CN105061473A - Sterilization medicine ceftezole sodium compound and preparation method thereof - Google Patents
Sterilization medicine ceftezole sodium compound and preparation method thereof Download PDFInfo
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- CN105061473A CN105061473A CN201510584236.9A CN201510584236A CN105061473A CN 105061473 A CN105061473 A CN 105061473A CN 201510584236 A CN201510584236 A CN 201510584236A CN 105061473 A CN105061473 A CN 105061473A
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- cefobutazine sodium
- sodium compound
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- germ killing
- cefobutazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a sterilization medicine ceftezole sodium compound and a preparation method thereof, and belongs to the technical field of medicine. An X-ray powder diffraction pattern, obtained by measuring by using a Cu-K alpha ray, of the ceftezole sodium compound is shown in the Figure I of the description. Through a research of the hygroscopicity of the ceftezole sodium compound, the inventor surprisingly discovers that the hygroscopicity of the compound provided by the invention is greatly lower than that of an existing crystalline compound, and that the purity is high, the liquidity is good, and the content of a polymer is low, thus, the ceftezole sodium crystalline compound provided by the invention is more stable, and is more suitable for the preparation of preparations, and clinical application is safe and reliable.
Description
Technical field
The invention belongs to medical art, relate to a kind of germ killing drugs Cefobutazine sodium compound and preparation method thereof.
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 anti-microbial activity, some degraded product may produce anaphylaxis, and therefore the stability of this kind of microbiotic in transfusion should cause extensive attention.Meanwhile, because its basic structure is the same with microbiotic 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 is very easily drawn 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 β-lactam antibitics type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in cefobutazine sodium bulk 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 application is safe and reliable.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of cefobutazine sodium crystalline compounds;
Second goal of the invention of the present invention is the preparation method proposing this cefobutazine sodium crystalline compounds.
In order to realize object of the present invention, the technical scheme of employing is:
A kind of germ killing drugs Cefobutazine sodium 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 cefobutazine sodium crystalline compounds, comprise the following steps:
(1) cefobutazine sodium crude product is joined in the mixing solutions of water, acetonitrile, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ethanol, trichloromethane, hexanaphthene is added while stirring;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, under the effect of sound field, cooling, growing the grain 3 hours, washing, vacuum-drying, obtains Cefobutazine sodium compound.
Wherein the volume of the mixing solutions of water, acetonitrile described in step (1) is 5 times of cefobutazine sodium weight, and the volume ratio of water, acetonitrile is 2:1; Intensification described in step (1) refers to and is warming up to 25 DEG C; Sound field frequency described in step (2) is 30KHz, output rating is 45W; The volume of the mixing solutions of ethanol, trichloromethane, hexanaphthene described in step (2) is 10 times of cefobutazine sodium weight, and the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1; Described in step (2), stirring velocity is 85 revs/min, and adding speed is 80 ml/min; Sound field frequency described in step (3) is 25KHz, output rating is 40W; Described in step (3), cooling is for be cooled to-5 DEG C with 10 DEG C/h.
Below technical scheme of the present invention is made further explanation:
Cefobutazine sodium 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 cefobutazine sodium and fungistatic effect are reduced, and superpolymer 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 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 cefobutazine sodium.Therefore, if can reduce the water absorbability of cefobutazine sodium, then the stability for cefobutazine sodium 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 Cefobutazine sodium 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 cefobutazine sodium crystalline compounds of the present invention is more stable, and 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.
Cefobutazine sodium 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 cefobutazine sodium 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 cefobutazine sodium 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 cefobutazine sodium crystalline compounds
(1) joined by cefobutazine sodium crude product in the mixing solutions of water that volume is 5 times of cefobutazine sodium weight, acetonitrile, the volume ratio of water, acetonitrile is 2:1, is warming up to 25 DEG C, is stirred to and dissolves completely;
(2) frequency be 30KHz, under output rating is the sound field of 45W, add the mixing solutions of ethanol that volume is cefobutazine sodium weight 10 times, trichloromethane, hexanaphthene while stirring, the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1, stirring velocity is 85 revs/min, and adding speed is 80 ml/min;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, frequency be 25KHz, under output rating is the sound field of 40W, be cooled to-5 DEG C with 10 DEG C/h, growing the grain 3 hours, washing, vacuum-drying, obtains Cefobutazine sodium compound.
