CN104910191A - Cefazedone sodium compound and preparation thereof - Google Patents
Cefazedone sodium compound and preparation thereof Download PDFInfo
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- CN104910191A CN104910191A CN201510351789.XA CN201510351789A CN104910191A CN 104910191 A CN104910191 A CN 104910191A CN 201510351789 A CN201510351789 A CN 201510351789A CN 104910191 A CN104910191 A CN 104910191A
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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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Abstract
The invention relates to the field of medicine and particularly relates to a cefazedone sodium trihydrate and a preparation thereof, wherein the structural formula of the cefazedone sodium trihydrate is shown by formula (I). The invention also relates to a dosage form of the cefazedone sodium trihydrate, wherein the dosage form of the pharmaceutical composition is an injection preparation. A stability test proves that the cefazedone sodium trihydrate provided by the invention has good stability and high bioavailability and is suitable for clinical application.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of cefazedone sodium compound and preparation thereof.
Background technology
Cefazedone sodium, English name: Cefazedone sodium salt, its chemical name is (6R, 7R)-7-(2-(3, the chloro-4-oxo-1 of 5-bis-(4H)-pyridyl) kharophen)-3-(((5-methyl isophthalic acid, 3,4-sulphur diazole-2-base) sulphur) methyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-sodium formiate.Cefazedone sodium is semi-synthetic cephalosporins microbiotic, by the synthesis of anti-bacteria cell walls, thus reach fungistatic effect, anti-microbial effect is had to gram-positive, part gram-negative bacteria and anerobe, can be used for respiratory tract infection, urinary tract infection, biliary tract and abdominal infection, gynecological infection skin and soft tissue infection, septicemia and endocarditis, the treatment of surgery, paediatric infection mitigation and latent infection.Therefore cefazedone sodium is applied comparatively wide clinically, meaning outbalance.
In prior art, for the crystal formation of cefazedone sodium, there is many research:
ZL201010217449.5 provides a kind of cefazedone composition of sodium, said composition comprises the cefazedone sodium crystal and 0.1-0.9% Sodium Benzoate that mass percent is 99.1-99.9%, the cefazedone sodium powder pin that above-mentioned cefazedone composition of sodium is prepared into is deposited at a relatively high temperature, the change of related substance is also smaller, long-time placement is not degraded substantially, is convenient to very much transport, stores.
ZL201210435757.4 relates to a kind of preparation method of cefazedone sodium with low water content, preparation process is as follows: (1) salify: cefazedone and sodium methylate are placed in anhydrous methanol, carry out salt-forming reaction, treat that cefazedone dissolves completely, reaction solution is cooled to 10 ~ 30 DEG C; (2) decolour: gac is added in reaction solution, stir decolouring, then cross filtering gac, and then ultrafiltration; (3) crystallization; (4) dry: filtration, washing leaching cake, dry, obtain cefazedone sodium with low water content.Cefazedone and sodium methylate are placed in anhydrous organic solvent and carry out salt-forming reaction by the present invention, obtain the cefazedone sodium solid of low water content, meanwhile, adopt ultrafiltration and ultrasonic crystallization technique, the obtained cefazedone sodium that moisture content is low, impurity is few, uniform particles, good fluidity, stability are high.
Patent application 201410327560.8 relates to a kind of preparation method of novel anti-infection medicine, preparation process is as follows: (1) salify: cefazedone and sodium acetate solvent are placed in anhydrous methanol, carry out salt-forming reaction, treat that cefazedone dissolves completely, control temperature is at 10-30 DEG C; (2) decolour: gac is added in reaction solution, stir decolouring, then cross filtering gac, keep filtrate temperature to be 10-30 DEG C, and then filter; (3) crystallization: slowly drip a certain amount of ethanol with the speed of 20L/H under agitation in the filtrate after filtration muddy to system, growing the grain 0.5-1 hour, and then add a certain amount of acetone, after growing the grain 0.5-1 hour, solution is cooled to 5 DEG C with the rate of temperature fall of 5-15 DEG C/h, then keeps stirring velocity 80-120 rev/min of stirring and crystallizing, growing the grain 1-3 hour; (4) dry: filtration, washing leaching cake, dry, obtain cefazedone sodium fine work.This preparation method compared with prior art compare simple to operate, cost is low, yield is high, pollute greatly reduce; Gained cefazedone sodium fine work moisture content is low, foreign matter content is low, stability is high.
