CN105001215A - Aztreonam compound serving as sterilization medicine and preparation method thereof - Google Patents
Aztreonam compound serving as sterilization medicine and preparation method thereof Download PDFInfo
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- CN105001215A CN105001215A CN201510478860.0A CN201510478860A CN105001215A CN 105001215 A CN105001215 A CN 105001215A CN 201510478860 A CN201510478860 A CN 201510478860A CN 105001215 A CN105001215 A CN 105001215A
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- aztreonam
- mixed solvent
- germ killing
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses an aztreonam compound serving as sterilization medicine and a preparation method thereof and belongs to the technical field of medicine. According to the aztreonam compound, Cu-Ka rays are used for conducting the measurement, and an X-ray powder diffraction pattern as shown in figure one is obtained. The test result indicates that the aztreonam crystal compound is high in purity, good in flowability and stability, low in polymer content, free of hygroscopicity and safe and reliability in clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of germ killing drugs aztreonam compound and preparation method thereof.
Background technology
Aztreonam is a kind of white or micro-yellow polymorphic powder, and the crystalline structure form having multiple crystal formation known at present has 4 kinds, i.e. α type, β type, γ type and δ type.Wherein, the aztreonam of alpha-crystal form is water-containing crystal body, usually comprises 7% ~ 14% moisture, storage stability is poor, therefore needs the aztreonam converting it into beta crystal, and the latter is anhydrous, there is the features such as moistureproof and good mobility, be more suitable for the bulk drug as medicinal preparations.
In order to improve the performance of aztreonam further, this invention of special proposition, the purity of aztreonam crystalline compounds of the present invention is high, good fluidity, good stability, and polymer content is low, and moist without drawing, clinical application is safe and reliable.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of germ killing drugs aztreonam compound;
Second goal of the invention of the present invention is the preparation method proposing this aztreonam crystalline compounds.
In order to realize object of the present invention, the technical scheme of employing is:
A kind of germ killing drugs aztreonam compound, the X-ray powder diffraction pattern that described compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
The invention still further relates to the preparation method of this aztreonam crystalline compounds, comprise the following steps:
Aztreonam is dissolved in the mixed solvent of the methyl alcohol of 30-40 DEG C, methyl-sulphoxide; First add the mixed solvent of ethanol and ether, limit edged stirs, control temperature 30-40 DEG C, growing the grain 2-4 hour; And then adding distilled water, after growing the grain 1-3 hour, cooling, then keeps stirring velocity 110-130 rev/min of stirring and crystallizing, growing the grain 2-3 hour; Filter, washing, drying under reduced pressure obtains aztreonam crystalline compounds.
The volume of wherein said methyl alcohol, the mixed solvent of methyl-sulphoxide is 7-9 times of aztreonam weight, and the volume ratio of methyl alcohol and methyl-sulphoxide is 1.5:5; The volume of the ethanol first added and the mixed solvent of ether is 8-10 times of aztreonam weight, and adding speed is 25-35ml/min, and the volume ratio of ethanol, ether is 2.5:1; The volume total amount of the distilled water added again is 6-8 times of aztreonam weight, and adding speed is 20-30ml/min; Described cooling refers to and is cooled to-5 DEG C with the speed of 5-15 DEG C/h.
Below technical scheme of the present invention is made further explanation:
Aztreonam is Beta-lactam medicine, the easy open loop of its monoamide ring, form impurity and easily self-polymerization occur after open loop, form high molecular polymer, thus reduction medicament contg, cause drug titers to reduce, the sterilization of aztreonam and fungistatic effect are reduced, and superpolymer can cause endogenous anaphylaxis.The good stability of the aztreonam compound that the present invention prepares, not easily open loop is decomposed, its polymer content trace.
Aztreonam has and draws moist, can cause the change of the physico-chemical properties such as the decline of caking, mobility, deliquescence, crystal formation change, thus affect the interior qualities such as product stability, validity, security after moisture absorption.And according to the literature, many microbiotic are stablized in the dry state, but will decompose after making moist.Therefore, water absorbability has very important impact for the stability of aztreonam.Therefore, if can reduce the water absorbability of aztreonam, then the stability for aztreonam has very important meaning.Meanwhile, bibulous medicine needs strictly to control the relative humidity between packing in formulation manufacturing processes, is no more than critical relative humidity, thus ensures quality product and stability.If not easily moisture absorption, then the production of convenient preparation, ensures stability simultaneously.
A kind of germ killing drugs aztreonam compound of the present invention, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.By to its hygroscopic research, the discovery that contriver is pleasantly surprised, its water absorbability of compound of the present invention is significantly less than existing crystalline compounds.Thus illustrate that aztreonam crystalline compounds of the present invention is more stable, and more adapt to the preparation of preparation.
