed powder of cefoperazone sodium/sulbactam sodium
Under room temperature, the powder mix homogeneously by cefoperazone sodium (66.7g, 0.1mol) with sulbactam sodium (25.5g, 0.1mol).0～5 ℃ of temperature control adds above-mentioned mixed cefoperazone sodium/sulbactam sodium powder in 260mL water for injection, adds sodium bicarbonate to regulate material liquid pH to 6.42, and passes through 0.22 μ m membrane filtration to freeze drying box.Within 2-3 hour, be cooled to-45 ℃, keep 2 hours.Open vacuum and reach 0.10～0.30mbar and carry out vacuum drying, maintain 2 hours, then design temperature is risen to 10 ℃, maintain 3 hours, design temperature is risen to 40 ℃, maintain 12 hours and make water sublimed thorough.Be warming up to 55 ℃ and be dried 10 hours, detecting moisture is 0.71%.Naturally be cooled to room temperature, obtain product.The indexs such as the homogeneity of the mixed powder of cefoperazone sodium/sulbactam sodium preparing after testing, and stability all reach standards of pharmacopoeia.
Embodiment 4
The preparation of the mixed powder of avocin/sulbactam sodium
Under room temperature, the powder mix homogeneously by avocin (54.0g, 0.1mol) with sulbactam sodium (25.5g, 0.1mol).0～5 ℃ of temperature control adds above-mentioned mixed avocin/sulbactam sodium powder in 220mL water for injection, adds sodium bicarbonate to regulate material liquid pH to 6.32, and passes through 0.22 μ m membrane filtration to freeze drying box.Within 2-3 hour, be cooled to-45 ℃, keep 2 hours.Open vacuum and reach 0.10～0.30mbar and carry out vacuum drying, maintain 2 hours, then design temperature is risen to 10 ℃, maintain 3 hours, design temperature is risen to 40 ℃, maintain 12 hours and make water sublimed thorough.Be warming up to 55 ℃ and be dried 10 hours, detecting moisture is 0.74%.Naturally be cooled to room temperature, obtain product.The indexs such as the homogeneity of the mixed powder of avocin/sulbactam sodium preparing after testing, and stability all reach standards of pharmacopoeia.
Adopt the method for the invention not need with an organic solvent, very low to the pollution of environment, freeze-dry process stable yield, cost is lower; And the mixed powder product homogeneity of the lyophilizing making is good, and dissolution velocity is fast, and chemical quality is stable, and is applicable to the antibiotic preparation of multiple compound recipe class, is applicable to large-scale production needs.
Claims (6)
1. the antibiotic powder mixing method of compound recipe class, it comprises the steps:
(1) under room temperature, antibiotic A and antibiotic B is even by the mixed in molar ratio of 0.5 ~ 2:1;
(2) temperature control is 0～10 ℃, and said mixture is dissolved in the water, and is mixed with the aqueous solution of 20-40%wt, and regulator solution pH to 6.0-6.5, with putting into freeze drying box after 0.22 μ m filtering with microporous membrane;
(3) in 2-3 hour, be cooled to-40～-50 ℃, keep 2～3 hours;
(4) open vacuum, pressure is adjusted to 0.10mbar～0.30mbar, maintain at least 2 hours, then temperature is elevated to 5～15 ℃, maintain at least 2 hours, and then temperature is risen to 30～40 ℃, maintain at least 10 hours;
(5) be warming up to 50～55 ℃, be dried to moisture and be less than 2.0%wt;
(6) be naturally cooled to room temperature, obtain the mixed powder of antibiotic A and antibiotic B;
Described antibiotic A is mezlocillin sodium, Amoxicillin Sodium, cefoperazone sodium, avocin, and described antibiotic B is sulbactam sodium.
2. the antibiotic powder mixing method of compound recipe class as claimed in claim 1, is characterized in that: in step (1), the mol ratio of antibiotic A and antibiotic B is 1: 1 or 2:1.
3. the antibiotic powder mixing method of compound recipe class as claimed in claim 1, is characterized in that: the aqueous solution configuring in step (2) is 30%wt.
4. the antibiotic powder mixing method of compound recipe class as claimed in claim 1, is characterized in that: the temperature in step (3) is-45 ℃.
5. the antibiotic powder mixing method of compound recipe class as claimed in claim 1, is characterized in that: the pressure in step (4) is 0.20 mbar.
6. the antibiotic powder mixing method of compound recipe class as claimed in claim 1, is characterized in that: the temperature in step (5) is 55 ℃.
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| CN201310031633.4A CN103040768B (en) | 2013-01-28 | 2013-01-28 | Powder mixing technology for compound antibiotic |
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| CN201310031633.4A CN103040768B (en) | 2013-01-28 | 2013-01-28 | Powder mixing technology for compound antibiotic |
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| CN103040768B true CN103040768B (en) | 2014-03-05 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103655578B (en) * | 2013-12-26 | 2015-08-26 | 湖南天圣药业有限公司 | The powder mixing method of a kind of cefoperazone sodium and sulbactam sodium |
| CN104856997A (en) * | 2014-02-21 | 2015-08-26 | 杭州长典医药科技有限公司 | Special piperacillin sodium-tazobactam sodium ultra-fine powder preparation and preparation method thereof |
| CN104382899B (en) * | 2014-11-20 | 2021-02-12 | 重庆福安药业(集团)股份有限公司 | Compound pharmaceutical composition of mezlocillin sodium and sulbactam sodium |
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Effective date of registration: 20200331 Address after: 274199 east side of dongwaihuan Road, Dingtao District, Heze City, Shandong Province (north of Runxin Fine Chemical Co., Ltd.) Patentee after: Shandong Erye Pharmaceutical Co.,Ltd. Address before: 212000 Jiangsu city of Suzhou Province Huang Dai Zhen An min Lu, Xiangcheng District Patentee before: SUZHOU ERYE PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: Mixing technology of a compound antibiotic Granted publication date: 20140305 Pledgee: Shandong Dingtao Rural Commercial Bank Co.,Ltd. Pledgor: Shandong Erye Pharmaceutical Co.,Ltd. Registration number: Y2024980009202 |