CN101265264B - Method for producing high-purity mezlocillin sodium and powder injection thereof - Google Patents
Method for producing high-purity mezlocillin sodium and powder injection thereof Download PDFInfo
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- CN101265264B CN101265264B CN2008100975383A CN200810097538A CN101265264B CN 101265264 B CN101265264 B CN 101265264B CN 2008100975383 A CN2008100975383 A CN 2008100975383A CN 200810097538 A CN200810097538 A CN 200810097538A CN 101265264 B CN101265264 B CN 101265264B
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Abstract
The invention provides a method for preparing high-purity Mezlocillin sodium, and a method for preparing Mezlocillin sodium powder for injection. The method includes the following steps: (1) absorbing Mezlocillin sodium or Mezlocillin sodium made from Mezlocillin acid crude drug and alkaline sodium salt with macroporous resin, eluting with purified water, and collecting the eluent; (2) purifying the primary pure product with a gel column, eluting with salt solution having certain concentration to obtain refined product with the Mezlocillin sodium content of greater than 99%, decoloring with activated carbon, filtering with 0.22 Mum microporous filter membrane, sterilizing, freeze drying to obtain the high-purity Mezlocillin sodium, pulverizing, and sterile packaging to obtain Mezlocillin sodium powder for injection.
Description
Technical field
The present invention relates to a kind of method for preparing high-purity mezlocillin sodium, also relate to a kind of method for preparing the mezlocillin sodium injection, belong to medical technical field.
Background technology:
Sodium mezlocillin is the semi-synthetic penicillins microbiotic, to Pseudomonas aeruginosa, escherichia coli, pneumobacillus, Bacillus proteus, enterobacter, citrobacter, Serratia, acinetobacter and to the gram positive coccus of penicillin sensitivity bacteriostatic action is arranged all, heavy dose has germicidal action.Anti-microbial activity to escherichia coli, enterobacter, pneumobacillus, citrobacter, Serratia and acinetobacter etc. is better than Gepcillin, Ampicillin Trihydrate; Anti-microbial activity to the positive Bacillus proteus of indoles, Pseudomonas aeruginosa is better than Gepcillin and sulbenicillin; Anti-microbial activity to gram positive organism such as streptococcus aureus is similar to Gepcillin, and more superior than Gepcillin, sulbenicillin to the anti-microbial activity of streptococcus faecium.Most of anerobes such as bacteroides fragilis had better anti-microbial effect.This product in vitro tests shows that it is to (lactamase instability that bacterium produced.Aminoglycoside antibiotics combined utilization such as this product and gentamicin, kantlex have remarkable synergy.
Be applicable to that the respiratory system due to the sensitive strain in the gram negative bacillis such as escherichia coli, enterobacter, Bacillus proteus, urinary system, Digestive tract, gynaecology and sexual organ official rank infect, infect as septicemia, purulent meningitis, peritonitis, osteomyelitis, skin and soft tissue infection and Eye Ear Nose And Throat section.
The mezlocillin for inj powder injection has been widely used in clinical, is one of present most widely used antibiotic medicine, and its preparation all is to be made through aseptic subpackaged by the mezlocillin sodium raw materials.Most of mezlocillins sodium raw materials exists purity not high, and dissolving back clarity is poor, the problem of poor stability in the aqueous solution, and this also is the common problem of all antibiotics.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing high-purity mezlocillin sodium, also provide the described method of a kind of usefulness to prepare the method for mezlocillin sodium injection simultaneously.
For achieving the above object, technical solution of the present invention is as follows:
The invention provides a kind of method for preparing high-purity mezlocillin sodium, it is characterized in that the Sodium mezlocillin crude product makes purity by the method that may further comprise the steps and is not less than 99% Sodium mezlocillin highly finished product:
(1) the Sodium mezlocillin crude product separates with macroporous resin adsorption (being preferably the D1300 macroporous resin);
(2) step (1) products obtained therefrom obtains the Sodium mezlocillin highly finished product with gel column (being preferably cross-linked dextran gel column) purifying.
