WO2011113361A1 - Hydrate cristallin de sodium de ceftizoxime, procédés de préparation et leurs utilisations - Google Patents

Hydrate cristallin de sodium de ceftizoxime, procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2011113361A1
WO2011113361A1 PCT/CN2011/071903 CN2011071903W WO2011113361A1 WO 2011113361 A1 WO2011113361 A1 WO 2011113361A1 CN 2011071903 W CN2011071903 W CN 2011071903W WO 2011113361 A1 WO2011113361 A1 WO 2011113361A1
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Prior art keywords
sodium
low molecular
hydrate
ceftizoxime
acid
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PCT/CN2011/071903
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English (en)
Chinese (zh)
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刘力
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Liu Li
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—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, cefaclor, or cephalexine
    • A61K31/546—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, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2

Definitions

  • the present invention relates to the field of medical technology, and in particular to providing an antibacterial drug ceftizoxime sodium crystal hydrate, a preparation method thereof and use thereof. Background technique
  • the cephalosporin sodium containing crystal water obtained by the present invention is surprisingly that the cephalosporin sodium containing crystal water has a wettability farther than the ceftizoxime sodium containing the crystal water, and the cephalosporin sodium ratio containing the crystal water It is more stable in the absence of crystal water, easy to store and transport, and easy to make into preparations. Further, the deliquescent of the anhydrate causes the air to be prevented from blocking or the like during the treatment, and the hydrate has a good slidability, thereby improving the operability of the preparation.
  • the thermal analysis (TG-DSC or TG-DTA) pattern of the hydrate of the present invention has a corresponding endothermic peak under the weightless platform, and the thermal analysis spectrum shows cephalosporin sodium crystallization hydrate
  • ceftizoxime sodium 1.82 hydrate, ceftizoxime sodium 1.75 hydrate, ceftizoxime sodium 1.5 hydrate, and the like for example, ceftizoxime sodium 1.82 hydrate, ceftizoxime sodium 1.75 hydrate, ceftizoxime sodium 1.5 hydrate, and the like.
  • the ceftizoxime sodium crystal hydrate of the present invention can be stably stored. Crystallizing ceftizoxime sodium of the present invention
  • the hydrate and anhydrate samples were subjected to the wettability test: about 5 g of the ceftizoxime sodium anhydrate and the crystalline hydrate of the present invention were placed in a surface of a dry constant weight surface, accurately weighed, 25 V, and the relative humidity was 70%, samples were taken at the test Oh and 24h, respectively, and the percentage of wet weight gain was calculated.
  • the results showed that the anhydrate has a much higher wettability than the hydrate of the present invention, and the ceftizoxime sodium crystal hydrate of the present invention can be more Stable storage, the test results are shown in Table 1.
  • cefotaxime sodium crystallization hydrate and the ceftizoxime sodium anhydrate sample were sealed in a vial for 6 months under RH 75% and 30 °C for 6 months accelerated test.
  • RH 75% and 30 °C for 6 months accelerated test Refer to the CP2010 version of ceftizoxime sodium test.
  • the preparation of the ceftizoxime sodium derivative, ceftizoxime sodium crystal hydrate comprises the following method: Method A. Adding cefotaxime acid, adding water, C1-C6 lower alcohol, C2-C8 lower ether in the reaction vessel (including diethyl ether, tetrahydrofuran, etc.), one or more of C2-C6 lower nitrile (including acetonitrile, etc.), stir, add C1-C12 lower amine at 15 °C, stir to dissolve, add activated carbon, stir 10 -40 minutes, filtered, washed, filtered, and added with sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium octanoate, sodium isooctanoate or water and C1- at 15 °C.
