CN101781316A - Ceftizoxime sodium crystalline hydrate and preparation method and application thereof - Google Patents
Ceftizoxime sodium crystalline hydrate and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a ceftizoxime sodium crystalline hydrate and a preparation method and application thereof. The ceftizoxime sodium crystalline hydrate has high storage stability, and is suitable for preparing medicaments for treating or preventing diseases such as infection of respiratory systems, liver and biliary systems, five sense organs and urinary tracts of human bodes or animals, infection of abdominal cavity, infection of pelvic cavity, ichorrhemia, infection of skin tissues, and infection of bones and joint caused by gram positive or negative bacteria, meningitis caused by streptococcus pneumonia or haemophilus influenza, and simple gonorrhea.
Description
Technical field
The present invention relates to medical technical field, specifically provide antibacterials---ceftizoxime sodium crystalline hydrate thing and its production and use.
Background technology
At present, disclosed document has only been reported ceftizoxime sodium (Ceftizoxime sodium) (C
13H
12N
5NaO
5S
2, molecular weight: 405.38, CAS number: 68401-82-1), up to the present, still do not have disclosed bibliographical information ceftizoxime sodium crystalline hydrate thing of the present invention and its production and use both at home and abroad.
Summary of the invention
Involved in the present invention is ceftizoxime sodium crystalline hydrate thing and its production and use, furtherly, relates to antibiotic infection medicine, i.e. alkyl acyl acetaldehyde sulfurous acid pharmaceutically-acceptable salts crystalline hydrate and its production and use, and its molecular formula is C
13H
12N
5NaO
5S
2NH
2O, n=1.5～1.85.
The ceftizoxime sodium that contains crystal water that the present invention obtains, surprisingly, the ceftizoxime sodium that contains crystal water is drawn moist far below the ceftizoxime sodium that contains non-crystallizable water, the ceftizoxime sodium that contains crystal water than do not contain crystal water more can be stable existence, be convenient to store and transportation, be easy to make preparation.In addition, the deliquescence of anhydride makes wants secluding air to prevent adhesion etc. when handling, and hydrate has good sliding, thereby improves the operability of preparation.
Surprisingly, distinctive, has corresponding endotherm(ic)peak under the weightless platform of the heat analysis of hydrate of the present invention (TG-DSC or TG-DTA) collection of illustrative plates, the thermogram spectrum demonstrates the ceftizoxime sodium crystalline hydrate thing, as ceftizoxime sodium 1.82 hydrates, ceftizoxime sodium 1.75 hydrates, ceftizoxime sodium 1.5 hydrates etc.
Ceftizoxime sodium crystalline hydrate thing of the present invention can stable storage.Ceftizoxime sodium hydrate and anhydride sample are drawn moist test: get ceftizoxime sodium anhydride and the about 5g of hydrate of the present invention, place the watch-glass of dry constant weight, precision is weighed, 25 ℃, relative humidity are 70%, respectively at test 0h and 48h sampling, calculate the percentage that draws wet weightening finish, the result shows, anhydride draws moist all more much higher than hydrate of the present invention, and ceftizoxime sodium crystalline hydrate thing of the present invention stable storage better the results are shown in Table 1.Under RH75%, 30 ℃ of conditions, with the accelerated stability test that carries out 6 months in the airtight cillin bottle of ceftizoxime sodium crystalline hydrate matter sample, ceftizoxime sodium HPLC method is measured the condition of content and purity: Cl8 (250mm * 4.6mm, 5 μ m) acetonitrile-phosphate buffered saline buffer (is got citric acid 1.42g, disodium hydrogen phosphate,anhydrous 1.73g, be dissolved in water and be diluted to 1000ml, regulate pH value to 3.6) (85: 15) be moving phase; The detection wavelength is 254nm, and column temperature is 40 ℃, and flow velocity 1ml/min measures and finds that its content is constant substantially, and related substance does not have obvious increase.Test-results illustrates that ceftizoxime sodium crystalline hydrate thing of the present invention has good storage stability.
