CN101843589B - Ceftizoxime sodium composition sterile powder for injection - Google Patents
Ceftizoxime sodium composition sterile powder for injection Download PDFInfo
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Abstract
The invention relates to ceftizoxime sodium composition sterile powder for injection. The powder contains 99.0 to 99.9 weight percent of ceftizoxime sodium and 0.10 to 1.00 weight percent of sodium benzoate, wherein the ceftizoxime sodium is in a crystallized form. As for the ceftizoxime sodium in the crystallized form, the temperature of solution of ceftizoxime sodium is controlled by adjusting the pH value of the solution and the saturation process of the solution is controlled by a method of adding appropriate amounts of different solvents into the solution in multiple times so as to obtain a ceftizoxime sodium crystal form with uniform grain size distribution. A method for preparing the powder has simple, convenient and easily-controlled production process and low preparation cost and the obtained ceftizoxime sodium in the crystallized form has uniform grain size distribution and is more stable than the ceftizoxime sodium in the market.
Description
Technical field
The invention belongs to the synthetic and formulation art of medicine, more particularly, what the present invention relates to is a kind of ceftizoxime sodium composition sterile powder for injection.
Background technology
Ceftizoxime sodium (ceftizoxime sodium) is to rise the exploitation of damp pharmaceutical industries company by Japan, and in nineteen eighty-two at first in Japan's listing, commodity are called ceftizox.This product belongs to the third generation cephalosporin antibiotic, and the tool broad-spectrum antibacterial action is stable to the wide spectrum lactamase (comprising penicillinase and cephalosporinase) of multiple gram positive bacteria and the generation of Glan negative bacterium.Rhodopseudomonass such as this product has powerful antibacterial action to enterobacteriaceae lactobacteriaceaes such as escherichia coli, Klebsiella Pneumoniae, proteus mirabilises, Pseudomonas aeruginosa and acinetobacter are poor with this product sensitivity.Ceftizoxime has good antibacterial action to hemophilus influenza and Neisseria gonorrhoeae.This product to the effect of staphylococcus aureus and staphylococcus epidermidis than first, second in generation cephalosporin for poor, methicillin-resistant staphylococcus aureus and enterococcus are to this product drug resistance, various streptococcus are all extremely sensitive to this product.Anaerobe such as dyspepsiacoccus, peptostreptococcus and part Bacteroides are responsive to this product more, and clostridium difficile is to this product drug resistance.This product mechanism of action is that this product reaches bactericidal action by the biosynthesis that suppresses the bacteria cell wall mucopeptide.Because it has wide spectrum, efficient, anti-enzyme, low toxicity and can pass through blood brain barrier, be widely used in clinically treat various in, severe infection.
Ceftizoxime for inj is clinical for the injectable powder of its sodium salt (ceftizoxime sodium) has been widely used in, is present most widely used antibiotic medicine, and its preparation all is to make by the ceftizoxime sodium raw materials is aseptic subpackaged.Problems such as most of ceftizoxime sodium raw materials exist purity not high, and dissolving back clarity is poor, poor stability in the aqueous solution, and side effect is bigger.Thereby, had a strong impact on the application of ceftizoxime or its salt.
200810139625.0 the method for injectable powder of a kind of method for preparing high-purity ceftizoxime or its salt, preparation ceftizoxime or its salt and high-purity ceftizoxime or its salt and the corresponding injectable powder for preparing according to described method are provided.This method will be generally used for species analysis and the Central Asia chromatographic column of isolating technology and combine with recrystallization and be used for especially sodium salt of purification ceftizoxime or its salt, though obtained highly purified ceftizoxime sodium medicine, the method complexity of chromatographic column, operating difficulties.
