CN110396104B

CN110396104B - New indication of Taistin ceftazidime medicinal preparation for treating gynecological infection

Info

Publication number: CN110396104B
Application number: CN201810837208.7A
Authority: CN
Inventors: 陆亚红; 古斯塔夫·比埃纳; 艾利克斯·奈丁
Original assignee: Cefaclor Antibiotics Co ltd
Current assignee: Cefaclor Antibiotics Co ltd
Priority date: 2018-07-26
Filing date: 2018-07-26
Publication date: 2020-10-27
Anticipated expiration: 2038-07-26
Also published as: CN110396104A

Abstract

The invention provides ceftazidime and a preparation method thereof, and also provides a ceftazidime medicinal preparation and a preparation method thereof. The ceftazidime is subjected to hydrolysis, decoloration, product precipitation and post-treatment of ceftazidime tert-butyl ester to prepare the ceftazidime with less impurities and stable properties. The preparation method has high controllability of the production process and stable product quality. The ceftazidime and the medicinal preparation taking the ceftazidime as the main active ingredient can well treat gynecological infections such as endometritis, pelvic cellulitis and other female genital tract infections caused by escherichia coli.

Description

New indication of Taistin ceftazidime medicinal preparation for treating gynecological infection

Technical Field

The invention relates to ceftazidime, in particular to a preparation method of a ceftazidime medicinal preparation and a new indication.

Background

Ceftazidime, english name: ceftazidime, marketed in 1983 by glactin (Glaxo) in england, a product currently available from Brand Name: redbars Fortaz; fudaxin Fortum; recovering to new; tazidime, Tazidime. The product is a third-generation cephalosporin antibiotic, and the antibacterial action mechanism of the product is to influence the synthesis of bacterial cell walls. Similar to other cephalosporins, the product can inhibit transpeptidation of transpeptidase in the final step of cell wall synthesis, so that cross-linking can not be formed, thereby affecting cell wall synthesis and leading to bacterial lysis and death.

The ceftazidime has strong antibacterial activity and wide antibacterial spectrum, and has strong effect on gram positive bacteria or gram negative bacteria. The product has high stability to beta lactamase produced by gram-positive bacteria and gram-negative bacteria, has strong antibacterial activity to pseudomonas aeruginosa, escherichia coli, klebsiella, proteus, enterococcus, salmonella, shigella, neisseria gonorrhoeae, neisseria meningitidis, staphylococcus aureus, hemolytic streptococcus, pneumococcus, aerobacter and the like, and particularly has the strongest effect on antibiotics of the pseudomonas aeruginosa. Although ceftazidime is widely used in clinic, has good treatment effect and extremely high medical value, the indications and new application of ceftazidime are in need of further expansion.

Because ceftazidime is used by injection, a lot of adverse reactions are generated, and most common adverse reactions are anaphylactic reactions. The anaphylaxis occurs rapidly, the treatment is difficult, and serious consequences can be caused once the treatment is not timely.

Although the ceftazidime injection is an aseptic preparation, the adverse reaction is greatly reduced, but because ceftazidime remains or impurities are introduced in the processes of synthesis, purification and preparation, the stability of the ceftazidime is poor, polymers are increased, and finally the allergic reaction is caused. In addition, some impurities can cause pharmacological harm to human bodies and are not beneficial to human health.

In view of the above problems, the present inventors have conducted quality studies on ceftazidime, thereby providing a safe, effective and quality-controllable ceftazidime and a preparation thereof.

Disclosure of Invention

As a result of intensive studies to solve the above problems, the present inventors have found that ceftazidime containing less impurities and having stable properties can be obtained by hydrolyzing, decoloring, precipitating a product, and post-treating ceftazidime t-butyl ester, thereby completing the present invention.

The object of the present invention is to provide the following:

in a first aspect, the present invention provides a method for preparing ceftazidime or a composition thereof, wherein the ceftazidime is prepared by a method comprising the following steps:

step 1), hydrolyzing ceftazidime tert-butyl ester under an acidic condition;

step 2), decoloring and removing pyrogen;

step 3), separating out a product;

and 4) post-processing.

In a second aspect, the invention also provides ceftazidime or a composition thereof,

the content of ceftazidime is more than 98 percent;

wherein, impurity A

The content of (A) is not higher than 0.2%;

preferably, the first and second electrodes are formed of a metal,

impurity B

The content of (A) is not higher than 0.2%;

more preferably still, the first and second liquid crystal compositions are,

impurity C

The content of (A) is not higher than 0.2%.

In a third aspect, the invention also provides a ceftazidime preparation taking ceftazidime or a composition thereof as a main active ingredient, which is characterized in that the preparation is sterile powder injection; the composition is prepared from the following components in parts by weight:

1-10 parts of ceftazidime;

0.1-10 parts of auxiliary materials;

the auxiliary materials are pharmaceutically acceptable cosolvent and synergist; the cosolvent is preferably sodium carbonate or arginine; the synergist is preferably abamectin, sulbactam or tazobactam.

In a fourth aspect, the invention also provides the use of ceftazidime, a pharmaceutically acceptable salt or a prodrug thereof, and a preparation in the treatment and preparation of medicaments for treating gynecological infection diseases or new indications.

Drawings

Fig. 1 shows the dosing profile of ceftazidime in experimental example 9.