  • the solid is fully analyzed, suction filtration, a small amount of C1-C6-grade alcohol, C2- C8 grade ether, C3-C6 grade ketone washed 1-3 times, filtered, the obtained solid water with C1-C6 lower alcohol, C2-C8 lower ether, C3-C8 lower ketone, C1-C6
  • One or more of the lower halogenated hydrocarbons are recrystallized one or more times, placed below 15 °C, the crystals are fully analyzed, filtered, using C1-C6 low molecular alcohol, C2-C8 lower ether, C3- C8 low molecular ketone, Washing one or more of the C1-C6 lower halogenated hydrocarbons, filtering, and drying to obtain ceftizoxime sodium crystal hydrate;
  • the cefotaxime acid used in the reaction used in the first step reaction C1-C12 low molecular amine: alkali (sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium octanoate, sodium isooctanoate
  • the molar ratio can generally be 1: 0.5-1.1: 0.5-1.1
  • the ratio of one or more (volume ml) of a lower nitrile (including acetonitrile, etc.) of C2-C6 (including diethyl ether, tetrahydrofuran, etc.) is generally: 1 (g): 1.5 to 20 (ml);
  • the volume ratio of water to organic solvent used in recrystallization is generally 1: 5 ⁇ 50.
  • C2-C8 lower ether including diethyl ether, tetrahydrofuran, etc.
  • C3-C8 low molecular ketone C2-C6 lower nitrile
  • sodium carbonate is added dropwise to the filtrate at 15 ° C
  • One or several kinds of solutions stir the reaction for 0.5-3 hours, adjust the pH to 6.5-7.2 with mineral acid or organic acid or its solution, slowly add C1-C6 low molecular alcohol, C2-C8 lower ether,
  • One or more of C3-C6 low molecular ketone, C2-C8 lower ester, C1-C6 lower halogenated hydrocarbon, placed below 15 °C, solids are analyzed
  • the equivalent ratio of cefotaxime acid: a base (one of sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium octanoate, sodium isooctanoate) used in the first step reaction is about 1: 1 - 1.1 ; cefotaxime acid (wt g) used in the first step reaction with water, or a C1-C6 low molecular alcohol, or a C2-C8 lower ether (including diethyl ether, tetrahydrofuran, etc.), or C2-C6
  • the ratio of one or more of the lower nitriles (including acetonitrile, etc.) (volume ml) is generally: 1 (g): 1.5 to 20 (ml).
  • the volume ratio of water to organic solvent used in crystallization or recrystallization is generally from 1:1 to 50.
  • the crystallization or recrystallization solvent of the ceftizoxime sodium crystal hydrate is selected from the group consisting of water, acetonitrile, tetrahydrofuran, decyl alcohol, ethanol, isopropanol, etc.; lower ester of C2-C8, including butyl acetate, ethyl acetate, and citric acid Ester; etc.; diethyl ether, hydrazine ether, isopropyl ether; one or more of dichlorodecane, chloroform, etc.; ceftizoxime sodium crystal crystal or recrystallization solvent, preferably water, decyl alcohol, ethanol, isopropanol, One or more of tetrahydrofuran, ethyl acetate, diethyl ether, diisopropyl ether, dichlorodecane, and chloro
  • the ceftizoxime sodium crystal hydrate is first dissolved in water during the recrystallization, and after dissolution, it can be decolorized by using activated carbon, and then crystallized by an organic solvent defined by the present invention.
  • the ceftizoxime sodium crystal hydrate of the present invention may have different crystal forms.
  • Alcohol such as decyl alcohol, ethanol, isopropanol, etc.
  • the number of carbon atoms of lower ether or low molecular ether is defined as C2-C8, such as diethyl ether, dibutyl ether, tetrahydrofuran, etc.
  • the lower alkyl ester has a carbon number defined as C2-C8, unless otherwise specified as a lower ester of citric acid, otherwise including butyl acetate, acetic acid Ethyl ester, ethyl decanoate, etc.
  • the number of carbon atoms of the low molecular aromatic hydrocarbon is defined as C6-C12, including benzene, toluene, etc.