In addition, ceftizoxime sodium is a crystalline powder.But material owing to influenced by various factors, changes intramolecularly or molecular linkage mode when crystallization, and it is different to cause molecule or atom to be arranged at lattice vacancy, forms different crystal structures.Same substance has two or more spatial arrangements and cell parameter, and the phenomenon that forms multiple crystal formation is called polymorphism.Though under certain temperature and pressure, having only a kind of crystal formation is stable on thermodynamics, owing to the process that changes stable state from metastable state into is very slow usually, therefore all there is polymorphism in many crystalline drugs.The solid polymorphic comprises conformation type polymorphic, configuration type polymorphic, color polymorphic and pseudo-polymorphic.According to the thermodynamics viewpoint, there is the exchange process of energy in transformation between the same medicine different crystal structure, that is to say that different crystal forms parameter such as free energy, entropy, volume, specific heat etc. aspect thermodynamics is different, this just causes between the same medicine different crystal forms physical propertys such as dissolubility, fusing point, and there is some difference, thereby make the different crystal forms of same medicine may have remarkable difference at aspects such as outward appearance, dissolubility, fusing point, dissolution, bioavailability and curative effects.The medicine polymorphism is one of key factor that influences drug quality and clinical efficacy, and therefore in drug quality control, crystal formation is one of them important quality control index.The polymorphism of medicine is to the quality important influence of product.The chemical compound that crystal structure is different, because the difference of its molecules align order, be in different energy state respectively, common unformed medicine has bigger potential energy, interparticle bond strength is little than crystal formation, total per surface free energy is bigger, the easy aquation in surface between particle, thus cause difference with the crystallinity drug solubility.Molecule is different with arrangement in steric configuration, conformation in the structure cell of different crystal forms, make its dissolubility have significant difference, cause preparation that different dissolution rates is arranged in vivo, directly influence preparation absorption in vivo, distribution, drainage and metabolism, finally because of the different differences that cause clinical drug effect of its bioavailability.Because ceftizoxime sodium is easily molten in water, forms amorphous powder easily.Adopt method for crystallising commonly used on the pharmaceutical manufacturing,, increase yield as improving the quality of products by conditions such as crystallization control temperature, solvent rate of addition, mixing speeds, improve crystal formation, but production operation inconvenience, cost is higher, and the ceftizoxime sodium quality of being produced does not meet medicinal standard yet.
Summary of the invention
The object of the present invention is to provide a kind of ceftiaoxline sodium for injection sterilized powder, the ceftizoxime sodium that contains crystal form in the described ceftiaoxline sodium for injection sterilized powder, the ceftizoxime sodium crystal of this crystal form is good, even particle size distribution, quality conformance with standard.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
Described ceftizoxime sodium composition sterile powder for injection contains 99.0～99.9wt% ceftizoxime sodium and 0.10～1.00wt% sodium benzoate, and wherein ceftizoxime sodium is the ceftizoxime sodium of crystal form.
According to aforesaid ceftizoxime sodium composition sterile powder for injection, wherein, the ceftizoxime sodium crystal of described crystal form uses that characteristic peak is 8.7 °, 12.2 °, 13.7 °, 15.3 °, 16.8 °, 17.6 °, 18.4 °, 19.7 °, 20.3 °, 21.3 °, 23.2 ° and 24.8 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the Cu-K alpha ray measures.
The present invention is by the pH value and the temperature of adjusting ceftizoxime sodium solution, and the adding appropriate solvent, and control solution saturation history obtains the well-crystallized that the ceftizoxime sodium uniform particle size distributes, and quality meets medicinal standard.
The ceftizoxime sodium of crystal form of the present invention adopts following method preparation:
Ceftizoxime sodium is soluble in water, 18～30 ℃ of pH value 6.3～6.9, the temperature of control solution, stirring mixed solution to the crystallization that adds dehydrated alcohol and acetone down in solution separates out, and then under agitation add ethyl acetate, growing the grain, sucking filtration, washing, drying obtains the ceftizoxime sodium of crystal form.