Fig. 2 shows the dosing profile of ceftazidime in experimental example 10.

Detailed Description

The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention.

The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

In the description of the present invention, it should be noted that the terms "first", "second", "third" and "fourth" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.

The present invention is described in detail below.

The invention provides ceftazidime or a composition thereof, wherein the structural formula of the ceftazidime is as follows:

the ceftazidime or the composition thereof is prepared by a method comprising the following steps:

synthesizing ceftazidime tert-butyl ester by using 7-amino-3- (1-picolyl) cephalosporanic acid, namely 7-APCA and ceftazidime side chain acid active ester as raw materials, hydrolyzing under an acidic condition to remove tert-butyl, and removing acid molecules under an alkaline condition to prepare ceftazidime or a composition thereof.

The preparation process is as follows:

the synthesis method of ceftazidime tert-butyl ester is not limited to any one of the prior art, and for example, the preparation process can be referred to as the patent document of 'original development quality ceftazidime and pharmaceutical preparation thereof' (application number is 201511028003.7).

In the preparation method of ceftazidime or the composition thereof, the operation of hydrolyzing and purifying the ceftazidime tert-butyl ester comprises the following steps:

step 1), hydrolyzing ceftazidime tert-butyl ester under acidic condition

Preferably, the ester bond in the t-butyl ester of ceftazidime is hydrolyzed using a hydrochloric acid solution.

Researches show that the beta-lactam mother ring structure in the ceftazidime tert-butyl ester is easy to hydrolyze, and particularly, when the temperature in a solution exceeds 35 ℃ during hydrolysis, the beta-lactam mother ring structure is easy to undergo ring-opening reaction. When the ceftazidime tert-butyl ester is dissolved in a hydrochloric acid solution for hydrolysis, heat can be released, the local temperature of the solution is too high, so that the beta-lactam mother ring structure is easily subjected to ring-opening hydrolysis, and the impurity content in the final product is increased; it may also cause an increase in the content of ceftazidime polymer in the product, resulting in a reduction in safety.

Preferably, the hydrolysis reaction of ceftazidime tert-butyl ester is carried out by using a hydrochloric acid solution at the controlled temperature of 5-10 ℃, so that the temperature of the reaction system is still low after the hydrolysis reaction is exothermic, and the stability of the mother ring structure can be well maintained.

The hydrolysis reaction of the ceftazidime tert-butyl ester is preferably carried out in a reaction kettle, so that the industrial production and the stability among different batches are facilitated.

Studies have found that delta in ceftazidime under acidic conditions₂The alkene structure is easier to isomerize into delta₃Alkene structure, i.e. production of ceftazidime delta₃An alkene structural isomer impurity A having the following structural formula:

represents a chiral carbon as an epimer.

In order to improve the product quality and reduce the content of impurity A, the hydrochloric acid concentration and the hydrolysis process need to be fully researched and controlled in the process of hydrolyzing the ceftazidime tert-butyl ester.

Preferably, 6 to 12mol/L hydrochloric acid solution, preferably 6 to 10mol/L hydrochloric acid solution is added into the reaction system; after the temperature is constant, the ceftazidime tert-butyl ester is placed into a reaction kettle in several times under stirring, so that the ceftazidime tert-butyl ester is dissolved in hydrochloric acid and gradually hydrolyzed.

The ceftazidime tert-butyl ester is placed for several times, so that polymerization possibly caused by overhigh local concentration in a reaction solution, unstable mother ring caused by overhigh local temperature and isomerization of an alkene structure can be avoided. Preferably, the ceftazidime tert-butyl ester is placed in the reaction kettle for 2-5 times, and more preferably, for 3-5 times.

Wherein, the dosage ratio of the ceftazidime tert-butyl ester to the hydrochloric acid solution is 1:1-3g/ml, preferably 1:1-2g/ml, and better still is 1:1-1.5g/ml, for example, 1:1.3 g/ml. When the hydrochloric acid solution is excessive, the ceftazidime tert-butyl ester can be completely hydrolyzed and reacted, and the yield of the product ceftazidime dihydrochloride is improved; meanwhile, the liquid capacity in the reaction system is less, which is beneficial to the subsequent precipitation operation.

The hydrolysis reaction of the ceftazidime tert-butyl ester is carried out for 2 to 5 hours, preferably 3 to 4 hours.

Preferably, the stirring speed is 150-300 r/min, and further 150-250 r/min, so that the solution in the reaction system can be fully mixed.

Step 2), decoloring and removing pyrogen

More preferably, activated carbon is added to the reaction system to decolorize, and pyrogens that may be present in the reaction system are removed by preliminary adsorption. In this case, the decolorization is preferably carried out using an activated carbon for needles having a particle diameter of 0.1 to 0.3 mm.

Because the activated carbon can adsorb the drug ceftazidime when being adsorbed and decolored, the adding amount and the adding time of the activated carbon need to be strictly controlled.

Wherein the adding amount of the active carbon is 0.1-1.0g/100ml, and the preferable adding amount is 0.1-0.5g/100 ml; preferably, the decoloring time is 15-60min, and further 20-45 min; the dosage and the time can meet the requirements of decoloring and pyrogen removal, and simultaneously reduce the adsorption of the medicine as much as possible.

