23 results about "Avibactam sodium" patented technology

The invention provides a method for preparing amorphous avibactam sodium by an anti-solvent method, which comprises the following steps: dropwise adding a solution of sodium isooctoate into a solution of avibactam tetrabutyl ammonium salt, then concentrating, quickly pouring the concentrated solution into an anti-solvent system at one time, and quickly separating out an amorphous solid. The amorphous avibactam sodium is prepared through anti-solvent precipitation, the process is stable and controllable, and the prepared product is high in purity and yield and can be stably stored; the method is simple in steps, and the solvent is a common solvent, so that the production cost is greatly reduced; generation of a large amount of acidic and alkaline wastewater is greatly reduced, and pollution to the environment is reduced; and the method has the advantages of short production period and low energy consumption, meets the requirements of large-scale production, and provides a feasible scheme for industrial production of the avibactam sodium amorphous product.

The application relates to a compound cefoperazone and avibactam powder injection and a preparation method thereof. The compound powder injection is obtained by uniformly mixing cefoperazone hydrochloride and avibactam sodium, tabletting and crushing. When the powder injection is prepared into an injection solution, the powder injection is easy to disperse and dissolve, is convenient to use, ensures the content of cefoperazone, is not prone to produce beta-lactamase bacterial drug resistance, and has a good market application prospect.

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of avibactam sodium and a preparation method thereof. The pharmaceutical composition comprises the following components: avibactam sodium, 2-(5-(2-oxoazetidin-1-yl)thiophene-2-yl)benzo[d]thiazole-6-carboxylic acid; the mass ratio of the avibactam sodium and the 2-(5-(2-oxoazetidin-1-yl)thiophene-2-yl)benzo[d]thiazole-6-carboxylic acid is 1:(2-3). The pharmaceutical composition has a significant synergistic antibacterial effect.

The present invention belongs to the technical field of preparation of ceftazidime avibactam sodium, and in particular to a kind of ceftazidime avibactam sodium for injection and a preparation method thereof. The preparation method of ceftazidime avibactam sodium for injection provided by the present invention comprises the following steps: avibactam sodium and ethanol aqueous solution are mixed and stirred to obtain a mixed solution, porous sodium carbonate is then added to the mixed solution to continue stirring, and the mixed material is vacuum heated after the stirring is completed, and crushed after the vacuum heating is completed to obtain a mixed powder, wherein the mass content of ethanol in the ethanol aqueous solution is 96 99%; the mixed powder and ceftazidime are mixed to obtain a mixed material; the mixed material is aseptically packaged, nitrogen-filled and rolled to obtain the ceftazidime avibactam sodium for injection. The preparation method provided by the present invention can effectively improve the stability of ceftazidime avibactam sodium.

The invention provides a method for detecting a residual solvent in avibactam sodium. According to the method, a gas chromatographic method is adopted, a capillary column with 6% cyanopropyl phenyl-94% dimethyl polysiloxane as a stationary phase is adopted, a carrier gas is nitrogen, a detector is a hydrogen flame ionization detector, and a sample introduction mode is headspace sample introduction. The method can be used for simultaneously detecting 12 residual solvents in avibactam sodium. The method has the advantages of strong specificity, high sensitivity, good repeatability, high accuracy and good durability, and is suitable for detecting the content of the residual solvent in avibactam sodium.

The invention relates to an industrially useful and pharmaceutically stable avibactam sodium monohydrate and a preparation method thereof. The compounds of the invention can be used as beta-lactamase inhibitors.

The invention belongs to the technical field of chemical synthesis of medicines, and particularly relates to a preparation method of avibactam sodium. According to the method, (2S, 5R)-trans-5-hydroxypiperidine-2-formic acid is taken as a starting raw material, hydroxyl in the (2S, 5R)-trans-5-hydroxypiperidine-2-formic acid is efficiently and selectively converted into hydroximido by adopting an electrochemical method, the condition is mild, the method is environment-friendly, and the pollution problem caused by using an equivalent metal reducing agent or an oxidizing agent in a traditional chemical method is avoided; after O-benzyl oxime ether is constructed, a (2S, 5R) absolute configuration required by avibactam sodium is constructed and maintained through stereoselective reduction and efficient amination. From (2S, 5R)-trans-5-hydroxypiperidine-2-formic acid to avibactam sodium, the route design is ingenious, the steps are shorter, and a novel, simple and efficient synthesis route is provided for synthesis of avibactam sodium.

