CN100522973C - Method of raising stability of potassium clavalanate in production, packing, storage and transportation - Google Patents
Method of raising stability of potassium clavalanate in production, packing, storage and transportation Download PDFInfo
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- CN100522973C CN100522973C CNB2004100569714A CN200410056971A CN100522973C CN 100522973 C CN100522973 C CN 100522973C CN B2004100569714 A CNB2004100569714 A CN B2004100569714A CN 200410056971 A CN200410056971 A CN 200410056971A CN 100522973 C CN100522973 C CN 100522973C
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- potassium
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- clavulanic
- nitrogen
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 29
- 238000003860 storage Methods 0.000 title claims abstract description 8
- 229910052700 potassium Inorganic materials 0.000 title claims description 46
- 239000011591 potassium Substances 0.000 title claims description 46
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims description 45
- 238000012856 packing Methods 0.000 title claims description 20
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 238000000926 separation method Methods 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 239000007789 gas Substances 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 3
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 abstract 4
- 238000004806 packaging method and process Methods 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 235000007686 potassium Nutrition 0.000 description 42
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 4
- 229960003324 clavulanic acid Drugs 0.000 description 4
- -1 clavulanic acid amine Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000011146 sterile filtration Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- XWMVMWTVLSLJGY-FAJPTIRJSA-N (2s,5r,6r)-6-[[(2r)-2-carboxy-2-thiophen-3-ylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21.C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 XWMVMWTVLSLJGY-FAJPTIRJSA-N 0.000 description 1
- 238000004378 air conditioning Methods 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229960002793 amoxicillin sodium Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003311 flocculating effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- ILVPFTMKCHREDJ-UHFFFAOYSA-N methyl 5-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1F ILVPFTMKCHREDJ-UHFFFAOYSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004075 ticarcillin disodium Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明公开了一种提高克拉维酸钾生产、包装和贮运过程中其稳定性的方法，该方法包括以下步骤：在克拉维酸钾的配制、过滤、成盐、液固分离和干燥的生产过程中，将生产环境的相对湿度控制在30%以下，并通以惰性气体保护；克拉维酸钾的包装和贮存采用铝瓶包装，铝瓶内充以惰性气体。试验表明，采用本方法保护的克拉维酸钾稳定性高，有效期可达2年以上。The invention discloses a method for improving the stability of potassium clavulanate during production, packaging, storage and transportation. The method comprises the following steps: preparation, filtration, salt formation, liquid-solid separation and drying of potassium clavulanate. During the production process, the relative humidity of the production environment is controlled below 30%, and protected by an inert gas; the packaging and storage of potassium clavulanate is packaged in an aluminum bottle, and the aluminum bottle is filled with an inert gas. Tests show that the potassium clavulanate protected by the method has high stability and the effective period can reach more than 2 years.
Description
Technical field
The present invention relates to a kind of method that improves beta-lactamase inhibitor stability, relate in particular to a kind of guard method that improves the stability of Clavulanic Potassium in production, packing and transporting procedures.
Background technology
Clavulanic Potassium is a kind of beta-lactamase inhibitor, itself have only weak anti-microbial activity, but it can effectively strengthen the activity that β-lactam antibiotics resists multiple Resistant strain.At present, the compound formulation of amoxycilline Trihydrate bp or ticarcillin and clavulanic acid is widely used in clinical.
Clavulanic Potassium is extremely unstable, meets heat and meets wet very fast degraded, meets oxygen and also can blast, and therefore must take appropriate measures in Clavulanic Potassium production, packing and transporting procedures to improve its stability, prevents its degraded and blast.
The production technique of Clavulanic Potassium mainly may further comprise the steps: the preparation of clavulanic acid amine, decolouring, filtration, salify, liquid-solid separation and drying process.In order to improve the stability of Clavulanic Potassium, in the production process of Clavulanic Potassium, take low temperature and low humidity to prevent the oxygen measure usually in the prior art.The pharmaceutical production ambient relative humidity generally is controlled at 45-65%, and under this relative humidity, Clavulanic Potassium can very fast degraded.The packing of Clavulanic Potassium and the storage Aluminum-plastic composite bags that adopt more, in order to prevent blast, adopt the good Aluminum-plastic composite bag of the splendid attire state that is evacuated more, and general vacuum tightness reaches-when 0.09MPa is following, can influence the particle distribution state of Clavulanic Potassium, in case may influence the mixture homogeneity of mixture when consequently Clavulanic Potassium mixes with Amoxicillin Sodium or Ticarcillin Disodium, cause the content of powder injection defective.
