CN105168223A - Anti-bacterial medicine-ceftezole sodium composition - Google Patents
Anti-bacterial medicine-ceftezole sodium composition Download PDFInfo
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- CN105168223A CN105168223A CN201510599448.4A CN201510599448A CN105168223A CN 105168223 A CN105168223 A CN 105168223A CN 201510599448 A CN201510599448 A CN 201510599448A CN 105168223 A CN105168223 A CN 105168223A
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Abstract
The invention discloses an anti-bacterial medicine-ceftezole sodium composition, and belongs to the technical field of medicines. The components of the composition comprise ceftezole sodium and arginine; the ceftezole sodium is in the state of crystals, and the X-ray powder diffraction pattern measured with Cu-K alpah rays is as shown in figure 1. According to the anti-bacterial medicine ceftezole sodium composition, the new crystal form of the ceftezole sodium is different from the crystal structure in the prior art; tests verify that the new crystal form compound is high in purity, good in fluidity and stability, low in polymer content, not prone to being wetted and safe and reliable in clinical application; a powder injection prepared by the new crystal form compound is good in stability, good in stability after achieving compatibility with solvent, extremely low in insoluble particle content and very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of antibacterials ceftezole composition of sodium.
Background technology
Cefobutazine sodium is first generation cephalosporin for injections, is developed by Japanese Teng Ze company, and first in state's listings such as Japan, Korea S, Italy.Containing unstable beta-lactam nucleus in the structure of cefobutazine sodium, easy generation hydrolysis and rearrangement reaction, cause structural damage and lose antibacterial activity, some catabolite may produce anaphylaxis, and therefore the stability of this kind of antibiotic in transfusion should cause extensive attention.Meanwhile, because its basic structure is the same with antibiotic in the many semisynthetic beta-lactam gone on the market, also can forms high molecular polymer, also can cause type Ⅰ hypersensitivity reaction in Clinical practice, very harmful to patient.Meanwhile, cefobutazine sodium very easily draws wet, has very adverse influence to its stability.Prior art improves its stability from aspects such as raising content, reduction impurity mostly.
Research proves, the anaphylactogen causing beta-lactam antibiotic type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in cefobutazine sodium crude drug, improve stability, make it can ensure the lower effective way being the reaction of reduction anaphylactic shock and occurring of the content of its high molecular polymer existed in long term storage.Therefore, be necessary to provide the Cefobutazine sodium compound that a kind of high molecular polymer content is low, performance is more superior.
The present invention, through large quantifier elimination, obtains a kind of crystal compound being different from prior art, and the purity of cefobutazine sodium crystalline compounds provided by the invention is high, good fluidity, not easily moisture absorption, good stability, and polymer content is low, and clinical practice is safe and reliable.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of antibacterials ceftezole composition of sodium.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of antibacterials ceftezole composition of sodium, consisting of of described compositions: cefobutazine sodium 1 weight portion, arginine 0.001-0.003 weight portion; Described cefobutazine sodium 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: cefobutazine sodium 1 weight portion, arginine 0.002 weight portion.
Preferably, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take ceftezole sodium crystal and arginine 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 ceftezole sodium crystal in described compositions comprises the following steps:
Prepare the saturated methanol solution of cefobutazine sodium crude product of 30 DEG C, then the isobutanol of 5 times and the mixed solvent of petroleum ether that volume is saturated methanol solution volume is added, described isobutanol, the volume ratio of petroleum ether are 2:1.5, after stirring, cooling limit, limit is stirred, cooling rate is 5 DEG C/h, mixing speed is 130 revs/min, add the ether that volume is mixed solvent volume 4 times simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain cefobutazine sodium 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.
Cefobutazine sodium 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 cefobutazine sodium and fungistatic effect are reduced, and high polymer can cause endogenous anaphylaxis.The good stability of the Cefobutazine sodium compound that the present invention prepares, not easily open loop is decomposed, its polymer content trace.
Cefobutazine sodium 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 cefobutazine sodium.Therefore, if can reduce the hygroscopicity of cefobutazine sodium, then the stability for cefobutazine sodium 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.
The present invention prepare Cefobutazine sodium compound, use X-ray powder diffraction pattern that the measurement of 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 cefobutazine sodium crystalline compounds of the present invention is more stable, more adapt to the preparation of preparation.