  • the low molecular ketone of C3-C8 is defined as a ketone of 3-8 carbon atoms, including
  • the product of the present invention may be dried at different temperatures (e.g., 20-70 ° C), drying time (0.5 hours to several days), or with other desiccants (including silica gel, phosphorus pentoxide, anhydrous chlorination).
  • the final product is dried under ambient conditions of calcium, anhydrous sodium sulfate, or the like, or by atmospheric or reduced pressure.
  • the drying temperature is preferably from 30 to 50 °C.
  • the sterile powder of the ceftizoxime sodium crystal hydrate of the present invention can be prepared in a similar manner as the commercially available injection-grade cephalosporin sterile powder.
  • the ceftizoxime sodium crystal hydrate of the present invention is used: the ceftizoxime sodium crystal hydrate of the present invention is used for preparing a solid preparation, a suppository, an injection, wherein the injection comprises a freeze-dried powder preparation for injection, and a sterile powder preparation for injection.
  • Large infusion preparation wherein the large infusion preparation comprises a double chamber, that is, a large infusion, a non-PVC solid-liquid double-chamber, a large infusion, a non-PVC multi-layer co-extruded membrane, a large infusion; a tablet, Capsules, granules, etc.; and can be used to prepare ceftizoxime sodium anhydrate.
  • the preparation of the anhydrate can be obtained by the different method of drying the crystalline hydrate of the present invention, which can be prepared at different temperatures (such as 50-100 ° C), drying time (hours to several days), or with other desiccants. (including silica gel, molecular sieve, phosphorus pentoxide, sodium hydroxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate, etc.) under ambient conditions, or with atmospheric pressure or reduced pressure
  • the final product is dried by a method in which the benzene is distilled with water and dried in combination with other drying methods described herein.
  • granules which may contain pharmaceutically acceptable fillers, such as starch, modified starch, Lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, phosphate 4, amino acid, etc.; pharmaceutically acceptable disintegrating agents, such as starch, modified starch, microcrystalline cellulose, cross-linked carboxy-based fibers , sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, surfactant (sodium lauryl sulfate, etc.); pharmaceutically acceptable wetting agents and binders, such as Starch, mercaptocellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinylpyrrolidone, alginic acid and its salts; pharmaceutically acceptable lubricants and glidants, such as
  • the crystal hydrate of the present invention is different from the deliquescent of the anhydrate in that it is isolated from air to prevent blocking or the like during the treatment, and the crystalline hydrate has good slidability, thereby improving the operability of the preparation; and making the prepared solid preparation have good Its dissolution properties make it easy to be absorbed into the blood circulation, improve bioavailability, and facilitate its rapid function. On the other hand, it prevents it from appearing in the aseptic dispensing process, which is not easy to cause clogging during dispensing due to moisture absorption, resulting in a difference in the amount of the load, resulting in insufficient dosage, resulting in product failure, or because of unqualified products.
  • ceftizoxime sodium crystal hydrate which is prepared by:
  • lyophilized powder preparations including double chambers, large infusions, non-PVC solid-liquid double chambers, large infusions, and non-PVC multi-layer co-extruded membranes, can be prepared according to conventional methods.
  • the preparation method of the lyophilized powder preparation is as follows: taking ceftizoxime sodium crystal hydrate, adding pharmaceutically acceptable lyophilized support agent or auxiliary agent, stabilizer, water for injection, stirring to dissolve, if necessary, pharmacy can be used Acceptable acid and base to adjust pH to 6.0 ⁇ 8.0, add activated carbon 0.005 ⁇ 0.5% (W / V), stir for 15 ⁇ 45min, filter, hydrate, sterile filtration, according to 0.5 ⁇ 2g / bottle, freeze-drying, pressure Plug, get the finished product.
  • the pharmaceutically acceptable pH adjusting agent may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a Lewis acid or a base in a broad sense, and may contain one or more kinds, and may be hydrochloric acid.