The present invention also provides a kind of method for preparing the mezlocillin sodium injection, it is characterized in that may further comprise the steps:
(1) the Sodium mezlocillin crude product separates with macroporous resin adsorption (being preferably the D1300 macroporous resin);
(2) step (1) products obtained therefrom is with gel column (being preferably cross-linked dextran gel column) purifying, collects the mezlocillin sodium content and is not less than 99% component;
(3) step (2) gained Sodium mezlocillin highly finished product are through activated carbon decolorizing, and behind filtering with microporous membrane, lyophilize is crushed to 50-200 order, preferred 60-100 purpose fine powder, and packing under 100 grades of conditions in sterilisable chamber then makes the mezlocillin sodium injection.
The above-mentioned described method of the present invention, wherein the macroporous resin separation is carried out wash-out with pure water or distilled water as eluent in the step (1).
Wherein, above-mentioned described method is wherein used cross-linked dextran gel column in the step (2), is preferably the gel column of SephadexC series, more preferably SephadexC
15, SephadexC
25Or SephadexC
50Post, carry out purifying,, collect the mezlocillin sodium content and be not less than 99% component as eluent with the salts solution of 0.05～0.2mol/L concentration.
Above-mentioned described method, wherein said salts solution are selected from ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution and DL-Lactic acid ammonium salt solution.
Above-mentioned described method, wherein the gel column eluting temperature is 4 ℃～35 ℃, preferred 20 ℃～30 ℃.
Above-mentioned described method, wherein step (3) is middle with 0.22 μ m filtering with microporous membrane.
The above-mentioned described method of the present invention, wherein the Sodium mezlocillin crude product forms after by mezlocillin acid crude oxygenation sodium, sodium hydroxide, yellow soda ash or sodium bicarbonate in the step (1).
As the embodiment of the invention, a kind of method for preparing high-purity mezlocillin sodium is provided, it is characterized in that comprising the steps:
(1) adds sodium hydroxide in the acid crude of mezlocillin, form the Sodium mezlocillin crude product;
(2) the Sodium mezlocillin crude product of step (1) separates with the D1300 macroporous resin adsorption, carries out wash-out with distilled water, collects the Sodium mezlocillin elutriant;
(3) step (2) gained Sodium mezlocillin elutriant carries out gel filtration chromatography after concentrating, it is gel that column packing is selected Sephadex C for use, ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution or DL-Lactic acid ammonium salt eluant solution with 0.05～0.2mol/L concentration, 4～30 ℃ of eluting temperatures, collection mezlocillin sodium content is not less than 99% component.
As another embodiment of the present invention, a kind of method for preparing the mezlocillin sodium injection is provided, it is characterized in that comprising the steps:
(1) adds sodium hydroxide in the acid crude of mezlocillin, form the Sodium mezlocillin crude product;
(2) the Sodium mezlocillin crude product of step (1) separates with the D1300 macroporous resin adsorption, carries out wash-out with distilled water, collects the Sodium mezlocillin elutriant;
(3) step (2) gained Sodium mezlocillin elutriant carries out gel filtration chromatography after concentrating, it is gel that column packing is selected Sephadex C for use, ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution or DL-Lactic acid ammonium salt eluant solution with 0.05～0.2mol/L concentration, 4～30 ℃ of eluting temperatures, collection mezlocillin sodium content is not less than 99% component, obtains the Sodium mezlocillin highly finished product;
(4) the Sodium mezlocillin highly finished product of step (3) gained are through activated carbon decolorizing, 0.22um behind the filtering with microporous membrane, lyophilize, be crushed to 60-100 purpose fine powder, in sterilisable chamber, be distributed into every bottle then under 100 grades of conditions and contain Sodium mezlocillin and calculate 0.1～2.0 gram, make the mezlocillin sodium injection by the mezlocillin.
In the technology of the present invention method, adopt macroporous resin can play the effect of adsorbing Sodium mezlocillin, and other impurity will directly flow out macroporous resin, thereby realize the preliminary purification of Sodium mezlocillin.In addition, macroporous resin also has decolorization, can remove the pigment impurity in the solution.
