CN105055407A - Medicine aztreonam composition for curing infectious diseases - Google Patents
Medicine aztreonam composition for curing infectious diseases Download PDFInfo
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- CN105055407A CN105055407A CN201510584488.1A CN201510584488A CN105055407A CN 105055407 A CN105055407 A CN 105055407A CN 201510584488 A CN201510584488 A CN 201510584488A CN 105055407 A CN105055407 A CN 105055407A
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Abstract
The invention discloses a medicine aztreonam composition for curing infectious diseases, belonging to the technical field of medicines. The composition is prepared from aztreonam and anhydrous sodium carbonate; the aztreonam is a crystal, and an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement is shown as picture 1. The new crystal form of the aztreonam provided by the invention is different from crystal form structures in the prior art, by means of experimental verification, the new crystal form compound is surprisedly found to be high in purity, good in mobility and stability, low in polymer content, free of hygroscopicity and safe and reliable in clinic application, and a powder-injection prepared by using the new crystal form compound is good in stability, good in stability after being matched with a solvent, extremely low in insoluble particle content and very suitable for clinic application.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine aztreonam composition for the treatment of infectious disease.
Background technology
Aztreonam is a kind of white or micro-yellow polymorphic powder, and the crystal 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 crude drug as pharmaceutical formulation.
In order to improve the performance of aztreonam further, this invention of special proposition, the novel crystal forms of aztreonam provided by the present invention is different from the crystalline structure of prior art, by verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, polymer content is low, moist without drawing, clinical practice is safe and reliable, utilize the injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine aztreonam composition for the treatment of infectious disease.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine aztreonam composition for infectious disease, consisting of of described compositions: aztreonam 1 weight portion, natrium carbonicum calcinatum 0.1-0.3 weight portion; Described aztreonam is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
Preferably, consisting of of described compositions: aztreonam 1 weight portion, natrium carbonicum calcinatum 0.15-0.25 weight portion.
Preferably, consisting of of described compositions: aztreonam 1 weight portion, natrium carbonicum calcinatum 0.2 weight portion.
Preferably, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
The preparation method of the aztreonam crystal in described compositions comprises the following steps:
1) dimethyl formamide and water are mixed with mixed solution A with the volume ratio of 4:1;
2) aztreonam crude drug is got, add the mixed solution A that step 1) is prepared, the volume of wherein said mixed solution A is 10ml:1g with the ratio of the quality of aztreonam, stirs and makes all to dissolve in backward gained solution to add 0.1%g/ml activated carbon decolorizing, filtration, obtain settled solution;
3) diisopropyl ether and isopropyl alcohol are mixed with mixed solution B with the volume ratio of 1:3.5;
4) under room temperature, be to step 2 at power under the ultrasonic field of 0.6KW) add mixed solution B in the settled solution of gained, wherein the addition of mixed solution B is 6 times of the volume of mixed solution A, finish closedown ultrasonic field, be cooled to 0 DEG C, leave standstill 3 hours, crystallize out, drying obtains described aztreonam crystalline compounds.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Aztreonam is Beta-lactam medicine, the easy open loop of its monoamides 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 high polymer 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 physicochemical properties such as the decline of caking, mobility, deliquescence, crystal formation change, thus affect the interior qualities such as product stability, effectiveness, safety after moisture absorption.And according to the literature, many antibiotic are stablized in the dry state, but will decompose after making moist.Therefore, hygroscopicity has very important impact for the stability of aztreonam.Therefore, if can reduce the hygroscopicity of aztreonam, then the stability for aztreonam has very important meaning.Meanwhile, bibulous medicine needs strictly to control the relative humidity between subpackage in formulation manufacturing processes, is no more than critical relative humidity, thus ensures product quality 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 inventor is pleasantly surprised, its hygroscopicity 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 99.8%, 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.
The injectable powder that aztreonam crystalline compounds of the present invention is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the aztreonam crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of aztreonam crystal
1) dimethyl formamide and water are mixed with mixed solution A with the volume ratio of 4:1;
2) aztreonam crude drug is got, add the mixed solution A that step 1) is prepared, the volume of wherein said mixed solution A is 10ml:1g with the ratio of the quality of aztreonam, stirs and makes all to dissolve in backward gained solution to add 0.1%g/ml activated carbon decolorizing, filtration, obtain settled solution;
3) diisopropyl ether and isopropyl alcohol are mixed with mixed solution B with the volume ratio of 1:3.5;
4) under room temperature, be to step 2 at power under the ultrasonic field of 0.6KW) add mixed solution B in the settled solution of gained, wherein the addition of mixed solution B is 6 times of the volume of mixed solution A, finish closedown ultrasonic field, be cooled to 0 DEG C, leave standstill 3 hours, crystallize out, drying obtains described 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 aztreonam crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of aztreonam composition
Consist of: aztreonam crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.1 weight portion.