Table 1. draws the wet test result
Sample time, (48 hours) were compared with 0 hour, weightening finish %
Ceftizoxime sodium 1.75 hydrates 1.37
Ceftizoxime sodium anhydride 7.69
The preparation of ceftizoxime sodio-derivative---ceftizoxime sodium crystalline hydrate thing comprises following method:
Method A. is in reaction vessel, add ceftizoxime acid, add water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), in the acetonitrile one or more, stir, 10 ℃ of low molecular amine that drip C1-C12 down, stirring and dissolving, add gac 0.1g, stirred 30 minutes, filter, washing, filter, in filtrate, drip yellow soda ash under 10 ℃, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, one or more of Sodium isooctanoate and water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), the solution of one or more in the low molecule ketone of C3-C8, stirred 0.5-3 hour, with about mineral acid or organic acid or its solution adjusting pH to 7.0, slowly drip the low mass molecule alcohol of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6, the lower member ester of C2-C8, in the lower halogenated hydrocarbon of C1-C6 one or more, place below 10 ℃, solid is fully separated out, suction filtration, the low mass molecule alcohol of a small amount of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6 is washed 1-3 time, filter, the low mass molecule alcohol of gained solid water and C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C8, one or more solvent recrystallization one or many in the lower halogenated hydrocarbon of C1-C6, place below 10 ℃, crystallization is fully separated out, filter, drying gets the ceftizoxime sodium crystalline hydrate thing;
Wherein, the low molecular amine of employed ceftizoxime acid: C1-C12 in the reaction: the mol ratio of alkali (yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate) generally can be 1: 0.5-1.1: 0.5-1.1; The ratio of one or more (volume ml) in the low mass molecule alcohol of ceftizoxime acid (weight g) and water, C1-C6, tetrahydrofuran (THF), the acetonitrile is for being generally: 1 (g): 1.5～20 (ml); The water that uses in crystallization or the recrystallization is generally 1: 5～50 with the volume of organic solvent ratio.
Perhaps method B. is in reaction vessel, add ceftizoxime acid, add water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), in the acetonitrile one or more, stir, under 10 ℃, in filtrate, drip yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, one or more of Sodium isooctanoate and water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), the solution of one or more in the low molecule ketone of C3-C8, stirring reaction 0.5-3 hour, with about mineral acid or organic acid or its solution adjusting pH to 7.0, slowly drip the low mass molecule alcohol of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6, the lower member ester of C2-C8, in the lower halogenated hydrocarbon of C1-C6 one or more, place below 10 ℃, solid is fully separated out, filter, the low mass molecule alcohol of a small amount of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C8 is washed 1-3 time, filter, the low mass molecule alcohol of gained solid water and C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6, in the lower halogenated hydrocarbon of C1-C6 one or more carry out the one or many recrystallization for recrystallisation solvent, filter the dry ceftizoxime sodium crystalline hydrate thing that gets.
Wherein, employed ceftizoxime acid in the reaction: the mol ratio of alkali (yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate) generally can be 1: 0.5-1.1: 0.5-1.1; The ratio of one or more (volume ml) in the low mass molecule alcohol of ceftizoxime acid (weight g) and water, C1-C6, tetrahydrofuran (THF), the acetonitrile is for being generally: 1 (g): 1.5～20 (ml); The water that uses in crystallization or the recrystallization is generally 1: 5～50 with the volume of organic solvent ratio.
The crystallization of ceftizoxime sodium crystalline hydrate thing or recrystallization solvent are selected from water, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol etc.; The lower member ester of C2-C8 comprises N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; Ether, methyl ethyl ether, isopropyl ether; In methylene dichloride, the chloroform etc. one or more; Ceftizoxime sodium crystallization crystallization or recrystallization solvent, preferably water, methyl alcohol, ethanol, Virahol, one or more in tetrahydrofuran (THF), ethyl acetate, ether, isopropyl ether, methylene dichloride, the chloroform.In preparation method of the present invention, in recrystallization process,, can use activated carbon decolorizing after the dissolving earlier with water dissolution ceftizoxime sodium crystalline hydrate thing, the organic solvent that limits with the present invention makes its crystallization again.Ceftizoxime sodium crystalline hydrate thing of the present invention can have different crystal formations.