The inventive method obviously also is suitable for preparing high-purity mezlocillin sodium and mezlocillin sodium injection by the crude product mezlocillin.By adding alkali mezlocillin is changed into Sodium mezlocillin.Used alkali can be sodium hydroxide or sodium hydroxide and the mixture that contains the soda material, and the soda material that contains of the present invention can be sodium oxide, yellow soda ash or sodium bicarbonate.The present invention preferably uses sodium hydroxide, both can use sodium hydrate solid, also can use sodium hydroxide solution, as further preferred, uses the sodium hydroxide solution of 5%-20%.In order to make mezlocillin change into Sodium mezlocillin fully, help macroporous resin simultaneously and under suitable pH condition, adsorb, pH value of solution should be adjusted to and be not less than 5.Simultaneously,, can consume a large amount of alkali first, increase cost if pH is too high; Second the danger in the time of can increasing operation, and to equipment generation corrosive nature, so pH is unsuitable too high, should not be higher than 13.As preferably, alkalization back pH value of solution is 6-10.When carrying out wash-out, the purified water consumption there is certain limitation, should satisfies that at least 95% Sodium mezlocillin on the macroporous resin is eluted with purified water; But can not carry out wash-out and constantly add purified water for the Sodium mezlocillin of the remaining minute quantity of wash-out simultaneously, can cause effluent volume excessive like this, increase the processing load of subsequent purification step.Among the present invention, the volume of the purified water that described wash-out is used is 5-30 a times of sample introduction sample volume, is preferably 10-20 doubly.
Can concentrate the gained elutriant among the present invention, obtain relative density and be not less than 1.05 concentrated solution.The used concentration method of the present invention is this area concentration method commonly used, can select that thin film evaporation concentrates, reduction vaporization concentrates, atmospheric evaporation concentrates for use and multiple-effect any one in concentrating, also any two kinds of methods or several different methods wherein can be combined use, as long as can reach the purpose of concentrate eluant.The relative density of gained concentrated solution is 1.05-1.50, can effectively reduce the volume of elutriant like this, alleviates the burden of subsequent purification step.
The inventive method is used the gel column purifying again with the separating obtained elementary purified product of macroporous adsorbent resin, with certain density salts solution wash-out, collects the mezlocillin sodium content and is not less than 99% part, can obtain the Sodium mezlocillin highly finished product.Gained Sodium mezlocillin highly finished product with 0.22 μ m filtering with microporous membrane degerming after, lyophilize, high-purity mezlocillin sodium, can be used as the raw material powder of powder injection.The principle of carrying out purifying with gel column is to utilize the difference of the molecular weight of different substances to separate.Because Sodium mezlocillin is bigger with the molecular weight difference of other impurity in the gained concentrated solution, so can select for use various types of gel columns to separate all to obtain highly purified Sodium mezlocillin.Gel column of the present invention can be any one in polyacrylamide gel post, cross-linked dextran gel column, sepharose post or the polystyrene gel post.As preferably, can use the gel column of SephadexC series.The Sephadex gel column is a cross-linked dextran gel column, is to use gel column widest in area, and the commercially available prod of various models is arranged.In the gel column of SephadexC series, the present invention preferably uses SephadexC
15, SephadexC
25Or SephadexC
50In the present invention, in order to shorten the purifying cycle, improve the purifying ability and to reduce seldom hangover, adopt gradient elution to carry out wash-out.The present invention adopts the solution of ammonium formiate, ammonium acetate, propionic acid ammonium and these four kinds of salt of DL-Lactic acid ammonium salt as eluent, and preferred solution concentration is 0.05～0.2mol/L.
In elution process, improve temperature and help setting up fast the liquid-solid phase balance, accelerate separation and purification speed.But it is too fast that the too high meeting of temperature causes solute to spread in liquid, causes separation efficiency to reduce, and therefore needs to select suitable eluting temperature.In the present invention, the eluting temperature of described gradient elution is 4 ℃-40 ℃, preferred 20 ℃-30 ℃.
Adopt the high-purity mezlocillin sodium of method for preparing to can be used as the raw material for preparing the mezlocillin sodium injection.The preparation technology of described mezlocillin sodium injection is this area common technology, the Sodium mezlocillin that obtains is crossed the 50-200 mesh sieve pulverize, the preferred 60-100 mesh sieve of crossing, then in sterilisable chamber under hundred grades of conditions packing promptly get the mezlocillin sodium injection.As required, the Sodium mezlocillin of every bottle of packing by the mezlocillin, is preferably 0.1g-2.0g.