In order to improve the performance of cefazedone sodium further, improve the effect of preparation clinical practice application, special proposition the present invention.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of cefazedone sodium compound.
A second aspect of the present invention object is to propose the pharmaceutical composition containing this cefazedone sodium compound.
In order to realize object of the present invention, the technical scheme of employing is:
A kind of cefazedone sodium compound, this cefazedone sodium compound is cefazedone sodium trihydrate, and its structural formula is such as formula shown in (I):
Wherein, cefazedone sodium trihydrate use the measurement of Cu-K alpha-ray to obtain X-ray powder diffraction pattern as shown in Figure 1;
The preparation method of cefazedone sodium compound of the present invention is:
(1) cefazedone sodium crude product is ground, cross 200 ~ 300 mesh sieves, join in the methanol solution of 50 ~ 60%;
(2) add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 2:1 ~ 3, be then warming up to 40 ~ 45 DEG C;
(3) after mixed solvent adds, be cooled to-5 DEG C ~ 5 DEG C, after obtaining crystal, leave standstill crystallization; Filter, washing, vacuum-drying 4 ~ 8 hours, obtains cefazedone sodium trihydrate.
Wherein: in step (1), the weight ratio of cefazedone sodium crude product and methanol solution is 1:20 ~ 25;
In step (2), stirring velocity is 360 ~ 720 revs/min; The weight of mixed solvent is 3 ~ 6 times of cefazedone sodium methanol solution weight, and adding speed is 30 ~ 50 ml/min;
In step (3), cooling rate is 1 ~ 2 DEG C/h.
The invention still further relates to a kind of pharmaceutical composition containing cefazedone sodium compound of the present invention, the formulation of this pharmaceutical composition is selected from injection formulations, and injection formulations is selected from aseptic powder injection, freeze-dried powder and liquid drugs injection, and preferred aseptic powder injection.
Below technical scheme of the present invention is made further explanation.
The present invention proposes a kind of trihydrate of cefazedone sodium, proterties is white crystalline powder, and this hydrate, under Air drying condition, the loss of crystal water can not occur.Cefazedone sodium of the present invention confirms containing 3 crystal water, and studies as follows it:
1. ultimate analysis
Get the cefazedone sodium trihydrate that the present invention prepares and carry out ultimate analysis, adopt U.S. Perkin-Elmer company PE 2,400 II elemental analyser, ultimate analysis (%) measured value: C (34.210), H (3.200), Cl (11.355), N (11.220), Na (3.680), O (20.500), S (15.400); Conform to the theoretical value of ultimate analysis, ultimate analysis (%) theoretical value is: C (34.207), H (3.198), Cl (11.354), N (11.218), Na (3.683), O (20.500), S (15.403).
2. differential thermal analysis and thermogravimetric analysis
Get the cefazedone sodium trihydrate that the present invention prepares and carry out differential thermal analysis, structure shows, the present invention has endotherm(ic)peak between 110 DEG C ~ 140 DEG C, proves in sample containing crystal water.Its thermogravimetric analysis figure shows the crystal water that its about 120 DEG C lose three molecules fast, and without obvious changes in weight before 110 DEG C, confirms that its water molecules lost is crystalline water molecules, but not dissociating water molecule.
3. weight loss on drying and water analysis
Get the cefazedone sodium trihydrate that the present invention prepares and be dried to constant weight at 180 DEG C, weightlessness is 8.65%; The weightlessness adopting cassette moisture content tester to measure cefazedone sodium trihydrate of the present invention is 8.65%, conforms to theoretical value 8.648%.