The lower alcohol among the present invention or the carbonatoms of low mass molecule alcohol are defined as C1-C6 (that is: the alcohol of 1-6 carbon atom), as methyl alcohol, ethanol, Virahol etc.; The carbonatoms of rudimentary ether or low molecule ether is defined as C2-C8, as ether, butyl ether etc.; The carbonatoms of lower halogenated hydrocarbon is defined as C1-C6, comprises methylene dichloride, ethylene dichloride, chloroform etc.; The carbonatoms of lower member ester is defined as C2-C8, unless specialize to outside the formic acid lower member ester, otherwise for comprising N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; The carbonatoms of low molecule straight or branched alkane or naphthenic hydrocarbon is defined as C5-C10, comprises pentane, normal hexane, hexanaphthene, sherwood oil etc.; The carbonatoms of low molecule aromatic hydrocarbon is defined as C6-C12, comprises benzene, toluene etc.; The carbonatoms of the lower acid of C1-C6 is defined as the organic acid of 1-6 carbon atom, comprises formic acid, acetate, propionic acid etc.; The low molecule ketone of C3-C8 is defined as the ketone of 3-8 carbon atom, comprises acetone, butanone, hexone etc.; The low molecular amine of C1-C12 is defined as the organic amine of 1-12 carbon atom, comprises dimethylamine, diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine etc.; The marking method of amount of carbon atom that about any class description is " rudimentary or low molecule " compound is as long as occur once in text, and the quantity of having indicated among the carbonatoms of the similar compound of other any unmarked being described as " rudimentary or low molecule " and the Ben Wenben is consistent.
The drying mode of product of the present invention can be in differing temps (as 20-100 ℃), time of drying (0.5 hour to a few days) or with under the envrionment conditions of other siccative (comprising silica gel, Vanadium Pentoxide in FLAKES, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate etc.) or use the mode of normal pressure or decompression that last product is carried out drying.Its drying temperature is preferably at 30-60 ℃.
Ceftizoxime sodium crystalline hydrate thing purposes of the present invention: ceftizoxime sodium crystalline hydrate thing of the present invention is used to prepare solid preparation, injection, wherein injection comprises injection freeze-dried powder, aseptic subpackaged powder injection, tablet, capsule, granule etc.; And can be used for preparing the ceftizoxime sodium anhydride.The preparation of anhydride can be obtained through different drying meanss by crystalline hydrate of the present invention, its preparation can or have other siccative in differing temps (as 60-100 ℃), time of drying (a few hours are to a few days) and (comprise silica gel, molecular sieve, Vanadium Pentoxide in FLAKES, sodium hydroxide, anhydrous sodium carbonate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous magnesium sulfate etc.) envrionment conditions under or and use the mode of normal pressure or decompression that last product is carried out drying, also can be earlier by the method for benzene distillation band water, and in conjunction with obtaining after other drying means drying of describing herein.
Be used to prepare tablet (comprising buccal tablet, fast disintegrating tablet etc.), capsule, granule, wherein can contain pharmaceutically acceptable weighting agent, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent is as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent (sodium lauryl sulphate etc.); Pharmaceutically acceptable wetting agent and tackiness agent are as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant are as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence are as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.;
The deliquescence that crystalline hydrate of the present invention is different from anhydride makes wants secluding air to prevent adhesion etc. when handling, and crystalline hydrate has good sliding, thereby improves the operability of preparation; And the solid preparation that makes preparation has good dissolving out capability, makes it be absorbed easily and enters blood circulation, improves bioavailability, and helps bringing into play fast its effect.From another aspect, making it prevent produces obstruction and makes loading amount generation difference cause underdosage when carrying out being difficult for when aseptic subpackaged to cause packing because of the moisture absorption, thereby bring the defective of product, or because underproof product is not inspected by random samples the actual omission of formation, and then come into the market, in clinical treatment,, perhaps jeopardize patient's life because of underdosage to patient's the negative effect of treatment agency.Perhaps when packing, cause whole production line to be forced to suspend because of the moisture absorption, seriously reduce the throughput of equipment, increase the hidden danger of work time cost etc. greatly.