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: accelerated test
Cefobutazine sodium crystalline compounds prepared by Example 1 and commercially available ceftezole sodium raw materials, simulation listing packaging, put 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 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 2:
Table 2 hygroscopicity test results
According to above-mentioned experiment, the water absorbability 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 cefobutazine sodium crystalline compounds prepared by 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 flare opening, until the cone top formed contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) 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 (9)
1. a germ killing drugs Cefobutazine sodium compound, is characterized in that: the X-ray powder diffraction pattern that described Cefobutazine sodium compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. prepare a method for germ killing drugs Cefobutazine sodium compound as claimed in claim 1, it is characterized in that, comprise the following steps:
(1) cefobutazine sodium crude product is joined in the mixing solutions of water, acetonitrile, heat up, be stirred to and dissolve completely;
(2) under the effect of sound field, the mixing solutions of ethanol, trichloromethane, hexanaphthene is added while stirring;
(3) after the mixing solutions of ethanol, trichloromethane, hexanaphthene adds, under the effect of sound field, cooling, growing the grain 3 hours, washing, vacuum-drying, obtains Cefobutazine sodium compound.
3. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: the volume of the mixing solutions of water, acetonitrile described in described step (1) is 5 times of cefobutazine sodium weight, and the volume ratio of water, acetonitrile is 2:1.
4. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: intensification described in described step (1) refers to and is warming up to 25 DEG C.
5. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: sound field frequency described in described step (2) is 30KHz, output rating is 45W.
6. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, it is characterized in that: the volume of the mixing solutions of ethanol, trichloromethane, hexanaphthene described in described step (2) is 10 times of cefobutazine sodium weight, the volume ratio of ethanol, trichloromethane, hexanaphthene is 2:1:1.
7. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: described in described step (2), stirring velocity is 85 revs/min, and adding speed is 80 ml/min.
8. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: sound field frequency described in described step (3) is 25KHz, output rating is 40W.
9. the preparation method of germ killing drugs Cefobutazine sodium compound according to claim 2, is characterized in that: described in described step (3), cooling is for be cooled to-5 DEG C with 10 DEG C/h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510584236.9A CN105061473A (en) | 2015-09-15 | 2015-09-15 | Sterilization medicine ceftezole sodium compound and preparation method thereof |
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| CN201510584236.9A CN105061473A (en) | 2015-09-15 | 2015-09-15 | Sterilization medicine ceftezole sodium compound and preparation method thereof |
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| CN105061473A true CN105061473A (en) | 2015-11-18 |
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| CN201510584236.9A Pending CN105061473A (en) | 2015-09-15 | 2015-09-15 | Sterilization medicine ceftezole sodium compound and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735250A (en) * | 2009-12-02 | 2010-06-16 | 王明 | Ceftezole sodium compound with novel route |
| CN102286001A (en) * | 2011-08-30 | 2011-12-21 | 郑州大学 | Method for preparing ceftezole sodium |
| CN104262361A (en) * | 2014-09-25 | 2015-01-07 | 浙江东盈药业有限公司 | Process for preparing ceftezole sodium |
-
2015
- 2015-09-15 CN CN201510584236.9A patent/CN105061473A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735250A (en) * | 2009-12-02 | 2010-06-16 | 王明 | Ceftezole sodium compound with novel route |
| CN102286001A (en) * | 2011-08-30 | 2011-12-21 | 郑州大学 | Method for preparing ceftezole sodium |
| CN104262361A (en) * | 2014-09-25 | 2015-01-07 | 浙江东盈药业有限公司 | Process for preparing ceftezole sodium |
Non-Patent Citations (1)
| Title |
|---|
| 胡昌勤，等: "头孢替唑钠的结晶性研究", 《药学学报》 * |
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Application publication date: 20151118 |
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