  • Phosphoric acid, propionic acid, acetic acid and acetate such as sodium acetate, lactic acid and lactic acid pharmaceutically acceptable salts, citric acid pharmaceutically acceptable salts, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, phosphoric acid Salt, tartaric acid and pharmaceutically acceptable salts thereof, borax, boric acid, succinic acid, caproic acid, adipic acid, fumaric acid, maleic acid, polyhydroxycarboxylic acid and pharmaceutically acceptable salts, such as glucuronic acid, One or more of gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid and the like.
  • the pharmaceutically acceptable antioxidants and stabilizers thereof may be sulfurous acid, sulfite, bisulfite, pyro-cateride, di-di-ortho-acid salt, cis-acid salt, organic straight compound straight urea , glutathione, dimercaptopropanol, thioglycolic acid and salt, thiolactic acid and salt, thiodipropionic acid and salt, phenolic compounds, such as gallic acid and salt, caffeic acid and its salts, ferulic acid and a salt thereof, di-tert-butyl-p-phenol, 2,5-dihydroxybenzoic acid and a salt thereof, salicylic acid or a salt thereof; ascorbic acid and a salt thereof, erythorbic acid and a salt thereof, nicotinamide, tartaric acid, nitrate, phosphoric acid
  • the heat removal source and the sterilization method may be an activated carbon dehydration source with a dosing amount of 0.005 to 3 %, a microporous membrane sterilization and hot pressing sterilization, or an ultrafiltration sterilization or deheating source.
  • the ultrafilter may be a flat plate type, a coil type, a tube type, a hollow fiber type or a round box type, etc., preferably a roll type and a hollow fiber type ultrafilter, and the molecular weight of the interception is 50,000 to 300,000.
  • the filter removes the remaining heat source by using an ultrafiltration membrane with a molecular weight of 4000 to 30000, preferably an ultrafiltration membrane with a molecular weight of 6000 to 30000.
  • suppository consists of ceftizoxime sodium crystal hydrate (weight ratio is generally 1-4%), and the rest is composed of suppository matrix, which may be ethanol, glycerin, glycerin gelatin, polyethyl Glycol 200 - 8000, poloxamer, petrolatum, semi-synthetic hard fatty acid fat (package) Including polyoxyl (40) stearate, propylene glycol stearate, fatty acid glycerides, etc., carbomer series (931, 934, 940, 974, etc.), Tween 60-80, etc.
  • suppository matrix which may be ethanol, glycerin, glycerin gelatin, polyethyl Glycol 200 - 8000, poloxamer, petrolatum, semi-synthetic hard fatty acid fat (package) Including polyoxyl (40) stearate, propylene glycol stearate, fatty acid glycer
  • the suppository may contain other pharmaceutically acceptable additives such as stabilizers and absorption enhancers.
  • Preparation method Mix the main drug with the substrate, heat it in a water bath, stir it, melt it, stir it to the hook, and quickly pour it into the suppository mold which has been coated with the lubricant, to slightly overflow the plug mold, and then flatten it after cooling. .
  • the ceftizoxime sodium crystal hydrate of the invention is suitable for: preparing a respiratory system of human or animal caused by Gram-positive or negative bacteria-sensitive bacteria, hepatobiliary system, facial features, urinary tract infection, abdominal infection, pelvic cavity Use in the treatment or prevention of infections, sepsis, skin and soft tissue infections, bone and joint infections, pneumococcal infection or Haemophilus influenzae caused by meningitis and simple gonorrhea.
  • the ceftizoxime sodium crystalline hydrate is used for preparing a composition with a ⁇ -lactamase inhibitor, and the ⁇ -lactamase inhibitor includes tazobactam or a pharmaceutically acceptable salt thereof or sulbactam or a pharmaceutically acceptable salt thereof or carat Retinoic acid or a pharmaceutically acceptable salt thereof, such as tazobactam sodium, tazobactam sodium hydrate, sulbactam sodium, potassium clavulanate, and the like.