The injection of ceftizoxime sodium crystalline hydrate thing, its preparation method is:
The preparation of aseptic subpackaged powder pin: use aseptic raw material to carry out packing according to common convention.
The preparation method of freeze-dried powder is: get the ceftizoxime sodium crystalline hydrate thing, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, stablizer, water for injection, stir and make dissolving, if need, available pharmaceutically acceptable acid-alkali accommodation pH is 6.0～8.0, adds activated carbon 0.005～0.5% (W/V) and stirs 15～45min, filters, moisturizing, sterile filtration, by the packing of 0.5～2g/ bottle, lyophilize, tamponade gets finished product.
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be generalized Lewis acid or alkali, can contain one or several, can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, the Citric Acid pharmaceutical salts, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, multi-hydroxy carboxy acid and pharmaceutical salts are as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, in the glucoheptonic acid etc. one or several.
Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and salt, thiolactic acid and salt, thio-2 acid and salt, phenol compound, as gallic acid and salt, coffic acid, caffeiate, forulic acid, ferulate, di-t-butyl Pyrogentisinic Acid, 2,5-resorcylic acid, 2,5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Xitix and ascorbate salt, saccharosonic acid and erythorbate, niacinamide, tartrate, nitrate, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, as in EDTA disodium, EDTA four sodium, N-two (2-hydroxyethyl) glycine etc. one or several.
Source and the degerming mode of reducing phlegm and internal heat can be the gac that adds dosing amount 0.005～3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process, that ultra-fine filter can be selected for use is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc., preferred rolling and tubular fibre formula ultra-fine filter, it is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopt the ultra-filtration membrane of holding back relative molecular mass 4000～30000 to remove the residue thermal source, the ultra-filtration membrane of preferred relative molecular mass 6000～30000 again.
Ceftizoxime sodium crystalline hydrate thing of the present invention is applicable to; Be used for preparing application to the medicine of treatment of diseases such as meningitis due to respiratory system, liver and gall, face, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenzae of the human or animal due to Gram-positive or the negative bacteria sensitive organism and simple property gonorrhoea or prevention.
The consumption usage: generally speaking, for the ceftizoxime sodium crystalline hydrate thing: 1. adult's usual amounts: a 1～2g, per 8～12 hours 1 time; Severe infections person's dosage can increase to 3～4g one time, per 8 hours 1 time.During treatment non-complex urinary tract infections, a 0.5g, per 12 hours 1 time.2.6 individual month and baby more than 6 months and usual pediatric dose: by 50mg/kg of body weight, per 6～8 hours 1 time.3. kidney function damage person: the patient of kidney function damage needs to adjust dosage according to its degree of damage.Available water for injection, sodium chloride injection, the slowly intravenous injection of 5% glucose injection dissolving back also can be added in 10% glucose injection, electrolyte injection or amino acid injection iv drip 30 minutes～2 hours.
Description of drawings
Fig. 1 is the thermogram spectrum of ceftizoxime sodium 1.75 hydrates.
Hot analytical test condition: the Setsys of Setaram company 16, about sample size 5mg, heat-up rate: 10K/min, N
2Flow velocity: 50ml/min, temperature: about room temperature～400 ℃.