The purity of cefobutazine sodium crystalline compounds of the present invention can reach 99.9%, and its structure is confirmed through proton nmr spectra.The preparation method of cefobutazine sodium crystalline compounds of the present invention is simple, and purity is high, and yield is high, most suitable large-scale industrial production.
The composition powder injection obtained by cefobutazine sodium crystalline compounds of the present invention, 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 ceftezole sodium 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 ceftezole sodium crystal
Prepare the saturated methanol solution of cefobutazine sodium crude product of 30 DEG C, then the isobutanol of 5 times and the mixed solvent of petroleum ether that volume is saturated methanol solution volume is added, described isobutanol, the volume ratio of petroleum ether are 2:1.5, after stirring, cooling limit, limit is stirred, cooling rate is 5 DEG C/h, mixing speed is 130 revs/min, add the ether that volume is mixed solvent volume 4 times simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain cefobutazine sodium 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 ceftezole sodium crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of ceftezole composition of sodium
Consist of: ceftezole sodium crystal 1 weight portion prepared by the present invention, arginine 0.001 weight portion.
Preparation method is:
(1) take ceftezole sodium crystal and arginine 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 ceftezole composition of sodium
Consist of: ceftezole sodium crystal 1 weight portion prepared by the present invention, arginine 0.002 weight portion.
Preparation method is:
(1) take ceftezole sodium crystal and arginine 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 ceftezole composition of sodium
Consist of: ceftezole sodium crystal 1 weight portion prepared by the present invention, arginine 0.003 weight portion.
Preparation method is:
(1) take ceftezole sodium crystal and arginine in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
experimental example 1:accelerated test
Example 1 and commercially available ceftezole sodium raw materials, simulation listing packaging, puts in sealing clean container, in 25 DEG C ± 2 DEG C, place 6 months under the condition of humidity 60% ± 5%, 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 shown in 1.
Table 1 Acceleration study result
experimental example 2: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 2:
Table 2 hygroscopicity test results
According to above-mentioned experiment, the hygroscopicity of cefobutazine sodium crystalline compounds prepared by the present invention is low, good stability.
experimental example 3:mobility is tested
The mobility of this experimental example to the cefobutazine sodium crystalline compounds of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, cefobutazine sodium crystalline compounds is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of cefobutazine sodium crystalline compounds accumulation horizon.Experimental result is as shown in table 3.
Table 3 mobility experimental result
From the interpretation of table 3, the mobility of the cefobutazine sodium crystalline compounds that the embodiment of the present invention 1 prepares is fine.
Claims (4)
1. an antibacterials ceftezole composition of sodium, is characterized in that: described compositions consist of cefobutazine sodium 1 weight portion, arginine 0.001-0.003 weight portion; Described cefobutazine sodium 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. antibacterials ceftezole composition of sodium according to claim 1, is characterized in that: described compositions consist of cefobutazine sodium 1 weight portion, arginine 0.002 weight portion.
3. antibacterials ceftezole composition of sodium according to claim 1 and 2, 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 ceftezole sodium crystal and arginine in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
4. antibacterials ceftezole composition of sodium according to claim 1, is characterized in that, the preparation method of the crystal of described cefobutazine sodium is:
Prepare the saturated methanol solution of cefobutazine sodium crude product of 30 DEG C, then the isobutanol of 5 times and the mixed solvent of petroleum ether that volume is saturated methanol solution volume is added, described isobutanol, the volume ratio of petroleum ether are 2:1.5, after stirring, cooling limit, limit is stirred, cooling rate is 5 DEG C/h, mixing speed is 130 revs/min, add the ether that volume is mixed solvent volume 4 times simultaneously, stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain cefobutazine sodium crystalline compounds.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510599448.4A CN105168223A (en) | 2015-09-21 | 2015-09-21 | Anti-bacterial medicine-ceftezole sodium composition |
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| CN201510599448.4A CN105168223A (en) | 2015-09-21 | 2015-09-21 | Anti-bacterial medicine-ceftezole sodium composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160922A (en) * | 2017-07-20 | 2019-01-08 | 海南灵康制药有限公司 | A kind of 1/2 water Cefobutazine sodium compound |
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2015
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160922A (en) * | 2017-07-20 | 2019-01-08 | 海南灵康制药有限公司 | A kind of 1/2 water Cefobutazine sodium compound |
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