CN102924483A - Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form - Google Patents
Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form Download PDFInfo
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Abstract
The invention relates to a ceftazidime crystal compound, a preparation method of the compound and a pharmaceutical composition of the compound in a sterile mixed powder form. The structural formula of the ceftazidime crystal compound is as shown in a formula (I); and the crystal compound is measured by using a powder X-ray diffraction measurement method, and an X-ray powder diffraction map expressed by a 2theta+/-0.2-degree diffraction angle shows characteristic diffraction peaks at 5.7 degrees, 7.6 degrees, 9.1 degrees, 11.8 degrees, 12.2 degrees, 12.6 degrees, 13.3 degrees, 15.5 degrees, 16.7 degrees, 18.4 degrees, 20.5 degrees, 25.8 degrees, 26.3 degrees and 31.8 degrees. The crystal compound is high in purity and stability, and almost does not absorb moisture.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to a kind of ceftazime crystalline compounds, its preparation method and without the pharmaceutical composition of bacterium mix powder form.
Background technology
Ceftazime; chemistry (6R by name; 7R)-7-[[(2-amino-4-thiazolyl)-[(1-hydroxyl-1-methyl ethoxy) imino-] ethanoyl] amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-3-picoline inner salt pentahydrate; for using clinically more widely cynnematin, its structural formula is:
In order to ensure the human body drug safety, the state-promulgated pharmacopoeia regulation for the ceftazime microbiotic, requires the content of ceftazidime pentahydrate to be not less than 95%, and the content of polymkeric substance is not higher than 0.3%, and its color and luster is not higher than look No. 6.The ceftazime microbiotic is in depositing process, particularly suffer in the situation of high temperature (＞50 ℃), degraded and polyreaction often occur, generate ceftazime dipolymer, trimer and polymer etc. polymkeric substance, thereby cause the active constituents of medicine content, color and luster is strengthened, and polymeric impurities content raises.In addition, expired ceftazime microbiotic because the shelf-time is long, also usually makes the active constituents of medicine content, darkens, and polymer content raises.Also have, in some cases, because controlling of production process is improper, resulting ceftazidime pentahydrate, ceftazime dipolymer, trimer and polymer etc. polymer content is high especially.And polymer content easily makes human body produce anaphylaxis when high.So for this base polymer foreign matter content high ceftazidime pentahydrate or ceftazime pharmaceutical preparation, be necessary further to carry out purifying, obtain ceftazidime pentahydrate crystal high-quality, that purity is high.
GB2063871 has disclosed the preparation method of ceftazidime pentahydrate crystal, and the method is that the pH of adjusting ceftazime hydrochlorate or the alkali salt aqueous solution is 3.3-4.0, and the ceftazidime pentahydrate crystal structure is separated out.The ceftazidime pentahydrate that above-mentioned polymeric impurities content is higher or ceftazime pharmaceutical preparation, for example, when polymeric impurities content is higher than 4%, method crystallization purifying according to GB2063871, polymeric impurities often is accompanied by the ceftazidime pentahydrate crystal and separates out together, so the content of polymeric impurities is still very high in the resulting ceftazidime pentahydrate crystal.
GB2157682 discloses a kind of recovery method of ceftazime, the method is to adopt the NOT-function large hole mesh resin, with pH be that the 2.0-5.5 ceftazime aqueous solution is removed, thereby absorb ceftazime, carry out again wash-out, isolate ceftazime or its salt or its hydrate.According to the method, final product may be ceftazime or its salt or its hydrate, and the impurity polymer content reduces, product color shoals, but the method need to be used the NOT-function large hole mesh resin, carries out wash-out, separation again, operation is many, complex operation, and cost is high.
US4659813 discloses a kind of preparation method of ceftazidime pentahydrate crystal, the method is, under about 5～15 ℃ temperature, pH is about ceftazime aqueous solution of 5.5～about 6.5, regulating its pH with acid is about 4.0～about 4.7, and in crystallisation process by the adding of control acid, make pH be maintained at about 4.0～about 4.7, thereby separate out the ceftazidime pentahydrate crystal.Although this method is to improving product purity, reducing polymer content has certain help, and the ceftazime preparation very high for polymer content, that color and luster is very poor in this way, still can not get high-quality ceftazidime pentahydrate crystal.Simultaneously, this method is dissolved in material in the higher system of pH first, causes ceftazime to be degraded to some extent, and the rate of recovery reduces like this.