Embodiment
The preparation of embodiment 1 ceftizoxime sodium 1.75 hydrates adds ceftizoxime acid 10g in the 50ml triangular flask, water 20ml, stirring makes into suspension, drips triethylamine 4ml, stirring and dissolving down at 5 ℃, add gac 0.1g, stirred suction filtration, washing 30 minutes, suction filtration, drip 20ml Sodium isooctanoate and alcohol mixed solution (containing Sodium isooctanoate 6.5g) under 5 ℃ in filtrate, stir, Glacial acetic acid is regulated about pH to 7.0, slowly drip acetone 50ml and ethanol 150ml mixing solutions, place below 5 ℃, solid is fully separated out, suction filtration, small amount of ethanol is washed 3 times, suction filtration, the gained solid is placed below 5 ℃ with water-ethanol-acetone mixed solvent recrystallization, crystallization is fully separated out, suction filtration about 40 ℃ of vacuum-drying 4h, gets off-white color crystallization 5.8g, X powder diffraction: measuring in 3-80 ° of scope has a plurality of obvious characteristics peak, fusing point: 205 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct), HPLC: purity 99%; It is 7.26% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 7.1%, and this and sample contain result's (theoretical value 7.22%) of 1.75 crystal water in limit of error, ultimate analysis theoretical value: C 35.74%, H 3.58%, and N 16.03%, S 14.68%, Na5.26%; Measured value: C 35.68%, H 3.63%, and N 16.11%, and S 14.76%, Na5.34%.
The preparation of embodiment 2 ceftizoxime sodium 1.75 hydrates adds ceftizoxime acid 20g in the 250ml triangular flask, water 50ml stirs and makes into suspension, at 5 ℃ of aqueous solution 20ml that drip anhydrous sodium carbonate 2.9g down, stirring makes molten, add gac 0.2g, stirred suction filtration 30 minutes, washing, suction filtration is regulated about pH to 7.0 with glacial acetic acid, slowly drips acetone 100ml and ethanol 250ml, place below 5 ℃, solid is fully separated out, suction filtration, small amount of ethanol is washed 3 times, suction filtration, gained solid water, ethanol, Virahol, isopropyl ether is that recrystallisation solvent carries out recrystallization, places below 5 ℃, and crystallization is fully separated out, suction filtration, about 40 ℃ of vacuum-drying 4h, get off-white color crystallization 14.1g, fusing point: 204 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: purity 99.0%; It is 7.16% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 7.21%, and this and sample contain result's (theoretical value 7.22%) of 1.75 crystal water in limit of error, ultimate analysis theoretical value: C 35.74%, H 3.58%, and N 16.03%, S 14.68%, Na5.26%; Measured value: C 35.63%, H 3.65%, and N 16.08%, and S 14.61%, Na5.21%.
Embodiment 3 gets ceftizoxime sodium hydrate 100g, and stirring makes molten, with N.F,USP MANNITOL 20g, EDTA disodium 0.05g adds about injection water 400～500ml, and stirring makes molten, regulating pH with citric acid about 1-5M and disodium phosphate soln is 6.5～7.5, add activated carbon 0.01～0.5% (W/V) and stir 15-30min, filter, with 0.22 micron filtering with microporous membrane, press 0.5g/ bottle or the packing of 1g/ bottle, vacuum lyophilization, tamponade gets finished product.
Embodiment 4 gets aseptic ceftizoxime sodium hydrate 10Kg, presses 0.5g/ bottle or 0.75g/ bottle or 1g/ bottle or the packing of 2g/ bottle with aseptic subpackaged technology, jumps a queue, tamponade, rolls aluminium lid and gets finished product.
Embodiment 6 ceftizoxime sodium, 1.75 crystalline hydrate sheets or capsule (50mg/ grain)
Prescription: ceftizoxime sodium 1.75 crystalline hydrate 50g
Microcrystalline Cellulose 145g
Sodium starch glycolate 5g
5%PVP K30 (50% aqueous ethanolic solution) is an amount of
Magnesium Stearate 2g
Ceftizoxime sodium 1.75 crystalline hydrates, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution with 5%PVP 30 is tackiness agent system softwood in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet or can capsule.