Because ceftizoxime sodium is easily molten in water, forms amorphous powder easily.Adopt method for crystallising commonly used on the pharmaceutical manufacturing,, increase yield as improving the quality of products by conditions such as crystallization control temperature, solvent rate of addition, mixing speeds, improve crystal formation, but production operation inconvenience, cost is higher, and the ceftizoxime sodium quality of being produced does not meet medicinal standard yet.The present invention controls the temperature of solution by regulating the pH value of ceftizoxime sodium solution, and adopts gradation to add the method for suitable different solvents in solution, with the saturation history of control solution, obtains the good crystal formation that the ceftizoxime sodium uniform particle size distributes.
According to aforesaid method, wherein, described dehydrated alcohol and acetone adopt the method that drips to add.
According to aforesaid method, wherein, described dropping is the speed dropping with 420～480ml/h.
In the ceftizoxime sodium crystallization process, adding progressively reaches capacity or hypersaturated state ceftizoxime sodium with insoluble solvent dehydrated alcohol of ceftizoxime sodium and acetone in the ceftizoxime sodium solution, can progressively separate out crystal; Instantaneous too high for fear of supersaturation concentration, the crystal crystallize is too fast, produces sticking group, and among the present invention, solvent dehydrated alcohol and acetone adopt the mode that drips to add.
According to aforesaid method, wherein, the mixing speed the during mixed solution of adding dehydrated alcohol and acetone is 100～150 rev/mins; Mixing speed when adding ethyl acetate is 30～70 rev/mins.
Simultaneously, instantaneous too high for fear of the ceftizoxime sodium supersaturation concentration, the crystal crystallize is too fast, produces sticking group, among the present invention also the mixing speed when adding the mixed solution of dehydrated alcohol and acetone control.Among the present invention, the mixing speed the during mixed solution of adding dehydrated alcohol and acetone is controlled at 100～150 rev/mins.After supersaturated solution is separated out crystal, under the condition of 30～70 rev/mins of lower mixing speeds, continue again to add and the insoluble solvent ethyl acetate of ceftizoxime sodium, so that fine crystal is progressively grown up, form the crystal of uniform particle size size, make simultaneously to be adsorbed in crystalline impurity and progressively to break away from crystal and reach purification.
According to aforesaid method, wherein, the volume ratio of dehydrated alcohol and acetone is 1: 2～1: 4 in the mixed solution of described dehydrated alcohol and acetone; The mixed solution of described dehydrated alcohol and acetone and the volume ratio of ethyl acetate are 1: 1～1: 3.
According to aforesaid method, wherein, described washing is washed 1～3 time for the mixed solution with dehydrated alcohol and acetone.
Method for crystallising of the present invention regardless of batch crystallization, continuous crystallisation, stirred crystallization, leave standstill crystallization operations such as crystallization, can implement.
Ceftizoxime sodium composition sterile powder for injection of the present invention is under the sterile production environmental condition, with the ceftizoxime sodium of sodium benzoate and prepared crystal form by the described consumption mixing that feeds intake, be sub-packed in the antibiotic glass bottle then, jump a queue, roll lid, lamp inspection, be up to the standards, labeling, packing are promptly.
Promptly under the sterile production environmental condition, be sub-packed in the antibiotic glass bottle by machinery, preparation 0.5g, 0.75g, 1.0g, 1.5g or 2.0g dress injectable powder add injection water dissolved dilution during clinical use and get final product.
Above-mentioned ceftizoxime sodium composition sterile powder for injection is mainly used in the responsive microbial following infection of treatment: septicemia, infective endocarditis; The secondary infection of wound, burn, scald; Bronchitis, bronchiectasis infects, the secondary infection of chronic respiratory illness, pneumonia, pulmonary abscess, empyema; Cholangitis, cholecystitis; Peritonitis; Pyelonephritis, cystitis, prostatitis; Adnexitis, uterine cavity infects, pelvic inflammatory disease; Cerebrospinal meningitis etc. are a kind of antibiotic medicines.