Beneficial effect below by description of test technical scheme provided by the present invention.Embodiment 1 and embodiment 2 prepared mezlocillin sodium injections are carried out quality examination.Respectively the mezlocillin sodium injection that makes is placed under 60 ℃ of high temperature, illumination 4500Lx condition and carried out influence factor test investigation in 10 days; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition 18 months, carry out test of long duration and investigate, detect the variation of every quality index, the gained data are shown in table 1-3:
Table 1 influence factor result
Accelerated test is 6 months under 40 ℃ of table 2 high temperature, relative humidity 75% ± 5% condition
Test of long duration is 18 months under 25 ℃ of table 3 high temperature, relative humidity 60% ± 10% condition
By above data results as can be seen, the mezlocillin powder injection quality conformance with standard requirement that the present invention makes, and through influence factor 10 days, quicken experiments such as June and long-term 18 months after, every quality index does not have considerable change, all meet quality standard, illustrated that the sample quality stability of preparation of the present invention is fine.
Compared with prior art, method and the mezlocillin sodium injection for preparing high-purity mezlocillin sodium provided by the present invention has following advantage:
1, the present invention adopts the chromatography column purification process, and the purity of Sodium mezlocillin is greatly improved, and reaches more than 99%.
2, purge process is pollution-free, is convenient to industrial continuous production.
3, remove a lot of water-insoluble impurity, improved the clarity of mezlocillin sodium water solution.
4, improved the stability of mezlocillin sodium water solution.
Embodiment
Embodiment 1
Get the mezlocillin stirring and dissolving in purified water, behind the adding 2mol/L sodium hydroxide solution regulator solution pH to 8.7, use the D1300 macroporous resin adsorption, being eluted to distilled water does not almost have Sodium mezlocillin in the elutriant.Collect elutriant, behind the employing reduction vaporization concentrate eluant, adopt with SephadexC
15For the cross-linked dextran gel column of filler carries out column chromatography, ammonium formiate aqueous solution wash-out with 0.05mol/L, eluting temperature is 15 ℃, collects HPLC and detects integral area ratio 99% with top, adds liquor capacity 0.2% (g/ml) gac, room temperature condition decoloured 30 minutes down, after the degerming of 0.22um filtering with microporous membrane, lyophilize gets Sodium mezlocillin, purity is 99.5%, and yield is 87.8%.
After the sodium pure product lyophilize of above-mentioned mezlocillin, pulverized 60 mesh sieves, packing under 100 grades of conditions in sterilisable chamber contains Sodium mezlocillin in every bottle and calculates 0.1 gram by the mezlocillin, obtains the mezlocillin sodium injection.
Embodiment 2
Get the mezlocillin stirring and dissolving in purified water, behind the sodium carbonate solution regulator solution pH to 9.0 of adding 10%, use the D1300 macroporous resin adsorption, being eluted to distilled water does not almost have Sodium mezlocillin in the elutriant.Collect elutriant, behind the employing reduction vaporization concentrate eluant, adopt with SephadexC
25For the cross-linked dextran gel column of filler carries out column chromatography, ammonium acetate solution wash-out with 0.1mol/L, eluting temperature is 20 ℃, collects HPLC and detects integral area ratio 99% with top, adds liquor capacity 0.2% (g/ml) gac, room temperature condition decoloured 30 minutes down, after the degerming of 0.22um filtering with microporous membrane, lyophilize gets Sodium mezlocillin, purity is 99.6%, and yield is 88.2%.
After the sodium pure product lyophilize of above-mentioned mezlocillin, pulverized 100 mesh sieves, packing under 100 grades of conditions in sterilisable chamber contains Sodium mezlocillin in every bottle and calculates 2.0 grams by the mezlocillin, obtains the mezlocillin sodium injection.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (12)
1. method for preparing high-purity mezlocillin sodium is characterized in that the Sodium mezlocillin crude product makes purity by the method that may further comprise the steps and is not less than 99% Sodium mezlocillin highly finished product:
(1) the Sodium mezlocillin crude product separates with the D1300 macroporous resin adsorption;
(2) step (1) products obtained therefrom obtains the Sodium mezlocillin highly finished product with the cross-linked dextran gel column purifying of SephadexC series.