  • the weight ratio of the ceftizoxime sodium crystalline hydrate and the enzyme inhibitor comprising tazobactam or a pharmaceutically acceptable salt thereof or sulbactam or a pharmaceutically acceptable salt thereof or clavulanic acid or a pharmaceutically acceptable salt thereof is 30:1 - 1 : 1.
  • the composition has a stronger antibacterial action and is used in a medicament for the treatment or prevention of human or animal diseases caused by Gram-positive or negative bacterial-sensitive bacteria.
  • Dosage Usage Under normal circumstances, for ceftizoxime sodium crystal hydrate: 1. Adult commonly used amount: once l ⁇ 2g, once every 8 ⁇ 12 hours; the dose of severe infection can be increased to 3 ⁇ 4g, every 8 1 hour. For the treatment of non-complex urinary tract infections, 0.5g once every 12 hours. 2. The usual amount of infants and children for 6 months and more: 50mg/kg by weight, once every 6 ⁇ 8 hours. 3. Patients with impaired renal function: Patients with impaired renal function should adjust the dose according to the degree of damage. It can be dissolved slowly by injection water, sodium chloride injection, 5% dextrose injection, or intravenously in 10% glucose injection, electrolyte injection or amino acid injection for 0.5 ⁇ 2 hours.
  • vaginal tablets and vaginal capsules Under normal circumstances, the amount commonly used in adults: 3 times a day, each time 0.125 ⁇ 0.5g, the use of suppositories: For children aged 1-13, generally 125-250mg / time, three times a day , adult dose of 250-500mg / time, 3-4 times a day.
  • Figure 1 is a thermogram of ceftizoxime sodium 1.75 hydrate.
  • Figure 2 is a powder X-ray diffraction pattern of ceftizoxime sodium 1.75 hydrate (Example 1).
  • Figure 3 is a nuclear magnetic resonance carbon spectrum ( 13 C - Li R) diagram of ceftizoxime sodium 1.75 hydrate.
  • Figure 4 is a powder X-ray diffraction pattern of ceftizoxime sodium 1.75 hydrate (Example 2). detailed description
  • Test conditions Setaram Setsys 16, sample volume of about 5mg, heating rate: lOK / min, N2 flow rate: 50ml / min, temperature: generally room temperature ⁇ 400 °C or so.
  • the TG-DSC map has a corresponding endothermic peak under the weightless platform, and the thermal analysis map shows the crystalline hydrate of ceftizoxime sodium, such as 1.5 hydrate, 1.75 hydrate, and the like.
  • the ceftizoxime sodium 1.75 hydrate of the present invention may have corresponding characteristics at a position including the following 2 ⁇ value within the measurement range of the diffraction angle 2 ⁇ (3-60.) as measured by powder X-ray diffractometry.
  • Value (Fig. 2) approximately 3.38, 6.27, 7.53, 8.63, 11.31, 13.17, 14.12, 16.51, 17.80, 19.32, 20.60, 22.31, 23.42, 24.52, 25.37, 26.11, 26.99, 27.77, 30.09, 31.62, 33.15, 34.90, 36.98, 38.62, 40.48, 42.01, 45.19, 50.82.
  • the ceftizoxime sodium 1.75 hydrate of the present invention may be in a position including the following 2 ⁇ value within the measurement range of the diffraction angle 2 ⁇ (3-60.) as measured by powder X-ray diffractometry. There are corresponding eigenvalues (Fig. 4) of approximately 3.10, 11.31, 13.12, 16.46, 17.80, 19.31, 20.68,
  • the ceftizoxime sodium crystal hydrate of the present invention can be stably stored.
  • the cefotaxime sodium hydrate and the anhydrate sample were subjected to the wettability test: about 5 g of the ceftizoxime sodium anhydrate and the hydrate of the present invention were placed in a surface of a dry constant weight, accurately weighed, 25°. C. The relative humidity is 70%, and the samples were taken at the test Oh and 24h, respectively, and the percentage of wet weight gain was calculated.