The present invention also provides a kind of method for preparing the ceftizoxime sodium of crystal form, this method production operation is convenient, cost is lower, can improve the quality of products, increase yield, and adopt the ceftizoxime sodium crystal of crystal form of method of the present invention preparation good, even particle size distribution, quality meets medicinal standard.
The method for preparing crystalline cephem azoles oxime sodium provided by the present invention is: ceftizoxime sodium is soluble in water, control pH value 6.3-6.9, temperature 18-30 ℃ of solution, stirring mixed solution to the crystallization that adds dehydrated alcohol and acetone down in solution separates out, and then under agitation add ethyl acetate, growing the grain, sucking filtration, washing, drying gets crystalline cephem azoles oxime sodium.
Because ceftizoxime sodium is easily molten in water, forms amorphous powder easily.Adopt method for crystallising commonly used on the pharmaceutical manufacturing,, increase yield as improving the quality of products by conditions such as crystallization control temperature, solvent rate of addition, mixing speeds, improve crystal formation, but production operation inconvenience, cost is higher, and the ceftizoxime sodium quality of being produced does not meet medicinal standard yet.The present invention controls the temperature of solution by regulating the pH value of ceftizoxime sodium solution, and adopts gradation to add the method for suitable different solvents in solution, with the saturation history of control solution, obtains the good crystal formation that the ceftizoxime sodium uniform particle size distributes.
According to aforesaid method, wherein, described dehydrated alcohol and acetone adopt the method that drips to add.
According to aforesaid method, wherein, described dropping is the speed dropping with 420～480ml/h.
In the ceftizoxime sodium crystallization process, adding progressively reaches capacity or hypersaturated state ceftizoxime sodium with insoluble solvent dehydrated alcohol of ceftizoxime sodium and acetone in the ceftizoxime sodium solution, can progressively separate out crystal; Instantaneous too high for fear of supersaturation concentration, the crystal crystallize is too fast, produces sticking group, and among the present invention, solvent dehydrated alcohol and acetone adopt the mode that drips to add.
According to aforesaid method, wherein, the mixing speed the during mixed solution of adding dehydrated alcohol and acetone is 100～150 rev/mins; Mixing speed when adding ethyl acetate is 30～70 rev/mins.
Simultaneously, instantaneous too high for fear of the ceftizoxime sodium supersaturation concentration, the crystal crystallize is too fast, produces sticking group, among the present invention also the mixing speed when adding the mixed solution of dehydrated alcohol and acetone control.Among the present invention, the mixing speed the during mixed solution of adding dehydrated alcohol and acetone is controlled at 100～150 rev/mins.After supersaturated solution is separated out crystal, under the condition of 30～70 rev/mins of lower mixing speeds, continue again to add and the insoluble solvent ethyl acetate of ceftizoxime sodium, so that fine crystal is progressively grown up, form the crystal of uniform particle size size, make simultaneously to be adsorbed in crystalline impurity and progressively to break away from crystal and reach purification.
According to aforesaid method, wherein, the volume ratio of dehydrated alcohol and acetone is 1: 2～1: 4 in the mixed solution of described dehydrated alcohol and acetone; The mixed solution of described dehydrated alcohol and acetone and the volume ratio of ethyl acetate are 1: 1～1: 3.
According to aforesaid method, wherein, described washing is to wash with the mixed solution and/or the ethyl acetate of dehydrated alcohol and acetone earlier.
Method for crystallising of the present invention regardless of batch crystallization, continuous crystallisation, stirred crystallization, leave standstill crystallization operations such as crystallization, can implement.