4.HPLC purity detecting
Through HPLC purity detecting, the purity of the cefazedone sodium trihydrate that the present invention prepares is 99.85 ~ 99.90%, solvent trace (<0.001%).
5. droplet measurement
Measure through sem observation and particle size analyzer, the main particle diameter of the cefazedone sodium trihydrate that the present invention prepares is 550 ~ 750 μm, and Tile Width is 350 ~ 950 μm.
6. crystal formation detects
Get X-ray powder diffraction pattern that cefazedone sodium trihydrate that the present invention prepares uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1, its X-ray powder diffraction pattern represented with 2 θ ± 0.2 diffraction angle shows characteristic peak at 4.2 °, 14.0 °, 15.0 °, 24.3 °, 25.5 °, 26.9 °, 31.2 °, 31.5 ° places.After water dissolution, the change of crystal formation can not be there is in this crystal formation.
7. bioavailability
Get the cefazedone sodium trihydrate that the present invention prepares and carry out pharmacokinetic study, cefazedone sodium trihydrate of the present invention is through single dose 1.0g (in anhydride) quiet note, after 5 minutes, drug plasma peak concentration is 168.7 μ g/ml, being 82.4 μ g/ml after 30 minutes, is 1.7 μ g/ml after 8 hours; Higher than of the prior art: after 5 minutes, drug plasma peak concentration is 144.4 μ g/ml, being 78.4 μ g/ml after 30 minutes, is 1.6 μ g/ml after 8 hours; Cefazedone sodium trihydrate of the present invention is through quiet of single dose 2.0g (in anhydride) more than 30 minutes, and it is 198.9 μ g/ml that instillation terminates rear maximum plasma concentration, is 5.5 μ g/ml after 8 hours; Higher than of the prior art: it is 184 μ g/ml that instillation terminates rear maximum plasma concentration; Be 5.4 μ g/ml after 8 hours.
8. water absorbability
Get the cefazedone sodium trihydrate that the present invention prepares and carry out wettability test, confirm cefazedone sodium trihydrate of the present invention not easily moisture absorption, place weight in wet condition without considerable change.
The present invention prepares the hydrate crystal of cefazedone sodium trihydrate greater particle size, and Lens capsule is very concentrated, size uniformity, thus advantageously in the collection of crystal, thus be applicable to large-scale industrialization preparation, improve yield.The purity of cefazedone sodium trihydrate of the present invention is greatly improved.Confirm through stability test, having good stability of the cefazedone sodium trihydrate that the present invention prepares, is suitable for clinical application.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction pattern of cefazedone sodium trihydrate prepared by embodiment 1;
Fig. 2 is the thermogravimetric analysis figure of the cefazedone sodium trihydrate that embodiment 1 prepares.
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
The preparation of embodiment 1 cefazedone sodium trihydrate
1. ground by cefazedone sodium crude product, cross 200 mesh sieves, join in the methanol solution of 50%, the weight ratio of cefazedone sodium crude product and methanol solution is 1:20;
2. add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 2:1, be then warming up to 45 DEG C; Stirring velocity is 720 revs/min; The weight of mixed solvent is 6 times of cefazedone sodium methanol solution weight, and adding speed is 50 ml/min;
3. after mixed solvent adds, be cooled to 1 DEG C, cooling rate is 1 DEG C/h, leaves standstill crystallization after obtaining crystal; Filter, washing, vacuum-drying 8 hours, obtains cefazedone sodium trihydrate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.87%, yield 92.3%; The X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1, thermogravimetric analysis figure as shown in Figure 2, ultimate analysis (%) measured value is: C (34.210), H (3.200), Cl (11.355), N (11.220), Na (3.680), O (20.500), S (15.400).