The purity of aztreonam crystalline compounds of the present invention can reach 99.9%, and its structure is confirmed through proton nmr spectra.The preparation method of aztreonam crystalline compounds of the present invention is simple, and purity is high, and yield is high, most suitable large-scale industrial production.
Aztreonam crystalline compounds of the present invention can be used for preparing the multiple formulation used clinically, as freeze-dried powder, aseptic powder injection, liquid drugs injection etc.And confirm through stability test, adopt aztreonam crystalline compounds of the present invention, its stability, higher than prior art, is very suitable for clinical application.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern that the aztreonam crystalline compounds for preparing of embodiment 1 uses the measurement of Cu-K alpha-ray and obtains.
Embodiment
The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.
embodiment 1:the preparation of aztreonam crystalline compounds
Be dissolved in by aztreonam in the mixed solvent of methyl alcohol that 30 DEG C of volumes are 7 times of aztreonam weight, methyl-sulphoxide, the volume ratio of methyl alcohol and methyl-sulphoxide is 1.5:5; First add with the speed of 25ml/min the ethanol of 8 times and the mixed solvent of ether that volume is aztreonam weight, the volume ratio of ethanol, ether is 2.5:1, and limit edged stirs, control temperature 30 DEG C, growing the grain 2 hours; And then the distilled water of 6 times that volume total amount is aztreonam weight is added with the speed of 20ml/min, growing the grain, after 1 hour, is cooled to-5 DEG C with the speed of 5 DEG C/h, then keeps stirring velocity 110 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, washing, drying under reduced pressure obtains aztreonam crystalline compounds.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains.
embodiment 2:the preparation of aztreonam crystalline compounds
Be dissolved in by aztreonam in the mixed solvent of methyl alcohol that 35 DEG C of volumes are 8 times of aztreonam weight, methyl-sulphoxide, the volume ratio of methyl alcohol and methyl-sulphoxide is 1.5:5; First add with the speed of 30ml/min the ethanol of 9 times and the mixed solvent of ether that volume is aztreonam weight, the volume ratio of ethanol, ether is 2.5:1, and limit edged stirs, control temperature 35 DEG C, growing the grain 3 hours; And then the distilled water of 7 times that volume total amount is aztreonam weight is added with the speed of 25ml/min, growing the grain, after 2 hours, is cooled to-5 DEG C with the speed of 10 DEG C/h, then keeps stirring velocity 120 revs/min of stirring and crystallizing, growing the grain 2.5 hours; Filter, washing, drying under reduced pressure obtains aztreonam crystalline compounds.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.8% to the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains.
embodiment 3:the preparation of aztreonam crystalline compounds
Be dissolved in by aztreonam in the mixed solvent of methyl alcohol that 40 DEG C of volumes are 9 times of aztreonam weight, methyl-sulphoxide, the volume ratio of methyl alcohol and methyl-sulphoxide is 1.5:5; First add with the speed of 35ml/min the ethanol of 10 times and the mixed solvent of ether that volume is aztreonam weight, the volume ratio of ethanol, ether is 2.5:1, and limit edged stirs, control temperature 40 DEG C, growing the grain 4 hours; And then the distilled water of 8 times that volume total amount is aztreonam weight is added with the speed of 30ml/min, growing the grain, after 3 hours, is cooled to-5 DEG C with the speed of 15 DEG C/h, then keeps stirring velocity 130 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, washing, drying under reduced pressure obtains aztreonam crystalline compounds.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains.
experimental example 1:influence factor is tested
1, high temperature test
The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, places 10 days at 40 ± 2 DEG C of temperature, and in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, test-results compared with 0 day.
2, high humidity test
The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, place 10 days under the condition of 25 ± 2 DEG C of relative humidity 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, test-results compared with 0 day.
3, strong illumination test
The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, being placed in illumination is place 10 days under the condition of 4500lx, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result compared with 0 day.The results are shown in Table 1
Table 1 influence factor test-results
Result shows: the aztreonam crystalline compounds that the present invention prepares, and its stability is good, and under high temperature, high humidity, high light conditions, equal retention is stablized.Influence factor experiment is carried out to aztreonam crystalline compounds prepared by other embodiment of the present invention, obtains identical experimental result.
experimental example 2:acceleration study
The aztreonam crystalline compounds that Example 1-3 prepares, simulation listing packaging, put in sealing clean container, in 40 DEG C ± 2 DEG C, place 6 months under relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table 2.
Table 2: accelerated test result
Result shows: the aztreonam crystalline compounds that the present invention prepares, known through accelerated test result, its good stability, and polymer content is low, and total assorted content is low.
experimental example 3:wettability test
1 instrument
PL203 electronic balance, LRH-250-S fixed temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that salts solution is saturated, excessive salt should be had bottom moisture eliminator to exist) that bottom fills salt supersaturated solution, the built-in weighing bottle of moisture eliminator, places 48h to constant humidity in thermostat container.Sample thief is about 2g, puts in weighing bottle, accurately weighed, bottle cap is opened, puts into moisture eliminator top, put in 25 DEG C of fixed temperature and humidity incubators or 20 DEG C of stability test casees by differing temps requirement and preserve, parallel running 3 parts, weighs respectively at different time, calculates the rate of moisture absorption of different time.