  • the results showed that the anhydrate has a much higher wettability than the hydrate of the present invention, and the ceftizoxime sodium of the present invention.
  • Table 1 The results of better stable storage of crystalline hydrates are shown in Table 1.
  • HPLC purity 99%, HPLC retention time is consistent with HPLC retention time of ceftizoxime reference substance; specific rotation: Take the sample of the invention, accurately weigh, dissolve with water and quantitatively dilute to make each 1
  • the solution containing 1 Omg in ml is determined according to CP2010 version (Appendix VI E), the specific rotation is +139°; the moisture content is 7.26 % by Karl Fischer method, thermal analysis: platform loss is about 7.1% (see Figure 1) This is the result of the sample containing 1.75 crystal water (theoretical value 7.22%) within the error range;
  • suction filtration washing with water, suction filtration, adjust the pH of the filtrate to 6.9 with glacial acetic acid, then slowly add 100 ml of acetone and 250 ml of ethanol, place at 5 ° C or lower, and then solidify and analyze the solids, suction filtration, wash with a small amount of ethanol 3 times, pump Filtration, the obtained solid was recrystallized from 30 ml of water, 300 ml of ethanol, 20 ml of isopropyl alcohol and 5 ml of isopropyl ether as a crystallization solvent, and allowed to stand at 5 ° C or lower to precipitate the crystals, suction filtration, a small amount of dichloromethane, and suction filtration. Drying at around 40V for about 4 hours, giving a white solid 14.1g, melting point: 204 ° C decomposition
  • HPLC purity 99.1%, its HPLC retention time is consistent with the HPLC retention time of ceftizoxime reference substance; specific rotation: take the sample of the invention, accurately weighed Dissolve in water and quantitatively dilute to make a solution containing about 10 mg per ml, determined according to CP2010 (Appendix VI E), with a specific rotation of +135.
  • the Karl Fischer method measures moisture at 6.49%, and thermal analysis: platform weight loss is about 6.32%. This is in the range of error with the sample containing 1.5 crystal water (theoretical value 6.25%), and has a corresponding weight loss platform before 142 °C.
  • HPLC purity 99.2%, its HPLC retention time is consistent with the HPLC retention time of the ceftizoxime reference; specific rotation: Take the sample of the invention, accurately weigh, dissolve and quantify in water Dilute to make a solution containing about 10mg per lml, according to the CP2010 version (Appendix VI E), the specific rotation is +138 °; the Karls-off method to determine the moisture is 6.36 %, thermal analysis: platform weight loss is about 6.20%, which is The result of the sample containing 1.5 crystal water (theoretical value 6.25%) is within the error range, and the corresponding endothermic peak (DTA) under the weightless platform before 142 °C; Elemental analysis: Theoretical value: C 36.11%, H 3.50% , N 16.20%, S 14.83%, Na5.32%; Found: C 36.05%, H 3.58%, N 16.12%, S 14.72%, Na5.22%rac Example
  • ceftizoxime sodium crystal hydrate 100g (prepared according to the method of Example 1 or 2 or 3 or 4), stir to dissolve, add 20g of mannitol, 0.05g of EDTA disodium, add about 400ml of water for injection, stir to dissolve, use 1M citric acid and disodium hydrogen phosphate solution to adjust the pH to 6.5 ⁇ 7.5, add activated carbon 0.01 ⁇ 0.5% (W / V), stir for 15-30min, filter, filter with 0.22 micron microporous membrane, according to 0.5g / Bottle or lg/bottle, vacuum freeze-drying, tamping, finished product.
  • Example 6 Preparation of Aseptic Powder Needle of Cefazodime Sodium Crystalline Hydrate of the Invention
  • Example 8 Preparation of Aseptic Powder Needle of Composition of Cefotaxime Sodium Crystalline Hydrate of the Invention Sterile ceftizoxime sodium 1.75 crystal hydrate lKg (prepared according to Example 1 or Example 2) and sterile Mix 1 kg of sulbactam sodium and dispense in a sterile dispensing process at 0.25 g/bottle or 0.5 g/bottle or 0.75 g/bottle or lg/bottle or 1.5 g/bottle, stopper, tampon, and rolled aluminum cover. Finished product.