CN1775784A discloses a kind of purification process of ceftazime, more particularly, relate to by impure, contain the high ceftazime of polymeric impurities by the method for the high-quality ceftazidime pentahydrate of crystalline.Ceftazidime pentahydrate impure, that polymer content is high, ceftazime hydrochloride, ceftazime ambroxol salt or the expired or ceftazime preparation from retrieving on the market, be mixed with the ceftazime aqueous solution, then the pH with alkali or the acid adjusting ceftazime aqueous solution is 1.5-2.5, impurity, ceftazime polymkeric substance follow a small amount of ceftazime to separate out together at this moment, remove by filter these precipitates, it is 3.5-4.8 that resulting filtrate is regulated pH with alkali, and the ceftazidime pentahydrate crystal structure is separated out.The method is easy and simple to handle, and cost is low, and security is good, and yield is high, and resulting ceftazidime pentahydrate crystal purity is high, and polymer content is low, reaches the pharmacopeia specified requirement.
CN101607966A discloses a kind of preparation method of ceftazidime pentahydrate, carries out according to following step: step 1, inject water for injection in a dissolving vessel, add the ceftazime hydrochloride, after the dissolving, drop into activated carbon decolorizing, filter, filtrate is stand-by; Step 2, inject water for injection in another dissolving vessel, add the ceftazime hydrochloride, after the dissolving, drop into gac, decolouring is filtered, and filtrate changes crystallizer over to; Can not walk three, drip alkaline solution in the crystallizer in the second step, regulate pH to 4.0-6.0, the filtrate that drips again in the first step makes pH value pull back to 3.6,0-10 ℃ of maintenance temperature, stirring, crystallization; Filter after the step 4, growing the grain 3-4 hour, filter cake washs respectively with cold water and acetone, vacuum-drying 2-3 hour, obtains the ceftazidime pentahydrate crystal.Its advantage is: economize on the use of funds, simplify technique, reduce the waste gas discharge of wastewater; Easy and simple to handle, be fit to suitability for industrialized production; Purity is high, yield is high.
Although above-mentioned purification process has solved its purity problem to a certain extent, but through further research discovery, because ceftazime is in depositing process, particularly under the condition of high temperature (＞50 ℃), degraded and polyreaction often occur, along with the prolongation of shelf-time, its superpolymer content increases, and the risk that makes human body produce anaphylaxis increases.
The inventor is take existing ceftazime crude product as raw material, through lot of experiments, made a kind of ceftazime compound that is different from the new crystal of prior art, and by test, found that pleasantly surprisedly the ceftazime compound of this crystal formation has good thermostability, its purity is higher, and substantially non-hygroscopic, and technique is simple, and yield is high, repeatability is strong, is suitable for suitability for industrialized production.And the aseptic powder injection of preparation has the advantage of good stability equally take the ceftazime compound of this new crystal as raw material, thereby has finished the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of ceftazime crystalline compounds, and this crystalline compounds purity is high, and has preferably thermostability, and substantially non-hygroscopic.
The second purpose of the present invention is to provide the preparation method of described ceftazime crystalline compounds, and the method technique is simple, and yield is high, and repeatability is strong, is suitable for suitability for industrialized production.
The 3rd purpose of the present invention is to provide the pharmaceutical composition of a kind of ceftazime without the bacterium mix powder form, and described pharmaceutical composition contains the ceftazime crystalline compounds that ceftazime crystalline compounds provided by the present invention or preparation method of the present invention make.
For realizing the first purpose of the present invention, the present invention adopts following technical scheme:
A kind of ceftazime crystalline compounds, it is characterized in that, the structural formula of described ceftazime compound is suc as formula shown in (I), this crystalline compounds is measured with the powder x-ray diffraction assay method, locates to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 5.7 °, 7.6 °, 9.1 °, 11.8 °, 12.2 °, 12.6 °, 13.3 °, 15.5 °, 16.7 °, 18.4 °, 20.5 °, 25.8 °, 26.3 ° and 31.8 °.