Compared with prior art, the present invention has following advantage:
The ceftizoxime sodium that contains crystal form in the gained ceftiaoxline sodium for injection sterilized powder of the present invention, the ceftizoxime sodium of this crystal form are a kind of well-crystallized that distributes than uniform particle size, and it is more stable than the crystalline powder that provides in the prior art; Crystalline cephem azoles oxime sodium is placed for a long time, and product color is constant substantially.The easy easy control of production process helps operations such as filtration and drying, helps reducing production costs.Crystalline cephem azoles oxime sodium of the present invention has broad-spectrum antibacterial action to Gram-negative and positive aerobe, and clinical application effect is good.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of crystalline cephem azoles oxime sodium of the present invention.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, filter, regulating filtrate pH with glacial acetic acid is 6.3, and the temperature of control filtrate is 18 ℃, under the mixing speed that per minute 100 changes, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 2) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 420ml/h is separated out, and then under the stirring that per minute 30 changes, the supersaturation concentration of control solution, continue to add slowly the 200ml ethyl acetate, growing the grain with the mixed solution washed twice of 50ml dehydrated alcohol and acetone, is drained, drying under reduced pressure, the ceftizoxime sodium 4.68g of crystal form.
Use D/max-IIIA DIFFRATOMETER (RIGAKU CORPORATION, JANPAN) X-diffractometer, with Cu, K α 1, λ=1.54056A measures, and characteristic peak is 8.7 °, 12.2 °, 13.7 °, 15.3 °, 16.8 °, 17.6 °, 18.4 °, 19.7 °, 20.3 °, 21.3 °, 23.2 ° and 24.8 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern (see figure 1) of the ceftizoxime sodium of gained crystal form.
The preparation of [embodiment 2] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, filter, regulating filtrate pH with glacial acetic acid is 6.9, the temperature of control filtrate is 30 ℃, under the mixing speed that per minute 150 changes, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 4) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 480ml/h is separated out, and then under the stirring that per minute 70 changes, the supersaturation concentration of control solution, continue to add the 600ml ethyl acetate slowly, growing the grain is with the mixed solution washed twice of 50ml dehydrated alcohol and acetone, reuse 65ml ethyl acetate washed twice, drain, drying under reduced pressure, the ceftizoxime sodium 4.67g of crystal form.
The X-ray powder diffraction pattern of the ceftizoxime sodium of gained crystal form is consistent with embodiment 1.
The preparation of [embodiment 3] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, filter, regulating filtrate pH with glacial acetic acid is 6.5, and the temperature of control filtrate is 25 ℃, under the mixing speed that per minute 120 changes, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 3) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 450ml/h is separated out, and then under the stirring that per minute 50 changes, the supersaturation concentration of control solution, continue to add slowly the 400ml ethyl acetate, growing the grain with 65ml ethyl acetate washed twice, is drained, drying under reduced pressure, the ceftizoxime sodium 4.66g of crystal form.
The X-ray powder diffraction pattern of the ceftizoxime sodium of gained crystal form is consistent with embodiment 1.
The preparation of [embodiment 4] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, filter, regulating filtrate pH with glacial acetic acid is 6.6, the temperature of control filtrate is 26 ℃, under the mixing speed that per minute 130 changes, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 2.5) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 460ml/h is separated out, and then under the stirring that per minute 60 changes, the supersaturation concentration of control solution, continue to add the 250ml ethyl acetate slowly, growing the grain is with the mixed solution washed twice of 50ml dehydrated alcohol and acetone, reuse 65ml ethyl acetate washed twice, drain, drying under reduced pressure, the ceftizoxime sodium 4.67g of crystal form.
The X-ray powder diffraction pattern of the ceftizoxime sodium of gained crystal form is consistent with embodiment 1.
The preparation of [embodiment 5] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, filter, regulating filtrate pH with glacial acetic acid is 6.4, the temperature of control filtrate is 22 ℃, under the mixing speed that per minute 110 changes, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 3.5) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 430ml/h is separated out, and then under the stirring that per minute 40 changes, the supersaturation concentration of control solution, continue to add the 220ml ethyl acetate slowly, growing the grain is with the mixed solution washed twice of 50ml dehydrated alcohol and acetone, reuse 65ml ethyl acetate washed twice, drain, drying under reduced pressure, the ceftizoxime sodium 4.67g of crystal form.