Calculation formula: rate of moisture absorption=(medicinal powder weight after moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount × 100%.Result is as table 3:
Table 3 hygroscopicity test results
According to above-mentioned experiment, the water absorbability of aztreonam crystalline compounds prepared by the present invention is low, good stability.
Claims (6)
1. a germ killing drugs aztreonam compound, is characterized in that: the X-ray powder diffraction pattern that described compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. germ killing drugs aztreonam compound according to claim 1, is characterized in that: the preparation method of described compound comprises the following steps:
Aztreonam is dissolved in the mixed solvent of the methyl alcohol of 30-40 DEG C, methyl-sulphoxide; First add the mixed solvent of ethanol and ether, limit edged stirs, control temperature 30-40 DEG C, growing the grain 2-4 hour; And then adding distilled water, after growing the grain 1-3 hour, cooling, then keeps stirring velocity 110-130 rev/min of stirring and crystallizing, growing the grain 2-3 hour; Filter, washing, drying under reduced pressure obtains aztreonam crystalline compounds.
3. germ killing drugs aztreonam compound according to claim 2, is characterized in that: the volume of the mixed solvent of described methyl alcohol, methyl-sulphoxide is 7-9 times of aztreonam weight, and the volume ratio of described methyl alcohol and methyl-sulphoxide is 1.5:5.
4. germ killing drugs aztreonam compound according to claim 2, is characterized in that: the volume of the ethanol first added and the mixed solvent of ether is 8-10 times of aztreonam weight, and adding speed is 25-35ml/min, and the volume ratio of ethanol, ether is 2.5:1.
5. germ killing drugs aztreonam compound according to claim 2, is characterized in that: the volume total amount of the distilled water added again is 6-8 times of aztreonam weight, and adding speed is 20-30ml/min.
6. germ killing drugs aztreonam compound according to claim 2, is characterized in that: described cooling refers to and is cooled to-5 DEG C with the speed of 5-15 DEG C/h.
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| CN201510478860.0A CN105001215A (en) | 2015-08-03 | 2015-08-03 | Aztreonam compound serving as sterilization medicine and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645942A (en) * | 2020-12-17 | 2021-04-13 | 山东罗欣药业集团恒欣药业有限公司 | Novel crystal form of compound for treating bacterial infection and preparation method thereof |
Citations (8)
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| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
| CN101171251A (en) * | 2005-05-09 | 2008-04-30 | 西科尔公司 | Process for making aztreonam |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102127068A (en) * | 2010-12-31 | 2011-07-20 | 山西普德药业股份有限公司 | Method for synthesizing aztreonam compound |
| CN102532125A (en) * | 2011-12-12 | 2012-07-04 | 哈药集团制药总厂 | Synthesis method for aztreonam compound |
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 四川省惠达药业有限公司 | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof |
| CN103910721A (en) * | 2013-01-06 | 2014-07-09 | 重庆福安药业(集团)股份有限公司 | Aztreonam preparation method |
-
2015
- 2015-08-03 CN CN201510478860.0A patent/CN105001215A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826973A (en) * | 1984-07-20 | 1989-05-02 | E. R. Squibb & Sons, Inc. | Delta form of aztreonam and preparation thereof |
| CN101171251A (en) * | 2005-05-09 | 2008-04-30 | 西科尔公司 | Process for making aztreonam |
| CN101830895A (en) * | 2010-04-16 | 2010-09-15 | 海南新中正制药有限公司 | Aztreonam anhydrous crystal compound and preparation method thereof |
| CN102127068A (en) * | 2010-12-31 | 2011-07-20 | 山西普德药业股份有限公司 | Method for synthesizing aztreonam compound |
| CN102532125A (en) * | 2011-12-12 | 2012-07-04 | 哈药集团制药总厂 | Synthesis method for aztreonam compound |
| CN103044415A (en) * | 2012-12-17 | 2013-04-17 | 浙江华方药业有限责任公司 | Synthesis method for aztreonam |
| CN103910721A (en) * | 2013-01-06 | 2014-07-09 | 重庆福安药业(集团)股份有限公司 | Aztreonam preparation method |
| CN103232449A (en) * | 2013-05-08 | 2013-08-07 | 四川省惠达药业有限公司 | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645942A (en) * | 2020-12-17 | 2021-04-13 | 山东罗欣药业集团恒欣药业有限公司 | Novel crystal form of compound for treating bacterial infection and preparation method thereof |
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