The invention discloses a freeze-dried preparation of aztreonam avibactam sodium for injection and a preparation method thereof, wherein the preparation method comprises freeze-drying an aqueous solution of aztreonam avibactam sodium, wherein the freeze-drying comprises sequentially pre-freeze-thaw, secondary freezing, sublimation drying and analytical drying; the pre-freeze-thaw comprises: cooling the aqueous solution of aztreonam avibactam sodium to ‑30-‑50° C., keeping for 2-6 hours, then heating to ‑10-0° C., keeping for 1-10 hours; the secondary freezing comprises: cooling to ‑30-‑50° C., keeping for 2-6 hours. In the present invention, the pre-freeze-thaw is firstly thawed and then re-frozen again during the freeze-drying process, so that the moisture content in the final freeze-dried product can be reduced to less than 1.0%, and the prepared freeze-dried preparation of aztreonam avibactam sodium for injection has low moisture and good stability.

The invention discloses a method for detecting the content of avibactam sodium. The method adopts high performance liquid chromatography to analyze the avibactam sodium of the product, separates the avibactam sodium from impurities, effectively detects the content of the avibactam sodium, reduces the detection difficulty, has more accurate detection results, shortens the time consumption, and has higher detection sensitivity.

The invention discloses a chemical synthesis method of avibactam sodium, which comprises the following steps: with (2S)-5-[(benzyloxy) imino] piperidine-2-carboxylic acid ethyl ester as a starting material, carrying out selective reduction under the action of a hand-shaped inducer and a reducing agent to construct 5-site chiral carbon, and carrying out oxalic acid resolution to obtain high-purity oxalate, and then carrying out five-step reaction, namely intramolecular ureization, acylase catalytic hydrolysis amidation, debenzylsulfonic acid esterification salification and sodium ion exchange, so as to obtain the avibactam sodium. According to the method, the chiral inducer is adopted to induce selective reduction, and the acylase catalytic ammonolysis process is optimized, so that the content of isomer impurities in the product is remarkably reduced, and the purity and the overall yield of the product are improved. Wherein the acylase catalytic ammonolysis reaction conditions are mild, and the process safety risk is greatly reduced while the energy consumption is reduced.

The invention discloses a key intermediate of avibactam sodium and a preparation method thereof, comprising: dissolving a compound of formula 8 in a non-protonic polar organic solvent, and reacting with a carboxyl activator and an ammonia source in a one-pot manner in the presence of an organic base to obtain a key intermediate of avibactam sodium as shown in formula 2; the reaction mechanism is: the compound of formula 8 reacts with a carboxyl activator to obtain a compound of formula 9; the compound of formula 9 reacts with an ammonia source to generate a compound of formula 2; wherein LG in the compound of formula 9 is tert-butyloxycarbonyloxy, n-butyloxycarbonyloxy, isobutyloxycarbonyloxy, n-propyloxycarbonyloxy, isopropyloxycarbonyloxy, ethoxycarbonyloxy, methoxycarbonyloxy or benzyloxycarbonyloxy. The preparation method of the invention is simple to operate, has few by-products, and has high product yield and purity, and is suitable for industrial production.

This invention discloses an intermediate product of ceftazidime and avibactam sodium for injection and its preparation method, relating to the field of pharmaceutical manufacturing technology. It solves the problems of high energy consumption and poor uniformity, stability, and controllability of sterile powder mixing during large-scale production. The preparation method of the intermediate product includes adding ceftazidime and avibactam sodium to a mixer at a certain weight ratio, controlling the mixing speed of the mixer at 13-17 rpm and the mixing time at 20-60 min. By precisely controlling the combination of key process parameters—mixing speed and time—this invention effectively overcomes the problem of uneven mixing caused by the difference in physical properties of the two powders, ensuring that the RSD of the mixing uniformity is stably controlled within a high standard range of ≤5.0%.

A purification method for an Avibactam sodium intermediate and an Avibactam sodium intermediate. The purification method comprises: dissolving an Avibactam sodium intermediate containing an isomer impurity compound into an acetone solution; then adding an ethyl acetate solution into the obtained mixed solution, and performing stirring to obtain a precipitate; and finally, filtering the precipitate, washing the precipitate with an ethyl acetate solution, and then performing vacuum drying treatment to obtain a purified Avibactam sodium intermediate. According to the method, the content of the isomer impurity compound in the Avibactam sodium intermediate can be effectively reduced; in addition, by removing the isomer impurity compound in the Avibactam sodium intermediate or controlling the content of said isomer impurity compound, finally, isomer impurities in Avibactam sodium can be well controlled.