Preferably, the filtration is carried out twice when the active carbon is removed by filtration, and a filter membrane with the aperture capable of intercepting the active carbon is selected to remove the active carbon during the first filtration without increasing the filtration time and the filtration difficulty; the second filtration is carried out by using a 0.2 micron microporous filter membrane for filtration, thereby further playing a role in sterilization.

Step 3), precipitating the product

After filtering to remove the active carbon, controlling the temperature at 5-10 ℃, and adding an alkaline substance into the reaction system to adjust the pH value of the solution.

The basic substance may be an organic or inorganic base, and is preferably selected from triethylamine, tetramethylguanidine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate; more preferably sodium hydroxide or potassium hydroxide, the solution of which is simple to prepare, controllable in concentration and convenient to remove, and the viscosity of the reaction system is not increased or the emulsification phenomenon is not caused.

Preferably, the alkaline substance is diluted or dissolved and then is dripped into the reaction system; further, the molar concentration of the basic group of the basic substance after dilution or dissolution is 5 to 10mol/L, more preferably 6 to 9 mol/L. The alkaline substance with the concentration is less in volume amount added when the pH value of the reaction system is adjusted, so that the addition amount of a subsequent poor solvent can be reduced, and the generation amount of precipitated waste liquid is reduced.

The impurity B detected in the ceftazidime product has the following structural formula:

researches show that the impurity B is probably caused by the fact that the stability of the parent ring structure of ceftazidime is poorer under the alkaline condition, and the local concentration is easily overhigh instantly when alkaline solution is dripped, so that the beta-lactam ring is opened, and hydrogenated thiazine ring is cracked and removed, so that the content of the impurity B is increased, and the quality of the product is poor.

The basic substance is therefore added dropwise to the reaction system with stirring, preferably at a higher stirring rate than the hydrolysis of ceftazidime tert-butyl ester, for example at a rate of more than 250 rpm. The stirring speed is increased, so that the ring opening phenomenon of the mother ring caused by instantaneous overhigh local concentration can be reduced, and the content of the impurity B in the product is reduced.

Researches find that the mother ring hydrolysis phenomenon caused by instantaneous overhigh local concentration can be well reduced or avoided by controlling the dropping speed of the alkaline substance.

Researches also find that the way of separating out ceftazidime by increasing the pH value of a reaction system is easy to cause the solution to explode and nucleate, and the growth of the product cannot be controlled; and the adoption of the mode of reducing the pH value of the reaction system to separate out the ceftazidime can well avoid nuclear explosion and ensure the stable growth of the product.

Therefore, the invention particularly adjusts the pH of the reaction system to 3.0-4.0 at the dropping speed of 3-8 ml/min; the dropping speed of the alkaline substance is reduced to 2-5ml/min, the pH value of the reaction system is adjusted to 4.0-4.6, preferably 4.2-4.6, ceftazidime dihydrochloride is completely converted into ceftazidime sodium salt, nuclear explosion is avoided, and the adding amount of the subsequent acidic solution can be reduced.

Preferably, the acidic solution is a hydrochloric acid solution, and the molar concentration of hydrochloric acid in the hydrochloric acid solution is 4-9mol/L, and more preferably 4-7 mol/L.

Dropwise adding hydrochloric acid solution under stirring, wherein the dropwise adding speed is 2-7ml/min, and monitoring the pH value of the solution in the reaction system. When the pH value of the solution reaches 3.8, the dropping speed of the hydrochloric acid solution is reduced to 1-5ml/min, and the acid solution is stopped adding when the pH value of the reaction system reaches 3.65-3.55, more preferably 3.60 under stirring.

Preferably, the addition of the acidic solution is stopped when the pH value of the reaction system is slowly and uniformly adjusted to 3.65-3.55, more preferably 3.60 within 4 h.

Adding a ceftazidime seed crystal into the reaction system, wherein the purity of the ceftazidime is more than 99%, and the particle size D90 of the seed crystal is 1-50 μm, preferably 1-30 μm, and more preferably 1-20 μm. The seed crystal is added to promote the crystallization of the solution, so that the growth of the ceftazidime is more ordered and controllable.

The addition amount of the ceftazidime seed crystal is 0.16-0.50% (mass ratio of the ceftazidime seed crystal to the ceftazidime).

Then, the temperature of the reaction system is reduced to be below 5 ℃, particularly 0-3 ℃ within 2-4h, and the reaction system is kept stand and crystallized for 2-6h, preferably 3-5 h.

Adding a poor solvent into the reaction system under stirring to separate out the ceftazidime.

The poor solvent is a solvent in which ceftazidime has poor solubility, and preferably can be any one or combination of water, ethanol, acetonitrile, acetone and methanol.

Researches find that when the tert-butyl of the ceftazidime is separated out in a poor solvent, the tert-butyl of the ceftazidime is easy to have a displacement reaction with a more active methyl in a solution, and particularly in a methanol solution, the occurrence rate of the displacement reaction is higher.

Therefore, ethanol with lower methyl activity is particularly used as a poor solvent in the invention to separate out ceftazidime; more preferably, a mixed solvent containing ethanol is used as the poor solvent.

Preferably, 2-10% by volume of dichloromethane, more preferably 2-8%, most preferably 2-6% by volume of dichloromethane is added to the ethanol, and the impurity B has good solubility in dichloromethane, so that the content of the impurity B in the precipitated product can be reduced.