Embodiment 7 ceftizoxime sodium, 1.75 crystalline hydrate buccal tablets (100mg/ sheet)
Prescription: ceftizoxime sodium 1.75 crystalline hydrate 100g
N.F,USP MANNITOL 180g
Low-substituted hydroxypropyl cellulose 20g
5%PVPK30 (50% aqueous ethanolic solution) is an amount of
Magnesium Stearate 2g
Ceftizoxime sodium 1.75 crystalline hydrates, N.F,USP MANNITOL, low-substituted hydroxypropyl cellulose are crossed 100 mesh sieves, and mixing is tackiness agent system softwood in right amount with 50% the aqueous ethanolic solution of 5%PVP 30, cross the 18-24 mesh sieve and granulate, drying is excessively behind the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet.
Be appreciated that from this professional angle the variation of a lot of details is possible, therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to the foregoing description.
Claims (7)
1. ceftizoxime sodium crystalline hydrate thing, it is characterized in that: molecular formula is C
13H
12N
5NaO
5S
2NH
2O, n=1.5～1.85.
2. ceftizoxime sodium crystalline hydrate thing according to claim 1 is characterized in that: be ceftizoxime sodium crystallization 1.75 hydrates.
3. ceftizoxime sodium crystalline hydrate thing according to claim 1 is characterized in that: be ceftizoxime sodium crystallization 1.5 hydrates.
4. the preparation method of ceftizoxime sodium crystalline hydrate thing according to claim 1 is characterized in that: its preparation method comprises:
Method A. is in reaction vessel, add ceftizoxime acid, add water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), in the acetonitrile one or more, stir, 10 ℃ of low molecular amine that drip C1-C12 down, stirring and dissolving, add gac 0.1g, stirred 30 minutes, suction filtration, washing, filter, in filtrate, drip yellow soda ash under 10 ℃, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, one or more of Sodium isooctanoate and water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), the low molecule ketone of C3-C8, the solution of one or more in the lower halogenated hydrocarbon of C1-C6, stirring reaction 0.5-3 hour, with about mineral acid or organic acid or its solution adjusting pH to 7.0, slowly drip the low mass molecule alcohol of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C8, in the lower member ester of C2-C8 one or more, place below 10 ℃, solid is fully separated out, suction filtration, the low mass molecule alcohol of a small amount of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6 is washed 1-3 time, filter, the low mass molecule alcohol of gained solid water and C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6, one or more solvent recrystallization one or many in the lower halogenated hydrocarbon of C1-C6, place below 10 ℃, crystallization is fully separated out, filter, drying gets the ceftizoxime sodium crystalline hydrate thing;
Perhaps method B. is in reaction vessel, add ceftizoxime acid, add water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), in the acetonitrile one or more, stir, under 10 ℃, in filtrate, drip yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, one or more of Sodium isooctanoate and water, the low mass molecule alcohol of C1-C6, tetrahydrofuran (THF), the solution of one or more in the low molecule ketone of C3-C8, stirring reaction 0.5-3 hour, with about mineral acid or organic acid or its solution adjusting pH to 7.0, slowly drip the low mass molecule alcohol of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6, the lower member ester of C2-C8, in the lower halogenated hydrocarbon of C1-C6 one or more, place below 10 ℃, solid is fully separated out, filter, the low mass molecule alcohol of a small amount of C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C6 is washed 1-3 time, filter, the low mass molecule alcohol of gained solid water and C1-C6, the rudimentary ether of C2-C8, the low molecule ketone of C3-C8, in the lower halogenated hydrocarbon of C1-C6 one or more carry out the one or many recrystallization for recrystallisation solvent, filter the dry ceftizoxime sodium crystalline hydrate thing that gets.
5. ceftizoxime sodium crystalline hydrate thing purposes according to claim 1 is characterized in that: be used to prepare solid preparation, injection, wherein injection comprises injection freeze-dried powder, aseptic subpackaged powder injection, tablet, capsule, granule.