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of avibactam sodium and a preparation method of the pharmaceutical composition. The medicine composition is prepared from the following components: avibactam sodium and 2-(5-(2-oxo azetidine-1-yl) thiophene-2-yl) benzo [d] thiazole-6-carboxylic acid, and the medicine composition is prepared from the following components: the avibactam sodium and the 2-(5-(2-oxo azetidine-1-yl) The mass ratio of the avibactam sodium to the 2-(5-(2-oxo azetidine-1-yl) thiophene-2-yl) benzo [d] thiazole-6-carboxylic acid is 1 to (2 to 3). The pharmaceutical composition has a remarkable synergistic antibacterial effect.

The present invention relates to the field of preparation of compound powder injection, and specifically discloses a preparation process of ceftazidime avibactam sodium for injection, comprising the following steps: S1, ceftazidime and avibactam sodium are refined respectively; S11, dissolving: ceftazidime and avibactam sodium are dissolved respectively to obtain ceftazidime solution and avibactam sodium solution; S12, impurity removal; S13, crystallization: vitamin E and sodium sulfate are first added to the solution and stirred evenly, and then the temperature is lowered for crystallization; S14, powderization: the solution after crystallization is filtered and dried in sequence to obtain ceftazidime powder and avibactam sodium powder; S2, the ceftazidime obtained in step S1 is mixed evenly with sodium carbonate in a prescribed ratio; S3, the avibactam sodium obtained in step S1 and the ceftazidime containing sodium carbonate obtained in step S2 are mixed in a prescribed ratio. The present invention can improve the uniformity of the mixing of ceftazidime and avibactam sodium, and can improve the stability of the drug.

The invention discloses a method for preparing crystal form B avibactam sodium by reaction crystallization, comprising: step 1, adding avibactam tetrabutylammonium salt into an ethanol aqueous solution, stirring and dissolving to obtain an avibactam tetrabutylammonium salt solution; step 2, adding the ethanol aqueous solution into sodium isooctanoate, stirring and dissolving to obtain a sodium isooctanoate solution; step 3, dripping 2% to 20% of the avibactam tetrabutylammonium salt solution prepared in step 1 into the sodium isooctanoate solution, stirring and growing crystals, and continuously dripping the remaining amount of the avibactam tetrabutylammonium salt solution, stirring and crystallizing.

The present application discloses a method for refining an avibactam sodium intermediate 1, which comprises the step of refining a crude avibactam sodium intermediate 1 in a good solvent dichloromethane and a poor solvent methyl tert-butyl ether system to obtain a high-purity avibactam sodium intermediate 1. The refining method provided in the present application can effectively reduce the content of isomeric impurities A and open-loop impurities B, and improve the purity. The total purity of the refined avibactam sodium intermediate 1 is greater than 99.9%, the isomeric impurities A and the open-loop impurities B are less than 0.05%, and the other individual impurities are less than 0.10%. The reagents are conventionally available, the operation is simple and safe, and it is very suitable for industrial scale-up under conventional production conditions.

The invention relates to the technical field of pharmaceutical preparations, and discloses ceftazidime avibactam sodium for injection, which comprises the following components: 5-15 parts of ceftazidime, 5-15 parts of avibactam sodium, 10-20 parts of a nonionic surfactant, 5-15 parts of a polar solvent, 70-85 parts of deionized water and 0.5-5 parts of a protective additive. The invention also provides a preparation process of the ceftazidime avibactam sodium for injection. The preparation process comprises the following steps: mixing a nonionic surfactant and deionized water, and homogenizing to form a microemulsion system; gradually adding ethanol into the microemulsion system to enhance the stability of the system; active esters of ceftazidime and avibactam sodium are added; detecting the reaction progress by an online monitoring technology; unreacted raw materials and by-products are removed by adopting a membrane separation technology. According to the ceftazidime avibactam sodium for injection, innovative polyethylene glycol is introduced as a protective additive, so that the solubility and the stability of the ceftazidime avibactam sodium for injection are effectively improved.

The application specifically relates to a preparation method of ceftazidime and avibactam sodium for injection. The particle size of ceftazidime, avibactam sodium and sodium carbonate is controlled, specifically, the particle size of the ceftazidime raw material is controlled to be 120 mu m-140 mu m, the particle size of the sodium carbonate raw material is controlled to be 90 mu m-110 mu m, and the particle size of the avibactam sodium raw material is controlled to be 70 mu m-90 mu m, so that a remarkable mixing uniformity effect can be achieved, the content uniformity is remarkably improved, and the stability is also remarkably improved.