Wherein the amount of the poor solvent added is 2 to 4 times, for example, 3 times, the volume of the reaction solution; the poor solvent is preferably added in 15-30min to prevent excessive impurity in the product caused by excessive reaction solvent carried out by the product when the poor solvent is added too fast.

In order to maintain the sterility of the reaction system, it is preferable that the alkaline solution, the hydrochloric acid solution and the poor solvent added in step 3) are all subjected to sterilization or filter sterilization.

Filtering the reaction solution, and washing the filter cake for a few times by using sterile cold water at the temperature of 0-5 ℃ to obtain a ceftazidime pentahydrate primary product.

Step 4), post-treatment

Dispersing the ceftazidime pentahydrate primary product in ethanol at 0-5 ℃, and removing organic impurity residues and residual dichloromethane in the ethanol; stirring and cleaning at the rotation speed of 100-200 r/min for 10-30min, preferably 10-20min, and filtering to obtain a filtered product;

dispersing the filtered product in acetone at 0-5 deg.C, and further removing organic impurities and residual dichloromethane; meanwhile, the acetone has water absorption, and can further reduce the moisture in the product.

The washing product is stirred in acetone at a speed of 100-200 rpm for 10-30min, preferably 10-20 min. Filtering and drying to obtain a finished product of the ceftazidime pentahydrate.

The ceftazidime is easy to produce polymers and other degradation impurities in storage, and researches show that when the water content in the product is high, the contents of the polymers and other degradation impurities are correspondingly increased, which probably means that the existence of water is beneficial to the intermolecular polymerization reaction of the ceftazidime, and the mutual polymerization among parent nuclei, side chains and parent nuclei and side chains is promoted. When the moisture content is higher, the ceftazidime is also easily degraded under the light, and the (1-carboxyl-1-methyl ethoxy) imino group on the 7-position side chain of the ceftazidime is isomerized and converted into a ceftazidime E-type isomer, namely an impurity C, and the structural formula of the ceftazidime E-type isomer is as follows:

moisture content also has an effect on the polymer content of the product, and therefore, controlling the moisture content of the product is also critical to controlling the quality of the product.

In particular, in the present invention, vacuum drying is carried out at 40 to 45 ℃ and preferably at a vacuum degree of-0.096 MPa for a drying time of 4 to 8 hours.

Due to the reduction of the impurity content, the content of the polymer in the ceftazidime is correspondingly reduced, so that the clinical sensitization rate is reduced, and the use safety is improved.

In the ceftazidime or the composition thereof prepared by the method, the mass content of the ceftazidime is more than 98%, preferably not less than 98.5%. And after the ceftazidime or the composition thereof is subjected to a pharmaceutical accelerated test (40 +/-2 ℃ and relative humidity of 75% +/-5%), the mass content of the ceftazidime is not less than 97.5%. Effectively ensures the shelf life of the ceftazidime or the composition thereof, and is more favorable for improving the clinical curative effect of the ceftazidime preparation.

The invention also provides ceftazidime or a composition thereof with particularly low impurity content, wherein the impurity A content is not higher than 0.2%, preferably 0.01-0.15%, more preferably 0.02-0.1% and most preferably 0.02-0.08%.

Further, the mass content of the impurity B in the ceftazidime or the composition thereof is not higher than 0.2%, preferably 0.01-0.15%, more preferably 0.01-0.1%, and most preferably 0.01-0.08%.

More preferably, the ceftazidime or the composition thereof further contains impurity C, and the mass content of the impurity C is not higher than 0.2%, preferably 0.01-0.15%, more preferably 0.01-0.1%, and most preferably 0.01-0.08%.

The content of the polymer which is easy to cause allergy and formed by mutual aggregation of a plurality of molecules (including impurity molecules and ceftazidime molecules) is also remarkably reduced due to the control of a plurality of impurities, and the mass content of the polymer in the ceftazidime or the composition thereof provided by the invention is not higher than 1.0%, preferably 0.01-0.2%, more preferably 0.01-0.15%, and most preferably 0.01-0.1%.

The preparation method of ceftazidime provided by the invention is convenient, two-pot operation is not needed, and the product can be purified and separated out by one-step operation.

The invention also provides a ceftazidime preparation taking ceftazidime or a composition thereof as a main active ingredient, which is characterized in that the preparation is sterile powder injection. Preferably, the ceftazidime or the composition thereof is prepared by the preparation method provided by the invention.

In the ceftazidime formulation comprising:

1-10 parts of ceftazidime;

0.1-10 parts of auxiliary materials.

Preferably, the ceftazidime formulation comprises:

3-9 parts of ceftazidime;

1-3 parts of auxiliary materials.

In order to better dissolve, the ceftazidime and the auxiliary materials are respectively crushed, so that the particle size is reduced, and the dissolving time is shortened.

Preferably, the particle size D90 of the crushed ceftazidime or the composition thereof is 10-50 μm, and further 25-50 μm; the particle size of the auxiliary material is 50-100 μm, preferably 50-80 μm.