6. ceftizoxime sodium crystalline hydrate thing purposes according to claim 1 is characterized in that: be used to prepare the ceftizoxime sodium anhydride.
7. ceftizoxime sodium crystalline hydrate thing purposes according to claim 1 is characterized in that: be used for preparing the application to the medicine of treatment of diseases such as meningitis due to respiratory system, liver and gall, face, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenzae of the human or animal due to Gram-positive or the negative bacteria sensitive organism and simple property gonorrhoea or prevention.
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| CN201010127964A CN101781316A (en) | 2010-03-17 | 2010-03-17 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| PCT/CN2011/071903 WO2011113361A1 (en) | 2010-03-17 | 2011-03-17 | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof |
| CN2011100655137A CN102180889A (en) | 2010-03-17 | 2011-03-17 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
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| CN2011100655137A Pending CN102180889A (en) | 2010-03-17 | 2011-03-17 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
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Cited By (7)
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| CN102180889A (en) * | 2010-03-17 | 2011-09-14 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN104327099A (en) * | 2014-09-29 | 2015-02-04 | 联合康兴（北京）医药科技有限公司 | Cefoperazone sodium compound entity, composition and application |
| CN109160921A (en) * | 2017-07-26 | 2019-01-08 | 王秀香 | A kind of 1/2 water ceftizoxime sodium compound |
| CN109160920A (en) * | 2017-07-20 | 2019-01-08 | 海南美大制药有限公司 | An a kind of water ceftizoxime sodium compound |
| CN109553626A (en) * | 2018-12-29 | 2019-04-02 | 山东罗欣药业集团股份有限公司 | A kind of refining methd of ceftizoxime sodium |
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| CN103044450B (en) * | 2013-01-05 | 2013-11-20 | 黄金秀 | Ceftizoxime sodium compound and preparation method and drug composition of ceftizoxime sodium compound |
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| WO2022266330A1 (en) * | 2021-06-16 | 2022-12-22 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Compounds that synergize with copper to kill streptococcus pneumoniae |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1712008A (en) * | 2004-06-14 | 2005-12-28 | 天津新丰制药有限公司 | Ceftizoxime sodium compound preparation |
| CN101348492B (en) * | 2008-09-02 | 2011-07-27 | 海南数尔药物研究有限公司 | Ceftizoxime sodium and preparation thereof |
| CN101781316A (en) * | 2010-03-17 | 2010-07-21 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
-
2010
- 2010-03-17 CN CN201010127964A patent/CN101781316A/en active Pending
-
2011
- 2011-03-17 CN CN2011100655137A patent/CN102180889A/en active Pending
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180889A (en) * | 2010-03-17 | 2011-09-14 | 刘力 | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof |
| WO2011113361A1 (en) * | 2010-03-17 | 2011-09-22 | Liu Li | Ceftizoxime sodium crystalline hydrate, preparation methods and uses thereof |
| CN104327099A (en) * | 2014-09-29 | 2015-02-04 | 联合康兴（北京）医药科技有限公司 | Cefoperazone sodium compound entity, composition and application |
| CN104327100A (en) * | 2014-09-30 | 2015-02-04 | 华北制药河北华民药业有限责任公司 | Preparation technology of high-purity flomoxef sodium |
| CN109160920A (en) * | 2017-07-20 | 2019-01-08 | 海南美大制药有限公司 | An a kind of water ceftizoxime sodium compound |
| CN109160921A (en) * | 2017-07-26 | 2019-01-08 | 王秀香 | A kind of 1/2 water ceftizoxime sodium compound |
| CN109553626A (en) * | 2018-12-29 | 2019-04-02 | 山东罗欣药业集团股份有限公司 | A kind of refining methd of ceftizoxime sodium |
| CN114113359A (en) * | 2021-05-07 | 2022-03-01 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
| CN114113359B (en) * | 2021-05-07 | 2024-02-20 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011113361A1 (en) | 2011-09-22 |
| CN102180889A (en) | 2011-09-14 |
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