The X-ray powder diffraction pattern of the ceftizoxime sodium of gained crystal form is consistent with embodiment 1.
The preparation of [embodiment 6] crystalline cephem azoles oxime sodium
At ambient temperature, drop into the 5g ceftizoxime sodium to reactor, the water dissolution that adds 50ml, stirred 28 minutes, aseptic filtration, regulating filtrate pH with glacial acetic acid is 6.9, the temperature of control filtrate is 30 ℃, under the sterile production environmental condition of GMP compatible, under the mixing speed with per minute 150 commentaries on classics, mixed solution (volume ratio of dehydrated alcohol and acetone is 1: 4) to the crystallization that slowly drips 200ml dehydrated alcohol and acetone with the speed of 480ml/h in bacteria-free filtrate is separated out, and then under the stirring that per minute 70 changes, the supersaturation concentration of control solution continues to add slowly the 600ml ethyl acetate, growing the grain, with the mixed solution washed twice of 50ml dehydrated alcohol and acetone, reuse 65ml ethyl acetate washed twice is drained, drying under reduced pressure, the ceftizoxime sodium 4.67g of crystal form.
The X-ray powder diffraction pattern of the ceftizoxime sodium of gained crystal form is consistent with embodiment 1.
[embodiment 7] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 6 makes under the sterile production environmental condition of GMP compatible, is pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 0.5g, and is aseptic subpackaged in antibiotic glass bottle.
[embodiment 8] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 5 makes under the sterile production environmental condition of GMP compatible, is pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 0.75g, and is aseptic subpackaged in antibiotic glass bottle.
[embodiment 9] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 4 makes under the sterile production environmental condition of GMP compatible, is pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 1.0g, and is aseptic subpackaged in antibiotic glass bottle.
[embodiment 10] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 6 makes under the sterile production environmental condition of GMP compatible, is pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 1.5g, and is aseptic subpackaged in antibiotic glass bottle.
[embodiment 11] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 3 makes under the sterile production environmental condition of GMP compatible, is pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 2.0g, and is aseptic subpackaged in antibiotic glass bottle.
[embodiment 12] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 2 makes and commercially available sodium benzoate under the sterile production environmental condition of GMP compatible, are pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 0.5g, and is aseptic subpackaged in antibiotic glass bottle, the ceftiaoxline sodium for injection sterilized powder, the content of sodium benzoate accounts for 0.1% of medicine total amount in every medicine.
[embodiment 13] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 1 makes and commercially available sodium benzoate under the sterile production environmental condition of GMP compatible, are pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 0.75g, and is aseptic subpackaged in antibiotic glass bottle, the ceftiaoxline sodium for injection sterilized powder, the content of sodium benzoate accounts for 1.0% of medicine total amount in every medicine.
[embodiment 14] ceftiaoxline sodium for injection sterilized powder
The crystalline cephem azoles oxime sodium aseptic powder and the commercially available sodium benzoate that adopt embodiment 6 to make under the sterile production environmental condition of GMP compatible, are pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 1.0g, and is aseptic subpackaged in antibiotic glass bottle, the ceftiaoxline sodium for injection sterilized powder, the content of sodium benzoate accounts for 0.5% of medicine total amount in every medicine.
[embodiment 15] ceftiaoxline sodium for injection sterilized powder
The ceftizoxime sodium aseptic powder of the crystal form that employing embodiment 6 makes and commercially available sodium benzoate under the sterile production environmental condition of GMP compatible, are pressed ceftizoxime (C
13H
13N
5O
5S
2) calculate, specification is 1.5g, and is aseptic subpackaged in antibiotic glass bottle, the ceftiaoxline sodium for injection sterilized powder, the content of sodium benzoate accounts for 0.3% of medicine total amount in every medicine.