  • Example 9 Composition of ceftizoxime sodium crystallization hydrate of the present invention Preparation of sterile powder needle Sterile ceftizoxime sodium 1.75 crystal hydrate 2Kg (prepared according to Example 1 or Example 2) and sterile Mix 1 kg of sulbactam sodium and dispense in a sterile dispensing process at 0.25 g/bottle or 0.5 g/bottle or 0.75 g/bottle or lg/bottle or 1.5 g/bottle, stopper, tampon, and rolled aluminum cover. Finished product.
  • Example 10 Preparation of Sterile Powder Needle of the Composition of Cefotaxime Sodium Crystalline Hydrate of the Invention
  • the sterile ceftizoxime sodium 1.75 crystal hydrate 8Kg prepared according to the method of Example 1 or Example 2) and sterile 1kg of tazobactam sodium was mixed and dispensed in a sterile dispensing process at 0.5625g/bottle or 1.125g/bottle or 2.25g/bottle.
  • the product was stoppered, plugged, and rolled.
  • Example 11 Preparation of Aseptic Powder Needle of Composition of Cefotaxime Sodium Crystalline Hydrate of the Invention Sterile ceftizoxime sodium 1.75 crystal hydrate 4Kg (prepared according to Example 1 or Example 2) and sterile 1kg of tazobactam sodium, mixed in 0.25g / bottle or 0.5g / bottle or 0.75g / bottle or lg / bottle or 1.5g / bottle in aseptic packaging process, stopper, plug, rolled aluminum cover Get the finished product.
  • Example 12 Preparation of Aseptic Powder Needle of the Composition of Cefotaxime Sodium Crystalline Hydrate of the Invention
  • the sterile ceftizoxime sodium 1.75 crystal hydrate 15Kg prepared according to the method of Example 1 or Example 2) and sterile Mix the potassium lkg of clavulanate and dispense in 0.4g/bottle or 0.8g/bottle or lg/bottle or 1.6g/bottle in the aseptic packaging process, stopper, press plug, and roll the aluminum cover to obtain the finished product.
  • Example 13 Ceftizoxime Sodium 1.75 Crystalline Hydrate Tablets or Capsules (250 mg/capsule)
  • ceftizoxime sodium 1.75 crystal hydrate, microcrystalline cellulose, sodium carboxymethyl starch is passed through a 100 mesh sieve, mixed, pressed into a large piece, and then the tablet is pressed into a granule of 18 - 24 mesh sieve, and hard fat is added.
  • ceftizoxime sodium 1.5 hydrate or ceftizoxime sodium 1.75 hydrate prepared according to the methods of Examples 1-4
  • magnesium stearate were sieved through a 100 mesh sieve, mixed, and filled with capsules.
  • Example 15 Ceftizoxime Sodium 1.75 Crystalline Hydrate Oral Tablets (125 mg/tablet)
  • ceftizoxime sodium 1.75 crystal hydrate 125g instant sorbitol 360g microcrystalline cellulose 20g low-substituted hydroxypropyl cellulose 10g magnesium stearate 2g ceftizoxime sodium 1.75 crystal hydrate (according to embodiment 1 or example 2 method preparation), instant sorbitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate over 100 mesh sieve, mixed, pressed into large pieces, and then pressed into a 18 - 24 mesh sieve Granules, tableted.