And subpackaging the crushed ceftazidime or the composition thereof and auxiliary materials in proportion, or subpackaging after mixing. The two are preferably ground and mixed, so that the medicine and the auxiliary materials can be uniformly mixed, the particle size of the medicine can be further reduced, and the dissolving time in use can be shortened.

Preferably, the milling is performed using a ball mill, and due to the closed operation of the ball mill, aseptic operation can be achieved, the possibility of contamination is reduced, and safety is improved.

More preferably, the ceftazidime or the composition thereof is aseptically subpackaged after the mixture of the ceftazidime and the auxiliary materials is finished, so as to prepare the ceftazidime preparation.

The ceftazidime or the composition thereof and the ceftazidime preparation provided by the invention can be used for treating gynecological infection diseases or new indications. Therefore, the invention also provides the application of the ceftazidime or the composition thereof and the ceftazidime preparation in preparing the medicaments for treating the gynecological infection diseases or new indications.

Further, the gynecological infection disease or new indication includes endometritis.

Preferably, the gynaecological infectious disease or new indication also includes pelvic cellulitis and other female genital tract infections caused by escherichia coli.

Therefore, the invention also provides the application of the ceftazidime or the composition and the ceftazidime preparation in preparing medicaments for treating endometritis, pelvic cellulitis and other female genital tract infections caused by escherichia coli.

According to the ceftazidime or the composition, the preparation method and the ceftazidime preparation provided by the invention, the following beneficial effects are achieved:

(1) the ceftazidime or the composition thereof provided by the invention has lower contents of polymer, impurity A, B and C, and high product stability; is beneficial to improving the use safety and the clinical treatment effect;

(2) the ceftazidime provided by the invention is low in water content and high in stability, and is beneficial to long-term storage and placement; various impurities generated by degradation are reduced, so that the clinical sensitization risk is reduced;

(3) the ceftazidime provided by the invention has high controllability in the production process, the quality of products in different batches is similar, and the quality of the products is controllable.

Examples

Example 1

7-APCA and ceftazidime side chain acid active ester are synthesized into ceftazidime tert-butyl ester in a dichloromethane solvent under the alkaline condition. Taking the ceftazidime tert-butyl ester, and sequentially carrying out the following operations:

hydrolysis:

controlling the temperature to be 5-6 ℃, adding 30L of 10mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 250 revolutions per minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 5 times, and continuously stirring for hydrolysis reaction for 4 hours.

And (3) decoloring:

adding 130g of medicinal activated carbon for injection into the reaction kettle, decoloring for 20min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

Alkalization:

under the condition that the rotating speed is 300 r/min, 8mol/L sodium hydroxide solution is dripped at the dripping speed of 5ml/min until the pH value of the solution is 4.0; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the sodium hydroxide is stopped adding when the pH value reaches 4.6.

Acidifying:

dropwise adding 6mol/L hydrochloric acid solution, and adjusting the pH value of the reaction system to 3.6 within 4 h.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 of the seed crystals was 15.65 μm, and the amount added was 320 g. Reducing the temperature of the reaction system to 1 ℃ within 4h, and standing for 5 h.

And (3) separating out a product:

under the condition of stirring speed of 200 r/min, 66L of ethanol solution containing 4% by volume of dichloromethane is added dropwise, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

And (3) post-treatment:

dispersing the ceftazidime pentahydrate primary product in 35L of absolute ethyl alcohol, stirring and cleaning for 15min at 150 rpm; filtering, dispersing the filter cake in 35L of anhydrous acetone again, stirring and cleaning at 150 rpm for 15 min; filtration and drying of the filter cake at 40 ℃ under vacuum for 6 h.

Example 2

Hydrolysis:

controlling the temperature to be 5-6 ℃, adding 21.5L of 12mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 200 revolutions per minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 5 times, and continuously stirring for hydrolysis reaction for 4 hours.

And (3) decoloring:

adding 66g of medicinal activated carbon for injection into the reaction kettle, decoloring for 30min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

Alkalization:

under the condition that the rotating speed is 300 revolutions per minute, 8mol/L of potassium hydroxide solution is dripped at the dripping speed of 7ml/min until the pH value of the solution is 4.0; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the potassium hydroxide is stopped adding when the pH value reaches 4.2.

Acidifying:

dropwise adding 4mol/L hydrochloric acid solution at a dropwise adding speed of 5ml/min until the pH value of the solution is 3.85; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the process is stopped when the pH value reaches 3.65.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 being 24.74 μm, in an amount of 317 g. Reducing the temperature of the reaction system to 1 ℃ within 4h, and standing for 4 h.

And (3) separating out a product:

under the condition of stirring speed of 200 r/min, 83L of ethanol solution containing 6% by volume of dichloromethane is added dropwise, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

And (3) post-treatment:

the working-up was as in example 1.

Example 3

Hydrolysis:

controlling the temperature to be 7-8 ℃, adding 40L of 10mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 250 revolutions per minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 3 times, and continuously stirring for carrying out hydrolysis reaction for 3 hours.

And (3) decoloring:

adding 165g of medicinal activated carbon for injection into the reaction kettle, decoloring for 45min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

Alkalization:

dripping 9mol/L sodium hydroxide solution at the dripping speed of 5ml/min under the condition that the rotating speed is 300 r/min until the pH value of the solution is 3.8; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the sodium hydroxide is stopped adding when the pH value reaches 4.6.