The preparation of embodiment 2 cefazedone sodium trihydrate
1. ground by cefazedone sodium crude product, cross 300 mesh sieves, join in the methanol solution of 60%, the weight ratio of cefazedone sodium crude product and methanol solution is 1:20;
2. add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 2:3, be then warming up to 42 DEG C; Stirring velocity is 720 revs/min; The weight of mixed solvent is 3 ~ 6 times of cefazedone sodium methanol solution weight, and adding speed is 30 ml/min;
3. after mixed solvent adds, be cooled to 5 DEG C, cooling rate is 2 DEG C/h, leaves standstill crystallization after obtaining crystal; Filter, washing, vacuum-drying 4 ~ 8 hours, obtains cefazedone sodium trihydrate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.78%, yield 92.4%; The X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1, thermogravimetric analysis figure as shown in Figure 2, ultimate analysis (%) measured value is: C (34.210), H (3.200), Cl (11.355), N (11.220), Na (3.680), O (20.500), S (15.400).
The preparation of embodiment 3 cefazedone sodium trihydrate
1. ground by cefazedone sodium crude product, cross 250 mesh sieves, join in the methanol solution of 55%, the weight ratio of cefazedone sodium crude product and methanol solution is 1:25;
2. add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 2:3, be then warming up to 44 DEG C; Stirring velocity is 480 revs/min; The weight of mixed solvent is 5 times of cefazedone sodium methanol solution weight, and adding speed is 40 ml/min;
3. after mixed solvent adds, be cooled to 0 DEG C, cooling rate is 1.5 DEG C/h, leaves standstill crystallization after obtaining crystal; Filter, washing, vacuum-drying 8 hours, obtains cefazedone sodium trihydrate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.77%, yield 92.3%; The X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1, thermogravimetric analysis figure as shown in Figure 2, ultimate analysis (%) measured value is: C (34.210), H (3.200), Cl (11.355), N (11.220), Na (3.680), O (20.500), S (15.400).
The preparation of embodiment 4 cefazedone sodium trihydrate
1. ground by cefazedone sodium crude product, cross 300 mesh sieves, join in the methanol solution of 60%, the weight ratio of cefazedone sodium crude product and methanol solution is 1:22;
2. add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 1:1, be then warming up to 42 DEG C; Stirring velocity is 720 revs/min; The weight of mixed solvent is 3 ~ 6 times of cefazedone sodium methanol solution weight, and adding speed is 42 ml/min;
3. after mixed solvent adds, be cooled to 2 DEG C, cooling rate is 1 DEG C/h, leaves standstill crystallization after obtaining crystal; Filter, washing, vacuum-drying 8 hours, obtains cefazedone sodium trihydrate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.80%, yield 92.2%; The X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1, thermogravimetric analysis figure as shown in Figure 2, ultimate analysis (%) measured value is: C (34.210), H (3.200), Cl (11.355), N (11.220), Na (3.680), O (20.500), S (15.400).
The preparation of embodiment 5 aseptic powder injection
Cefazedone sodium trihydrate embodiment 1 obtained, aseptically, direct packaging obtains sterile powder injection, and specification is with C
18h
14cl
2n
5naO
5s
3calculate 1000mg.
The preparation of embodiment 6 aseptic powder injection
Cefazedone sodium trihydrate embodiment 1 obtained mixes with sodium-chlor, and aseptically, direct packaging obtains sterile powder injection, and specification is with C
18h
14cl
2n
5naO
5s
3calculate 1000mg, sodium-chlor 80mg.
The preparation of embodiment 7 freeze-dried powder
1. the cefazedone sodium trihydrate for preparing of Example 1 is (with C
18h
14cl
2n
5naO
5s
3meter) 1000g, uses water for injection stirring and dissolving, adds N.F,USP MANNITOL 600g, complement to 20L with water for injection;
2. adjust ph is 6.5 ~ 7.5; Add the medicinal carbon that mass percent is 0.01%, adsorb 20 ~ 30 minutes, filtering decarbonization; Essence filter, adds sterilized water for injection to full dose, essence filter;
3. lyophilize: filtrate lyophilize step 2 obtained, is aseptically distributed into 1000, gland, aluminium seal, and to obtain final product.