Preparation method is:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 3:the preparation of aztreonam composition
Consist of: aztreonam crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.15 weight portion.
Preparation method is:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 4:the preparation of aztreonam composition
Consist of: aztreonam crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.2 weight portion.
Preparation method is:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 5:the preparation of aztreonam composition
Consist of: aztreonam crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.25 weight portion.
Preparation method is:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 6:the preparation of aztreonam composition
Consist of: aztreonam crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.3 weight portion.
Preparation method is:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
experimental example 1influence factor tests
1, hot 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, result of the test compared with 0 day.
2, high humility 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 humiditys 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test 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 result of the test
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's 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 constant temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that saline solution is saturated, excessive salt should be had bottom exsiccator to exist) that bottom fills salt supersaturated solution, the built-in weighing botle of exsiccator, places 48h to constant humidity in calorstat.Sample thief is about 2g, puts in weighing botle, accurately weighed, bottle cap is opened, puts into exsiccator top, put in 25 DEG C of constant temperature and humidity incubators or 20 DEG C of stability test casees by different temperatures requirement and preserve, operation repetitive 3 parts, weighs respectively at different time, calculates the hydroscopicity of different time.
Computing formula: hydroscopicity=(medicated 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 hygroscopicity of aztreonam crystalline compounds prepared by the present invention is low, good stability.
Claims (5)
1. treat a medicine aztreonam composition for infectious disease, it is characterized in that: described compositions consist of aztreonam 1 weight portion, natrium carbonicum calcinatum 0.1-0.3 weight portion; Described aztreonam is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine aztreonam composition for the treatment of infectious disease according to claim 1, is characterized in that: described compositions consist of aztreonam 1 weight portion, natrium carbonicum calcinatum 0.15-0.25 weight portion.
3. the medicine aztreonam composition for the treatment of infectious disease according to claim 2, is characterized in that: described compositions consist of aztreonam 1 weight portion, natrium carbonicum calcinatum 0.2 weight portion.
4., according to the medicine aztreonam composition of the arbitrary described treatment infectious disease of claim 1-3, it is characterized in that, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take aztreonam crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
5. the medicine aztreonam composition for the treatment of infectious disease according to claim 1, is characterized in that, the crystal preparation method of described aztreonam is:
1) dimethyl formamide and water are mixed with mixed solution A with the volume ratio of 4:1;
2) aztreonam crude drug is got, add the mixed solution A that step 1) is prepared, the volume of wherein said mixed solution A is 10ml:1g with the ratio of the quality of aztreonam, stirs and makes all to dissolve in backward gained solution to add 0.1%g/ml activated carbon decolorizing, filtration, obtain settled solution;
3) diisopropyl ether and isopropyl alcohol are mixed with mixed solution B with the volume ratio of 1:3.5;
4) under room temperature, be to step 2 at power under the ultrasonic field of 0.6KW) add mixed solution B in the settled solution of gained, wherein the addition of mixed solution B is 6 times of the volume of mixed solution A, finish closedown ultrasonic field, be cooled to 0 DEG C, leave standstill 3 hours, crystallize out, drying obtains described aztreonam crystalline compounds.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195618A (en) * | 2006-12-05 | 2008-06-11 | 北京广博先锋生物技术有限公司 | Method for producing beta crystal system anhydrous aztreonam |
| CN101579336A (en) * | 2009-07-07 | 2009-11-18 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
| CN102311431A (en) * | 2011-08-30 | 2012-01-11 | 海南海药股份有限公司 | Method for preparing anhydrous beta-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 |
| CN103655460A (en) * | 2012-09-18 | 2014-03-26 | 海口市制药厂有限公司 | Injection medicinal composition containing aztreonam, as well as preparation method and application thereof |
-
2015
- 2015-09-15 CN CN201510584488.1A patent/CN105055407A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101195618A (en) * | 2006-12-05 | 2008-06-11 | 北京广博先锋生物技术有限公司 | Method for producing beta crystal system anhydrous aztreonam |
| CN101579336A (en) * | 2009-07-07 | 2009-11-18 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN102086196A (en) * | 2011-01-28 | 2011-06-08 | 海南灵康制药有限公司 | Novel method for refining aztreonam |
| CN102311431A (en) * | 2011-08-30 | 2012-01-11 | 海南海药股份有限公司 | Method for preparing anhydrous beta-aztreonam |
| CN103655460A (en) * | 2012-09-18 | 2014-03-26 | 海口市制药厂有限公司 | Injection medicinal composition containing aztreonam, as well as preparation method and application thereof |
| 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 |
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Application publication date: 20151118 |