  • Example 16 Suppositories of ceftizoxime sodium crystal hydrate (125 mg/capsule)
  • Ceftizoxime sodium 1.75 Crystalline hydrate 12.5g (100 capsules) Stearic acid polyoxyl (40) fat 180g
  • ceftizoxime sodium crystal hydrate prepared according to the method of Example 1 or 2 or the method of Example 3
  • glycerin prepared according to the method of Example 1 or 2 or the method of Example 3
  • polyoxyl (40) stearate prepared according to the method of Example 1 or 2 or the method of Example 3
  • poloxamer mixed in a water bath, stirred, to be melted , stir until evenly, Pour into the mold of the suppository that has been coated with the lubricant quickly, until it is slightly spilled, and then flattened after cooling.
  • Example 17 Suppositories of ceftizoxime sodium 1.75 crystal hydrate (250 mg / granule)
  • ceftizoxime sodium crystalline hydrate of the present invention, and the preparation method and use thereof have been described by way of examples, and it is obvious to those skilled in the art that the ceftizoxime sodium crystals described herein can be crystallized without departing from the scope, spirit and scope of the present invention.
  • the hydrate, its preparation method and use are modified or combined and modified to achieve the technology of the present invention. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the spirit, scope and content of the invention.

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Abstract

L'invention concerne un hydrate cristallin de sodium de ceftizoxime, des procédés de préparation et leurs utilisations. L'hydrate cristallin de sodium de ceftizoxime présente une stabilité de stockage élevée et est approprié pour préparer des médicaments pour traiter ou prévenir des maladies ou des infections du système respiratoire, du système hépatobiliaire, des cinq organes des sens, des voies urinaires, et les infections intra-abdominales, les infections pelviennes, l'ichorrhémie, les infections des tissus mous de la peau, les infections des os et des articulations des humains et des animaux causées par des bactéries à Gram positif ou à Gram négatif, la méningite causée par Streptococcus pneumoniae ou Haemophilus influenzae, et la gonococcie simple et analogue.
PCT/CN2011/071903 2010-03-17 2011-03-17 Hydrate cristallin de sodium de ceftizoxime, procédés de préparation et leurs utilisations WO2011113361A1 (fr)

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CN111777625A (zh) * 2020-06-05 2020-10-16 华北制药河北华民药业有限责任公司 一种注射用头孢唑肟钠的制备方法
WO2022266330A1 (fr) * 2021-06-16 2022-12-22 Arizona Board Of Regents On Behalf Of The University Of Arizona Composés qui agissent en synergie avec le cuivre pour tuer le streptococcus pneumoniae

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CN101781316A (zh) * 2010-03-17 2010-07-21 刘力 头孢唑肟钠结晶水合物及其制备方法和用途
CN103044450B (zh) * 2013-01-05 2013-11-20 黄金秀 头孢唑肟钠化合物、其制备方法及其药物组合物
CN104327099A (zh) * 2014-09-29 2015-02-04 联合康兴（北京）医药科技有限公司 头孢哌酮钠化合物实体及组合物和用途
CN104327100B (zh) * 2014-09-30 2016-09-28 华北制药河北华民药业有限责任公司 高纯度氟氧头孢钠制备工艺
CN105622635B (zh) * 2016-03-10 2017-03-15 重庆福安药业集团庆余堂制药有限公司 一种减少过敏反应的头孢唑肟钠新晶型及其制剂
CN109160920A (zh) * 2017-07-20 2019-01-08 海南美大制药有限公司 一种一水头孢唑肟钠化合物
CN109160921A (zh) * 2017-07-26 2019-01-08 王秀香 一种1/2水头孢唑肟钠化合物
CN109553626B (zh) * 2018-12-29 2021-02-26 山东罗欣药业集团股份有限公司 一种头孢唑肟钠的精制方法
CN114113359B (zh) * 2021-05-07 2024-02-20 佛山市南海北沙制药有限公司 一种7-aca衍生物的中控检测方法

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WO2022266330A1 (fr) * 2021-06-16 2022-12-22 Arizona Board Of Regents On Behalf Of The University Of Arizona Composés qui agissent en synergie avec le cuivre pour tuer le streptococcus pneumoniae

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