Lyophilize is divided into pre-freeze, distillation and drying;
Pre-freeze: shelf temperature is down to-55 DEG C with the speed of 2.0 DEG C/min;
Distillation: be evacuated to 15Pa, rise to-25 DEG C with the speed of 5.0 DEG C/min, be incubated 3 hours; Rise to 15 DEG C with the speed of 1.2 DEG C/min again to keep 3 hours;
Dry: to rise to 40 DEG C with the speed of 1.8 DEG C/min, dry 2 hours.
Experimental example 1: mobility is tested
The mobility of this experimental example to the cefazedone sodium trihydrate of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, cefazedone sodium trihydrate 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 cefazedone sodium trihydrate accumulation horizon.Experimental result is as shown in table 1.
Table 1: mobility experimental result
| Batch | 1 | 2 | 3 | 4 | 5 | Mean value |
| θ(°) | 36 | 37 | 36 | 38 | 35 | 36.4 |
From the interpretation of table 1, the mobility of the cefazedone sodium trihydrate that the embodiment of the present invention 1 prepares is fine, also detects, obtain similar experimental result to the cefazedone sodium trihydrate of other embodiments of the invention.
Experimental example 2: the influence factor experiment of cefazedone sodium trihydrate
1. high temperature test
3 batches 101,102,103 of the cefazedone sodium trihydrate that Example 1 prepares, simulation listing packaging, put in sealing clean container, place 10 days at 40 ± 2 DEG C of temperature, 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
3 batches 101,102,103 of the cefazedone sodium trihydrate that Example 1 prepares, simulation listing packaging, put 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
3 batches 101,102,103 of the cefazedone sodium triplex that Example 1 prepares, simulation listing packaging, put 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.
Influence factor test-results is as shown in table 2.
Table 2:
Result shows: the cefazedone sodium trihydrate 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 the cefazedone sodium trihydrate that other embodiments of the invention prepare, obtains identical experimental result.
Experimental example 3: the Acceleration study of cefazedone sodium trihydrate
3 batches 201,202,203 of the cefazedone sodium trihydrate that Example 1 prepares, simulation listing packaging, put in sealing clean container, in 25 DEG C, place 6 months under 60%RH 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.Test-results is as shown in table 3.
Table 3:
Result shows: the cefazedone sodium trihydrate that the present invention prepares, and known through accelerated test result, its stability is good.Acceleration study is carried out to cefazedone sodium trihydrate prepared by other embodiment of the present invention, obtains identical experimental result.
Experimental example 4: the test of long duration of cefazedone sodium hydrate
3 batches 301,302,303 of the cefazedone sodium trihydrate of Example 1 gained, simulation listing packaging, put in sealing clean container, place 18 months under temperature 6 DEG C ± 2 DEG C conditions, at duration of test respectively at the 3rd, 6,9,12,18 sampling at the end of month once, each Interventions Requested are tested.Test-results is as shown in table 4:
Table 4:
Result shows: the cefazedone sodium hydrate that the present invention prepares, known through long-term test results, and its stability is good, and equal retention is stablized.Long-term experiment is carried out to cefazedone sodium hydrate prepared by other embodiment of the present invention, obtains identical experimental result.
Experimental example 5. water absorbability is tested
Get the cefazedone sodium trihydrate that the embodiment of the present invention 1 prepares, under 40 DEG C of temperature condition, free-water moisture (noncrystalline water) content under different relative humidity, measurement result is as shown in table 5.
Table 5
Find from experimental result, the not easily moisture absorption of the cefazedone sodium hydrate that the embodiment of the present invention 1 prepares, thus be more easy to preserve, increase the stability of medicine.The cefazedone sodium hydrate of other embodiments of the invention is also detected, obtains similar experimental result.