Acidifying:

5mol/L hydrochloric acid solution is dripped, and the pH value of the reaction system is adjusted to 3.55 within 4 hours.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 of the seed crystals being 7.49 μm, in an amount of 317 g. Reducing the temperature of the reaction system to 1 ℃ within 4h, and standing for 5 h.

And (3) separating out a product:

And (3) post-treatment:

the working-up was as in example 1.

Example 4

Hydrolysis:

controlling the temperature to be 7-8 ℃, adding 30L of 8mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 200 r/min; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 5 times, and continuously stirring for hydrolysis reaction for 4 hours.

And (3) decoloring:

adding 100g of medicinal activated carbon for injection into a reaction kettle, decoloring for 60min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

Alkalization:

dripping 9mol/L potassium hydroxide solution at the dripping speed of 5ml/min under the condition that the rotating speed is 200 revolutions per minute until the pH value of the solution is 4.0; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the potassium hydroxide is stopped adding when the pH value reaches 4.2.

Acidifying:

dropwise adding 7mol/L hydrochloric acid solution at a dropwise adding speed of 5ml/min until the pH value of the solution is 3.8; the dropping speed was reduced to 1ml/min and the pH of the solution was monitored at that time to 3.6.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 of the seed crystals was 31.52 μm, and the addition amount was 317 g. Reducing the temperature of the reaction system to 2 ℃ within 3h, and standing for 4 h.

And (3) separating out a product:

under the condition of stirring speed of 200 r/min, 50L of ethanol solution containing 4% by volume of dichloromethane is added dropwise, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

And (3) post-treatment:

the working-up was as in example 1.

Example 5

Hydrolysis:

controlling the temperature to be 9-10 ℃, adding 30L of 6mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 200 revolutions per minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 3 times, and continuously stirring for carrying out hydrolysis reaction for 3 hours.

And (3) decoloring:

265g of medical-grade needle activated carbon is added into the reaction kettle, decoloration is carried out for 15min under stirring, and the activated carbon is removed by filtration through a 0.2-micron microporous membrane.

Alkalization:

dripping 5mol/L sodium hydroxide solution at the dripping speed of 5ml/min under the condition that the rotating speed is 350 r/min until the pH value of the solution is 3.8; the dropping speed is reduced to 2ml/min, the pH value of the solution is monitored at any moment, and the sodium hydroxide is stopped adding when the pH value reaches 4.6.

Acidifying:

dropwise adding 9mol/L hydrochloric acid solution at a dropwise adding speed of 5ml/min until the pH value of the solution is 3.8; the dropping rate was reduced to 3ml/min, which was a pH value of the solution of 3.65.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 being 40.66 μm, in an amount of 317 g. Reducing the temperature of the reaction system to 2 ℃ within 2h, and standing for 3 h.

And (3) separating out a product:

under the condition of stirring speed of 200 r/min, 83L of ethanol solution containing 2% by volume of dichloromethane is added dropwise, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

And (3) post-treatment:

the working-up was as in example 1.

Example 6

Hydrolysis:

controlling the temperature to be 9-10 ℃, adding 40L of 6mol/L hydrochloric acid solution into the reaction kettle, and stirring at the speed of 150 revolutions per minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 3 times, and continuously stirring for carrying out hydrolysis reaction for 3 hours.

And (3) decoloring:

adding 330g of medical-grade needle activated carbon into the reaction kettle, decoloring for 10min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

Alkalization:

dripping 10mol/L potassium hydroxide solution at the dripping speed of 5ml/min under the condition that the rotating speed is 350 r/min until the pH value of the solution is 3.8; the dropping speed is reduced to 3ml/min, the pH value of the solution is monitored at any moment, and the potassium hydroxide is stopped adding when the pH value reaches 4.2.

Acidifying:

and dropwise adding 9mol/L hydrochloric acid solution, and adjusting the pH value of the reaction system to 3.55 within 2 h.

Growing the grains:

seed crystals of ceftazidime were added, the particle size D90 being 49.89 μm, in an amount of 317 g. Reducing the temperature of the reaction system to 3 ℃ within 1h, and standing for 3 h.

And (3) separating out a product:

under the condition of stirring speed of 200 r/min, 40L of ethanol solution containing 10% by volume of dichloromethane is added dropwise, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

And (3) post-treatment:

the working-up was as in example 1.

Example 7

The ceftazidime prepared in examples 1-6 was pulverized separately to obtain ceftazidime with D90 of 10.12, 10.59, 10.27, 10.10, 10.48, 10.33 μm.

Sodium carbonate was ground to a D90 of 50.89 microns.

Weighing 10kg of the pulverized ceftazidime and 3.3kg of sodium carbonate of the embodiments 1 to 6, placing the mixture in a ball mill, grinding and mixing the mixture, weighing 1g of the ceftazidime pentahydrate, sealing and packaging to obtain the ceftazidime A, B, C, D, E, F preparation.

Example 8

Crushing arginine to D90 of 60.77 microns.

Weighing 10kg of the pulverized ceftazidime prepared in example 7, weighing 3.3kg of arginine, pulverizing and mixing by a mechanical pulverizer, weighing 1g of ceftazidime pentahydrate, sealing and packaging to obtain ceftazidime preparations a, b, c, d, e and f.