[test example 1] stability test
This test example is the stability test of the ceftizoxime sodium of the prepared crystal form of the present invention.
According to the Pharmacopoeia of the People's Republic of China (2005 editions) appendix medicine stability test guideline, the ceftizoxime sodium sample of selecting commercially available ceftizoxime sodium sample to reach the crystal form for preparing by the embodiment of the invention 6 carries out 2-8 ℃ of reserved sample observing, ceftizoxime sodium kept sample test, the result shows (seeing Table 1):
Commercially available ceftizoxime sodium was placed 6 months, the solution color and luster is by rising to for No. 4 less than yellow green less than No. 6, yellow green, the solution color and luster changes very obvious, place after 12 months, the solution color and luster has been upgraded to less than No. 7, yellow green, and clarity is greater than 1, and content reduces to 94.6%, outward appearance is a milk yellow, and quality has not met the national drug standards.
The crystalline cephem azoles oxime sodium of the embodiment of the invention 6 preparations was placed 24 months, and solution color and luster, clarity and content are constant substantially, and product is stable, places 24 months, and drug quality still meets the national drug standards.
This shows that the crystalline cephem azoles oxime sodium of the embodiment of the invention 6 preparations is than commercially available ceftizoxime stable sodium.
Table 1, ceftizoxime sodium reserved sample observing result
Ceftizoxime sodium to the prepared crystal form of other embodiment of the present invention has also carried out identical test with the ceftiaoxline sodium for injection sterilized powder, and the result of its acquisition is similar.
The test of pesticide effectiveness of the ceftizoxime sodium of [test example 2] crystal form
Bacterial strain: test is escherichia coli 107 strains (comprising beta-lactamase-producing strain and anti-cefalotin, ampicillin, carbenicillin and aminoglycosides bacterial strain) with bacterial strain, pneumobacillus 134 strains, Bacillus proteus 41 strains, bacillus pyocyaneus 53 strains, staphylococcus aureus 52 strains.The evaluation of bacterial strain is carried out with the VITEK-AMS system, and identification of strains is to planting.
Test method: carry out MIC with broth dilution method (MIC) and measure, test operation is by accurate operation of standardization committee of U.S. clinical laboratory (NCCLS) nineteen ninety-five scale and interpretation as a result.
The result: the ceftizoxime sodium of crystal form is to the MIC of escherichia coli, pneumobacillus, Bacillus proteus
50, MIC
80Testing result shows that the ceftizoxime sodium of crystal form has shown good antimicrobial effect (table 2).
The ceftizoxime sodium antibacterial activity in vitro of table 2, crystal form
| Bacteria name | MIC 50 | MIC 80 |
| Escherichia coli (107 strain) | ≤0.05 | 0.10 |
| Pneumobacillus (134 strain) | ≤0.05 | 0.20 |
| Bacillus proteus (41 strain) | ≤0.05 | ≤0.05 |
| Bacillus pyocyaneus (53 strain) | 25 | 50 |
| Staphylococcus aureus (52 strain) | 6.25 | ≥400 |
Claims (9)
1. ceftizoxime sodium composition sterile powder for injection, it is characterized in that, described ceftizoxime sodium composition sterile powder for injection contains 99.0～99.9wt% ceftizoxime sodium and 0.10～1.00wt% sodium benzoate, and wherein ceftizoxime sodium is the ceftizoxime sodium of crystal form; Characteristic peak is 8.7 °, 12.2 °, 13.7 °, 15.3 °, 16.8 °, 17.6 °, 18.4 °, 19.7 °, 20.3 °, 21.3 °, 23.2 ° and 24.8 ° of demonstrations at 2 θ in the X-ray powder diffraction pattern that the ceftizoxime sodium use Cu-K alpha ray of described crystal form measures.