Experimental example 6: stability simultaneous test
The cefazedone sodium of Example 1 and following comparative example, simulation listing packaging, puts in sealing clean container, in 25 DEG C, place 6 months under 60%RH 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.Test-results is as shown in table 6.
Comparative example 1: commercially available cefazedone sodium raw materials;
The cefazedone sodium that in comparative example 2:ZL201210435757.4, embodiment 1 prepares;
The cefazedone sodium that in comparative example 3:ZL201010217449.5, embodiment 1 prepares;
Table 6:
Experimental example 7: water absorbability simultaneous test
Get the comparative example in the cefazedone sodium trihydrate of the embodiment of the present invention 1 and experimental example 6, under 40 DEG C of temperature condition, free-water moisture (noncrystalline water) content under different relative humidity, measurement result is as shown in table 7.
Table 7:
Claims (8)
1. a cefazedone sodium compound, is characterized in that, described cefazedone sodium is cefazedone sodium trihydrate, and its structural formula is such as formula shown in (I):
2. cefazedone sodium compound according to claim 1, is characterized in that, the X-ray powder diffraction pattern that described cefazedone sodium trihydrate uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
3. cefazedone sodium compound according to claim 1, is characterized in that, the preparation method of described cefazedone sodium trihydrate is:
(1) cefazedone sodium crude product is ground, cross 200 ~ 300 mesh sieves, join in the methanol solution of 50 ~ 60%;
(2) add dimethyl formamide while stirring and acetonitrile volume ratio is the mixed solvent of 2:1 ~ 3, be then warming up to 40 ~ 45 DEG C;
(3) after mixed solvent adds, be cooled to-5 DEG C ~ 5 DEG C, after obtaining crystal, leave standstill crystallization; Filter, washing, vacuum-drying 4 ~ 8 hours, obtains cefazedone sodium trihydrate.
4. cefazedone sodium compound according to claim 3, is characterized in that, in step (1), the weight ratio of cefazedone sodium crude product and methanol solution is 1:20 ~ 25.
5. cefazedone sodium compound according to claim 3, is characterized in that, in step (2), stirring velocity is 360 ~ 720 revs/min; The weight of mixed solvent is 3 ~ 6 times of cefazedone sodium methanol solution weight, and adding speed is 30 ~ 50 ml/min.
6. cefazedone sodium compound according to claim 3, is characterized in that, in step (3), cooling rate is 1 ~ 2 DEG C/h.
7. the pharmaceutical composition containing cefazedone sodium compound according to claim 1, it is characterized in that, the formulation of described pharmaceutical composition is injection formulations.
8. pharmaceutical composition according to claim 7, is characterized in that, the formulation of described injection formulations is selected from aseptic powder injection, freeze-dried powder and liquid drugs injection.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101856356A (en) * | 2010-07-05 | 2010-10-13 | 山东罗欣药业股份有限公司 | Cefazedone sodium composition powder injection |
| CN104086571A (en) * | 2014-07-10 | 2014-10-08 | 山东恒欣药业有限公司 | Preparation method of novel anti-infective drug |
| CN104119361A (en) * | 2014-07-10 | 2014-10-29 | 山东罗欣药业集团股份有限公司 | A purifying method of a novel antibiotic compound |
-
2015
- 2015-06-24 CN CN201510351789.XA patent/CN104910191B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101856356A (en) * | 2010-07-05 | 2010-10-13 | 山东罗欣药业股份有限公司 | Cefazedone sodium composition powder injection |
| CN104086571A (en) * | 2014-07-10 | 2014-10-08 | 山东恒欣药业有限公司 | Preparation method of novel anti-infective drug |
| CN104119361A (en) * | 2014-07-10 | 2014-10-29 | 山东罗欣药业集团股份有限公司 | A purifying method of a novel antibiotic compound |
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