The invention relates to a kit for rapidly identifying the enzyme type of carbapenemase of bacteremia of enterobacter sp. Capable of producing carbapenemase and application of the kit, and relates to the technical field of biological detection. The kit comprises imipenem and any one of avibactam sodium, revobactam and 2, 6-dipicolinic acid, and is characterized in that the kit comprises imipenem and any one of avibactam sodium, revobactam and 2, 6-dipicolinic acid. Compared with the prior art, the method has the advantages of high speed, high accuracy, few interference factors, low cost (less than 1 dollar) and the like when being used for detecting the carbapenemase enzyme type of the carbapenemase-producing enterobacter bacteremia, the survival rate of a patient suffering from the carbapenemase-producing enterobacter bacteremia can be remarkably increased, the hospitalization time is shortened, and the method is suitable for popularization and application. Hospitalization cost is reduced, and great economic and social benefits are achieved.

The invention discloses a detection method of avibactam sodium related substances, and relates to the technical field of medicine detection. According to the method, a high performance liquid chromatography method is adopted for detection, and chromatographic conditions are as follows: a C18 column is adopted as a chromatographic column; a mobile phase A is a 0.15 mol / L ammonium dihydrogen phosphate solution, a mobile phase B is 0.15 mol / L ammonium dihydrogen phosphate solution-acetonitrile (70: 30), and gradient elution is carried out; the sample injection volume is 5-20 [mu] l, the flow velocity is 0.8 ml / min, and the column temperature is 15-25 DEG C. The method for detecting the avibactam sodium related substances can effectively detect the avibactam sodium related substances, has the advantages of good specificity, high sensitivity, high accuracy and strong interference resistance, and can meet the avibactam sodium detection requirements.

The invention relates to the field of pharmaceutical preparations, and discloses a compound antibacterial preparation containing avibactam sodium and a preparation method thereof.The preparation is of a multi-layer structure, an inner layer is triple crosslinking hydrogel, and avibactam sodium included by beta-cyclodextrin and gelatin-Arabic gum microspheroidized meropenem are entrapped by the triple crosslinking hydrogel; according to the LPS-recognition-peptide-containing pH-sensitive hydrogel hydrogel, the interface barrier layer and the LPS-recognition-peptide-containing pH-sensitive outer hydrogel are coated outside, the structure effectively protects drugs, realizes continuous synergistic release, can respond to acidic pH of an infected microenvironment to accelerate release, and targets gram-negative bacteria through the LPS recognition peptide, so that the local drug concentration and the synergistic antibacterial efficacy are remarkably improved, and the drug resistance risk is reduced.

The invention discloses an aztreonam and avibactam sodium freeze-dried preparation for injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. Comprising the following steps: pre-cooling a freeze dryer plate layer to 5 DEG C; the method comprises the following steps: filling a freeze-drying solution containing aztreonam and avibactam sodium into a penicillin bottle, and putting the penicillin bottle filled with the freeze-drying solution into a box; the temperature is reduced to-35 DEG C to-50 DEG C within 2-6 hours, and the temperature is kept for 2-6 hours for freezing; the vacuum degree is reduced to 0.0-0.5 mbar, the temperature is increased to-25 DEG C to-5 DEG C within 2-8 hours, and heat preservation is conducted for 50-80 hours; raising the temperature to 20-30 DEG C in 2-8 hours, vacuumizing for 0.0-0.4 mbar, and keeping for 2-6 hours, raising the temperature to 40-50 DEG C in 0.5-2 hours, vacuumizing for 0.0-0.4 mbar, and keeping for 4-8 hours, and raising the temperature to 40-50 DEG C in 0.5-2 hours, vacuumizing for 0.0-0.4 mbar, and keeping for 4-8 hours; the concentration of aztreonam in the freeze-drying solution is 1.5 g / mL, the concentration of avibactam sodium is 0.5 g / mL, and the concentration of L-arginine in the solution is 0.09-0.135 g / mL. Through a conventional freeze-drying process, the prepared freeze-dried product has few appearance defects, the water content is lower than 1%, and the freeze-dried product has good re-dissolvability, does not have dendritic crystals during re-dissolution and has good stability and safety.