In a word, also there is not a kind of efficient ways at present to improve the stability of Clavulanic Potassium in production, packing and transporting procedures.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of protectiveness method that improves the stability of Clavulanic Potassium in production, packing and transporting procedures.
Technical problem to be solved by this invention is achieved through the following technical solutions:
In preparation, filtration, salify, liquid-solid separation and the exsiccant production process of Clavulanic Potassium, the relative humidity of production environment is controlled at below 30%, and passes to protection of inert gas; The Aluminum Bottle packing is adopted in the packing of Clavulanic Potassium and storage, fills with rare gas element in the Aluminum Bottle.
Wherein said rare gas element is the mixed gas of nitrogen or nitrogen and other rare gas element (for example helium, neon etc.), is preferably nitrogen, more preferably the nitrogen of purity 〉=99.5% (volume percent).Residual oxygen value in the Aluminum Bottle is 0.5%～1.0% (volume percent).
Also comprise in the aforesaid method prepared Clavulanic Potassium is packed, transported and store under 0～8 ℃.
The present invention adopts nitrogen protection to improve the stability of Clavulanic Potassium in production, packing and transporting procedures; be a kind of economy, simple oxygen isolation method; adopt nitrogen protection to produce Clavulanic Potassium down; the degraded of Clavulanic Potassium can be effectively reduced, and the possibility of blasting can be avoided.
The pharmaceutical production ambient relative humidity generally is controlled at 45～65%, and under this relative humidity, Clavulanic Potassium can very fast degraded.Through simultaneous test repeatedly with grope, find that relative humidity is the suitable humidity of producing Clavulanic Potassium below 30%, under this humidity, the Clavulanic Potassium degraded is not obvious.
The storage practice of 2000 editions regulation Clavulanic Potassiums of Chinese Pharmacopoeia is: tight envelope, preserve at dry place below-20 ℃.The Clavulanic Potassium that adopts method of the present invention to produce and pack is preserved down at 0～8 ℃, test of long duration shows, the Clavulanic Potassium degraded is not obvious, and validity period can reach more than 2 years, illustrated that present method can effectively improve the stability of Clavulanic Potassium in production, packing and transporting procedures.
Further illustrate beneficial effect of the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
Embodiment
[embodiment] utilizes guard method of the present invention to carry out the production of Clavulanic Potassium, packing and storing
The preparation of (1) 2-thylhexoic acid potassium solution
In retort, add 20kg2-thylhexoic acid potassium and 1500L propyl carbinol, stir make dissolving, sterile filtration, filtrate be cooled to 15 ℃ standby.
(2) clavulanic acid amine aqueous solution decolouring
Add propyl carbinol 3000L in bleacher, stir and add clavulanic acid amine 54.2kg down and makes its dissolving, be heated to 25 ℃, add 35kg gac and 30kg flocculating aids, decolour 20 minutes, filtration, sterile filtration is to the Clavulanic Potassium crystallizer again.
(3) crystallization of Clavulanic Potassium, filtration, drying and packing
Clavulanic acid amine filtrate is cooled to 15 ℃, stirs adding 2 ethyl hexanoic acid potassium solution down, be chilled to 0 ℃, under this temperature, stirred 1 hour, add the Clavulanic Potassium crystal seed, stop to stir growing the grain, centrifuge washing, dry packing.
All under nitrogen protection, carry out in the above-mentioned whole process of production.Nitrogen is produced by air Nitrogen plant (specifications and models: FDA, Beijing flies Da Jie and separates the manufacturing of gas isolation technique company limited), and when nitrogen reached 99.5% purity, nitrogen can utilize.The purity of nitrogen is by intelligent oxygen measuring instrument (specifications and models: YHL, 703 productions of China Aerospace Science and Technology Corporation) test automatically, automatic emptying when purity does not reach 99.5%.
In the above-mentioned whole process of production, use dehumidifying unit (specifications and models: SM-LSO-OS automatically, the production of Jin Gang air-conditioning equipment factory, Tianjin) relative humidity with production environment is controlled at below 30%, set the controlling moisture scope 20%～27%, when relative humidity〉27% the time, dehumidifying starts, and when relative humidity＜20%, dehumidifying stops.
