Ceftizoxime sodium composition sterile powder for injection
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 ºC 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.
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