Comparative example

Comparative example 1

Hydrolysis:

at room temperature (25 ℃), adding 40L of 12mol/L hydrochloric acid solution into a reaction kettle, and stirring at the speed of 100 revolutions/minute; weighing 20kg of ceftazidime tert-butyl ester, adding the ceftazidime tert-butyl ester for 3 times, and continuously stirring for hydrolysis reaction for 5 hours.

The other operation steps are the same as in example 1.

Comparative example 2

And (3) decoloring:

adding 660g of medical-grade needle activated carbon into the reaction kettle, decoloring for 20min under stirring, and filtering with a 0.2-micron microporous filter membrane to remove the activated carbon.

The other operation steps are the same as in example 1.

Comparative example 3

Hydrolysis and decolorization As in example 1, after the decolorization, 8mol/L sodium hydroxide solution was added dropwise at a rate of 5ml/min to a pH of 3.6 at a rate of 300 rpm.

The subsequent treatment was the same as in example 1.

Comparative example 4

When the product is separated out, under the condition that the stirring speed is 200 r/min, 66L of acetone is dropwise added, and stirring is continued for 1h after the addition is finished within 30 min. Filtering, taking 1.6L of cold water to wash the filter cake, and repeating for 3 times to obtain a ceftazidime pentahydrate primary product.

The rest of the operation was the same as in example 1.

Comparative example 5

The ceftazidime obtained in comparative examples 1-4 was pulverized to obtain ceftazidime with D90 of 10.43, 10.21, 10.14 and 10.19 microns.

The pulverized ceftazidime of comparative examples 1-4 was weighed and ceftazidime formulations a ', b', c ', d' were prepared according to the method of example 7.

Examples of the experiments

Experimental example 1

The contents of ceftazidime obtained in examples 1 to 6 and ceftazidime obtained in comparative examples 1 to 4, the polymer, impurities A, B and C were measured according to the method under the term of ceftazidime in the pharmacopoeia of the 2015 edition, and the results were as follows:

the results of the preparation of different batches of ceftazidime by using the method in example 1 show that the ceftazidime in different batches has stable quality and basically the same performance, which indicates that the method has controllable quality. The results are as follows:

batches of	Ceftazidime (calculated as dry matter)	Impurity A	Impurity B	Impurity C	Polymer and method of making same
						1	99.3％	0.04％	0.01％	0.01％	0.1％
2	98.2％	0.04％	0.01％	0.01％	0.1％
						3	99.7％	0.04％	0.01％	0.02％	0.1％
4	98.9％	0.05％	0.01％	0.03％	0.1％
						5	99.8％	0.04％	0.01％	0.02％	0.1％
6	98.5％	0.04％	0.02％	0.03％	0.1％

Experimental example 2

The powder properties of ceftazidime in example 7 were determined as follows:

	particle size D90	Bulk density	Tap density	Angle of repose
					Example 1	10.12	0.384	0.616	50
Example 2	10.59	0.370	0.589	51
					Example 3	10.27	0.376	0.615	53
Example 4	10.10	0.392	0.620	50
					Example 5	10.48	0.374	0.608	52
Example 6	10.33	0.377	0.618	50

It can be seen that the ceftazidime prepared in examples 1-6 is suitable for industrial preparation of preparations after being crushed, and is beneficial to industrial production.

Experimental example 3

The ceftazidime prepared in examples 1 to 6 and the ceftazidime prepared in comparative examples 1 to 4 were subjected to accelerated tests under test conditions (40 ℃ ± 2 ℃ and 75% ± 5% relative humidity), and after standing for 6 months, the content of ceftazidime, the polymer, the impurities A, B and C were measured, and the results were as follows:

the quality of the ceftazidime prepared in examples 1-6 is significantly better than that of the ceftazidime prepared in comparative examples 1-4.

Experimental example 4

The ceftazidime formulations prepared in examples 7 and 8 and the ceftazidime formulation prepared in comparative example 5 were subjected to accelerated tests under test conditions (40 ℃ ± 2 ℃ and 75% ± 5% relative humidity), and after standing for 6 months, the content of ceftazidime, the polymer, the impurities A, B and C were measured, and the results were as follows:

example 7:

example 8:

comparative example 5:

the ceftazidime formulations prepared in examples 7 and 8 were significantly better in quality than the ceftazidime formulation prepared in comparative example 5.

Experimental example 5

Endotoxin/pyrogen studies were performed on formulations A-F of example 7 and found to have endotoxin/pyrogen levels of less than 0.10EU/mg in formulations A-F.

Experimental example 6

The ceftazidime formulation prepared in example 7 was studied for insoluble particles according to the 2015 pharmacopoeia, and the results were as follows:

it can be seen that the ceftazidime preparation prepared in example 7 has very good re-dissolving performance, and insoluble particles above 25 microns are few, so that clinical allergic reaction is less caused.

Experimental example 7

Respectively inoculating Escherichia coli in different reproductive organs of a healthy female mouse for molding to obtain a model mouse with reproductive tract infection. External genital tract infections include cervical and vaginal infections, and internal genital tract infections include uterine and fallopian tube infections.

50 female mice infected with the external genital tract and 50 female mice infected with the internal genital tract are selected, the preparation A prepared in the embodiment 7 is taken and respectively injected by tail vein with the body weight of 200mg/kg, and the administration frequency is 24 h; after 3 days of treatment, mice were sacrificed, dissected and checked for genital tract infections.