2. ceftizoxime sodium composition sterile powder for injection according to claim 1 is characterized in that, the ceftizoxime sodium of described crystal form adopts following method preparation:
Ceftizoxime sodium is soluble in water, 18～30 ℃ of pH value 6.3～6.9, the temperature of control solution, stirring mixed solution to the crystallization that adds dehydrated alcohol and acetone down in solution separates out, and then under agitation add ethyl acetate, growing the grain, sucking filtration, washing, drying obtains the ceftizoxime sodium of crystal form.
3. ceftizoxime sodium composition sterile powder for injection according to claim 2 is characterized in that, the mixed solution of described dehydrated alcohol and acetone adopts the method that drips to add.
4. ceftizoxime sodium composition sterile powder for injection according to claim 3 is characterized in that, described dropping is the speed dropping with 420～480ml/h.
5. ceftizoxime sodium composition sterile powder for injection according to claim 2 is characterized in that, the mixing speed when adding the mixed solution of dehydrated alcohol and acetone is 100～150 rev/mins.
6. ceftizoxime sodium composition sterile powder for injection according to claim 2 is characterized in that, the mixing speed when adding ethyl acetate is 30～70 rev/mins.
7. ceftizoxime sodium composition sterile powder for injection according to claim 2 is characterized in that, the volume ratio of dehydrated alcohol and acetone is 1: 2～1: 4 in the mixed solution of described dehydrated alcohol and acetone; The mixed solution of described dehydrated alcohol and acetone and the volume ratio of ethyl acetate are 1: 1～1: 3.
8. ceftizoxime sodium composition sterile powder for injection according to claim 2 is characterized in that, described washing is washed 1～3 time for the mixed solution with dehydrated alcohol and acetone.
9. ceftizoxime sodium composition sterile powder for injection according to claim 2, it is characterized in that, described ceftizoxime sodium composition sterile powder for injection is under the sterile production environmental condition, with the ceftizoxime sodium of sodium benzoate and prepared crystal form by the described consumption mixing that feeds intake, be sub-packed in the antibiotic glass bottle then, jump a queue, roll lid, lamp inspection, be up to the standards, labeling, packing are promptly.
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| CN102329328B (en) | 2011-07-15 | 2012-09-26 | 海南灵康制药有限公司 | Novel method for purifying ceftizoxime sodium compound |
| CN102351883A (en) * | 2011-08-21 | 2012-02-15 | 苏州二叶制药有限公司 | Detection method and production process for ceftizoxime sodium preparation |
| CN102584862B (en) * | 2011-11-16 | 2013-07-10 | 山东罗欣药业股份有限公司 | Biapenem crystalline compound and composition powder-needle thereof |
| CN102936254B (en) * | 2012-11-14 | 2014-11-05 | 罗诚 | Drug composition containing ceftizoxime sodium compound |
| CN103044450B (en) * | 2013-01-05 | 2013-11-20 | 黄金秀 | Ceftizoxime sodium compound and preparation method and drug composition of ceftizoxime sodium compound |
| CN103910750B (en) * | 2014-04-18 | 2016-05-11 | 悦康药业集团有限公司 | A kind of Ceftizoxime sodium compound |
| CN104042563A (en) * | 2014-06-06 | 2014-09-17 | 杭州长典医药科技有限公司 | Ceftizoxime sodium ultrafine powder preparation and preparation method thereof |
| CN105622635B (en) * | 2016-03-10 | 2017-03-15 | 重庆福安药业集团庆余堂制药有限公司 | One kind reduces anaphylactoid ceftizoxime sodium novel crystal form and its preparation |
| CN107661338A (en) * | 2017-04-11 | 2018-02-06 | 石药集团中诺药业（石家庄）有限公司 | A kind of new ceftiaoxline sodium for injection |
| CN109553626B (en) * | 2018-12-29 | 2021-02-26 | 山东罗欣药业集团股份有限公司 | Refining method of ceftizoxime sodium |
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