2. method for preparing the mezlocillin sodium injection is characterized in that may further comprise the steps:
(1) the Sodium mezlocillin crude product separates with the D1300 macroporous resin adsorption;
(2) step (1) the products obtained therefrom cross-linked dextran gel column purifying of SephadexC series, collection mezlocillin sodium content is not less than 99% component;
(3) step (2) gained Sodium mezlocillin highly finished product are through activated carbon decolorizing, and behind filtering with microporous membrane, lyophilize is crushed to 50-200 purpose fine powder, and packing under 100 grades of conditions in sterilisable chamber then makes the mezlocillin sodium injection.
3. method according to claim 2 wherein in the step (3), is crushed to 60-100 purpose fine powder.
4. according to each described method of claim 1-3, wherein the macroporous resin separation is carried out wash-out with pure water or distilled water as eluent in the step (1).
5. according to each described method of claim 1-3, wherein use SephadexC in the step (2)
15, SephadexC
25Or SephadexC
50The cross-linked dextran gel column purifying,, collect the mezlocillin sodium content and be not less than 99% component as eluent with the salts solution of 0.05～0.2mol/L concentration.
6. method according to claim 5, wherein said salts solution are selected from ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution and DL-Lactic acid ammonium salt solution.
7. method according to claim 5, wherein the gel column eluting temperature is 4 ℃～35 ℃.
8. method according to claim 7, wherein the gel column eluting temperature is 20 ℃～30 ℃.
9. method according to claim 2, wherein step (3) is middle with 0.22 μ m filtering with microporous membrane.
10. according to each described method of claim 1-3, wherein the Sodium mezlocillin crude product forms after by mezlocillin acid crude oxygenation sodium, sodium hydroxide, yellow soda ash or sodium bicarbonate in the step (1).
11. a method for preparing high-purity mezlocillin sodium is characterized in that comprising the steps:
(1) adds sodium hydroxide in the acid crude of mezlocillin, form the Sodium mezlocillin crude product;
(2) the Sodium mezlocillin crude product of step (1) separates with the D1300 macroporous resin adsorption, carries out wash-out with distilled water, collects the Sodium mezlocillin elutriant;
(3) step (2) gained Sodium mezlocillin elutriant carries out gel filtration chromatography after concentrating, it is gel that column packing is selected Sephadex C for use, ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution or DL-Lactic acid ammonium salt eluant solution with 0.05～0.2mol/L concentration, 4～30 ℃ of eluting temperatures, collection mezlocillin sodium content is not less than 99% component.
12. a method for preparing the mezlocillin sodium injection is characterized in that comprising the steps:
(1) adds sodium hydroxide in the acid crude of mezlocillin, form the Sodium mezlocillin crude product;
(2) the Sodium mezlocillin crude product of step (1) separates with the D1300 macroporous resin adsorption, carries out wash-out with distilled water, collects the Sodium mezlocillin elutriant;
(3) step (2) gained Sodium mezlocillin elutriant carries out gel filtration chromatography after concentrating, it is gel that column packing is selected Sephadex C for use, ammonium formate solution, ammonium acetate solution, propionic acid ammonium solution or DL-Lactic acid ammonium salt eluant solution with 0.05～0.2mol/L concentration, 4～30 ℃ of eluting temperatures, collection mezlocillin sodium content is not less than 99% component, obtains the Sodium mezlocillin highly finished product;
(4) the Sodium mezlocillin highly finished product of step (3) gained are through activated carbon decolorizing, 0.22um behind the filtering with microporous membrane, lyophilize, be crushed to 60-100 purpose fine powder, in sterilisable chamber, be distributed into every bottle then under 100 grades of conditions and contain Sodium mezlocillin and calculate 0.1～2.0 gram, make the mezlocillin sodium injection by the mezlocillin.
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| CN102579351B (en) * | 2012-03-23 | 2013-04-10 | 浙江磐谷药源有限公司 | Injection mezlocillin sodium liposome and preparation method |
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Assignee: SHANDONG WEIFANG PHARMACEUTICAL FACTORY CO., LTD. Assignor: Hainan Baina Pharmaceutical Development Co., Ltd. Contract record no.: 2011990000938 Denomination of invention: Method for producing high-purity mezlocillin sodium and powder injection thereof Granted publication date: 20100630 License type: Exclusive License Open date: 20080917 Record date: 20110928 |
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