The quality condition of the Clavulanic Potassium that [test example] the present invention is prepared detects
1, for test agent: the Clavulanic Potassium that the embodiment of the invention is prepared charges under nitrogen, the 0-8 ℃ condition and deposited 2 years.
2, test method and result
Clavulanic Potassium that the embodiment of the invention is prepared adopts the Aluminum Bottle packing, in to fill with purity be 99.8% nitrogen.Nitrogen is by above-mentioned air Nitrogen plant preparation, after the hose system Sterile Filtration, feed in the clean aseptic Aluminum Bottle, by the residual oxygen value in oxygen measuring instrument (specifications and models: OX-100A: Zhejiang Nanjia Analyzer Factory, Meicheng Jiande City produces) the control Aluminum Bottle, the residual oxygen value in the control Aluminum Bottle is 0.8% (volume percent).Packaged Clavulanic Potassium was deposited 2 years under 0～8 ℃ of condition.According to the requirement under Chinese Pharmacopoeia version Clavulanic Potassium in 2000 the quality standard item, the trial-product of depositing 2 years is checked that comprehensively check result sees the following form:
Annotate: the raw material that related substance refers to bring in process of production, intermediate, degradation product, isomer, polymkeric substance, byproduct of reaction etc.
The Clavulanic Potassium of storing 2 years shows that through quality examination its quality meets every regulation of Chinese Pharmacopoeia version Clavulanic Potassium in 2000 quality standard, illustrates that the inventive method can effectively improve the stability of Clavulanic Potassium in production, packing and transporting procedures.
Claims (4)
1, a kind ofly improves its stable method in Clavulanic Potassium production, packing and the transporting procedures, it is characterized in that: in preparation, filtration, salify, liquid-solid separation and the exsiccant production process of Clavulanic Potassium, the relative humidity of production environment is controlled at below 30%, and passes to protection of inert gas; Under 0～8 ℃ of temperature, carry out packing, transportation and the storage of Clavulanic Potassium; The Aluminum Bottle packing is adopted in the packing of Clavulanic Potassium and storage, fills in the Aluminum Bottle with rare gas element, and the residual oxygen value in the Aluminum Bottle is 0.5%～1.0%.
2, according to the described guard method of claim 1, it is characterized in that: described rare gas element is the mixed gas of nitrogen or nitrogen and other rare gas element.
3, according to the described guard method of claim 2, it is characterized in that: described rare gas element is a nitrogen.
4, according to the described guard method of claim 3, it is characterized in that: the purity of described nitrogen is more than or equal to 99.5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100569714A CN100522973C (en) | 2004-08-24 | 2004-08-24 | Method of raising stability of potassium clavalanate in production, packing, storage and transportation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100569714A CN100522973C (en) | 2004-08-24 | 2004-08-24 | Method of raising stability of potassium clavalanate in production, packing, storage and transportation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1740177A CN1740177A (en) | 2006-03-01 |
| CN100522973C true CN100522973C (en) | 2009-08-05 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100569714A Expired - Fee Related CN100522973C (en) | 2004-08-24 | 2004-08-24 | Method of raising stability of potassium clavalanate in production, packing, storage and transportation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100522973C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109535184B (en) * | 2017-09-21 | 2020-11-20 | 联邦制药(内蒙古)有限公司 | A kind of method for preparing potassium clavulanate from tert-octylamine clavulanate |
-
2004
- 2004-08-24 CN CNB2004100569714A patent/CN100522973C/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| "克拉维酸钾阿莫西林干混悬剂稳定性影响因素的考察". 安富荣等.中国药学杂志，第35卷第2期. 2000 * |
| 中华人民共和国药典. 第268-269页. 2000 * |
| 阿莫西林克拉维酸钾片的工艺研究及稳定性考察结果. 聂中越等.中国药业，第10卷第9期. 2001 * |
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| Publication number | Publication date |
|---|---|
| CN1740177A (en) | 2006-03-01 |
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Effective date of registration: 20090710 Address after: Research and development department, Hebei Zhang Xin drug Limited by Share Ltd, No. 24 Jianguo Road, Hebei, Zhangjiakou Patentee after: Hebei Xinzhang Pharmaceutical Co., Ltd. Address before: No. 24 Jianguo Road, Hebei, Zhangjiakou Patentee before: Zhangyao Co., Ltd., Hebei |
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