And (4) judging the standard:

the effect is shown: disappearance of symptoms of infection and detection of disappearance of inflammation; effective, infection symptoms improve, and inflammation improvement is detected; the infection symptoms are not improved, and even the inflammation is aggravated.

The results are shown statistically as follows:

wherein, the treatment result of the mouse with the external genital tract infection is as follows: the number of the effective devices is 40, 9 effective devices are 9, and 1 ineffective device is 1.

The therapeutic results for the mice infected with the internal reproductive tract were: 38 are effective, 12 are effective, and 0 is ineffective.

Experimental example 8

800 healthy mice were divided into two groups of 400 females each. One group was administered at a dose of 500mg/kg by tail vein injection using the formulation A prepared in example 7, and one group was administered at a dose of 500mg/kg by tail vein injection using the formulation a' prepared in comparative example 5. Observing whether the mouse has symptoms of excitation, agitation, nasal flaring, nasal grasping, shortness of breath, hair rising, limb spasm, jumping and the like, and recording whether the mouse dies.

The results are shown statistically as follows:

preparation	Number of mice showing the above symptoms	Number of deaths
			Preparation A	12	0
Preparation a'	42	0

The experimental result shows that the safety of the preparation A and the preparation a' is high, and the sensitization of the preparation A is lower.

Experimental example 9

Preparation A prepared in example 7 was subjected to a clinical trial, and 50 female patients with endometritis were selected for the study, with the mean age (48.7. + -. 10.3) years.

The treatment method comprises the following steps: 1g of ceftazidime for intravenous drip injection, 2 times a day;

the treatment period is as follows: 5 days

Evaluation criteria:

the clinical symptoms disappear, the menstruation returns to normal, and the inflammation disappears through ultrasonic examination;

effective, clinical symptoms are improved, inflammation is improved by ultrasonic examination, and endometrium is thickened;

the above indexes are not reached, even aggravated.

The treatment results are as follows:

and (3) taking a blood sample for intravenous blood collection, detecting the blood concentration of ceftazidime in the blood sample, calculating the average value of the testee, and drawing a pharmaceutical time curve, wherein the pharmaceutical time curve is shown in figure 1. As can be seen, the peak concentration of ceftazidime (C) on the time curve_max) 70.4 mug/mL, peak time of about 1.0h and half-life of drug in plasma of about 1.6 h. The effective bacteriostasis time is long.

Statistically, the treatment results were as follows:

therapeutic effect	Show effect	Is effective	Invalidation
				Number of patients	34	9	7

No allergic events were found during the treatment.

Experimental example 10

A clinical trial was conducted on formulation A prepared in example 7, and 50 female patients with pelvic cellulitis were selected for study, with the mean age (49.6 + -11.5) years

the treatment period is as follows: 5 days

Evaluation criteria:

curing, namely eliminating symptoms and physical signs and recovering hemogram to be normal;

effective, partial relief of symptoms and signs;

no reduction or exacerbation of symptoms was noted.

The treatment results are as follows:

and (3) taking a blood sample for intravenous blood collection, detecting the blood concentration of ceftazidime in the blood sample, calculating the average value of the testee, and drawing a pharmaceutical time curve, wherein the pharmaceutical time curve is shown in figure 2. As can be seen, the peak concentration of ceftazidime (C) on the time curve_max) 74.0 mug/mL, peak time of about 1.0h and plasma half-life of the drug of about 1.6 h. The effective bacteriostasis time is long.

Statistically, the treatment results were as follows:

therapeutic effect	Cure of disease	Is effective	Invalidation
				Number of patients	31	11	8

No allergic events were found during the treatment.

The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.

Claims

1. A method for preparing ceftazidime,

the ceftazidime injection is characterized in that the content of the ceftazidime is more than 98 percent;

impurity A

The content of (A) is not higher than 0.2%;

impurity B

The content of (A) is not higher than 0.2%;

impurity C

The content of (A) is not higher than 0.2%;

the preparation method comprises the following steps:

step 1), carrying out hydrolysis reaction of ceftazidime tert-butyl ester by using a hydrochloric acid solution at the temperature of 5-10 ℃, wherein the concentration of the hydrochloric acid solution is 6-12 mol/L; the dosage ratio of the ceftazidime tert-butyl ester to the hydrochloric acid solution is 1:1-3 g/ml;

step 2), decoloring by using activated carbon for needles with the particle size of 0.1-0.3mm, and removing pyrogens;

step 3), dropwise adding an alkaline solution into the reaction system until the pH value is 4.0-4.6, and then adding a hydrochloric acid solution to adjust the pH value to 3.65-3.55; adding ethanol into the reaction system to separate out a product, and adding dichloromethane with the volume ratio of 2-10% into the ethanol;

step 4), post-treatment, namely respectively dispersing the precipitated products in ethanol and acetone for cleaning, filtering and drying in vacuum to obtain ceftazidime;

vacuum drying at 40-45 deg.C under-0.096 MPa for 4-8 hr.

2. The method of claim 1,

in the step 2) of the process,

the adding amount of the active carbon is 0.1-1.0g/100 ml;

the decolorizing time is 15-60 min.