Formula (I)
For realizing the second purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation method of ceftazime crystalline compounds of the present invention, the method comprises the steps:
1) preparation crude product solution: the ceftazime crude product is added by in the formulated mixed solvent of methyl-sulphoxide and tetrahydrofuran (THF), stir and make dissolving, add activated carbon decolorizing, filtration obtains crude product solution, and is for subsequent use;
2) preparation recrystallisation solvent: with acetone and ethyl acetate by volume 1～2.5: 11.5 ratio prepare recrystallisation solvent, described recrystallisation solvent volume is 6～14 times of ceftazime crude product weight;
3) crystallization: under stirring, to step 1) stream adds step 2 in the crude product solution of gained) the gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip ethanol, to there being crystal to separate out; Leave standstill 3～6h, filter, with the methyl-sulphoxide washing, drying obtains described ceftazime compound.
Among the present invention, described ceftazime crude product can be the ceftazidime pentahydrate that adopts the synthetic method of the method for prior art such as the disclosed ceftazime of CN102391289A to prepare, and also can be commercially available ceftazidime pentahydrate bulk drug.
Among the preparation method of the present invention, wherein, step 1) weightmeasurement ratio of ceftazime crude product and described mixed solvent is 1: 5～11 described in.
The volume ratio of methyl-sulphoxide and tetrahydrofuran (THF) is 2.5～7.5: 1 in the described mixed solvent
Step 3) stream adds step 2 in) stirring velocity during the gained recrystallisation solvent is 880～1000r/min; Stirring velocity when dripping ethanol is 400～600r/min.
The speed that described stream adds is 10～15ml/min; The speed of described dropping is 3～7ml/min.
Alleged among the present invention " weight " unit is gram or kilogram, and corresponding " volume " unit be milliliter or rises with it, and the weight unit of namely using when the ceftazime crude product is when restraining, and the volume unit of solvent is milliliter in the operating process; The weight unit of using when the ceftazime crude product is during as kilogram, and the volume unit of solvent is for rising in the operating process.
For realizing the 3rd purpose of the present invention, the present invention adopts following technical scheme:
A kind of pharmaceutical composition, described pharmaceutical composition contain the ceftazime crystalline compounds that ceftazime crystalline compounds of the present invention or preparation method of the present invention make.
Pharmaceutical composition of the present invention also contains anhydrous sodium carbonate.
The mol ratio of ceftazime crystalline compounds and anhydrous sodium carbonate is 1: 0.64～0.70 in the described pharmaceutical composition.
Described pharmaceutical composition is that ceftazime crystalline compounds and anhydrous sodium carbonate are made aseptic powder injection by described mixed in molar ratio by after aseptic subpackaged.
Sterilized powder of the present invention can carry out packing by the specification of 0.5g/ bottle, 1.0g/ bottle, 2.0g/ bottle etc.The specification here is in the ceftazime active ingredient, and namely 1g ceftazime active ingredient is equivalent to the 1.282g ceftazidime pentahydrate.
Compared with prior art, the present invention has following advantage:
(1) ceftazime crystalline compounds purity provided by the present invention is high, and has preferably thermostability, and substantially non-hygroscopic;
(2) preparation method's technique of ceftazime provided by the present invention is simple, and yield is high, and repeatability is strong, is suitable for suitability for industrialized production;
(3) the pharmaceutical composition stability that contains this ceftazime crystalline compounds provided by the present invention is fine, thereby has improved drug safety and validity, has reduced the incidence of untoward reaction.
Description of drawings
Fig. 1 is the X-ray powder diffraction figure of ceftazime crystalline compounds of the present invention.
Embodiment
In the present invention, adopt the content of high effective liquid chromatography for measuring ceftazime and the content that size exclusive chromatography is measured high molecular polymer (high performance liquid chromatography and size exclusive chromatography are that the relevant condition of appendix VD and appendix VH is measured according to second of pharmacopeia in 2005).
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
The preparation of [embodiment 1] ceftazime crystalline compounds
1) preparation crude product solution: it is in the formulated mixed solvent of 5: 1 ratio by methyl-sulphoxide and tetrahydrofuran (THF) by volume that ceftazime crude product 200g is added 1500ml, stirs and makes dissolving, adds activated carbon decolorizing, and filtration obtains crude product solution, and is for subsequent use;
2) preparation recrystallisation solvent: with acetone and 2: 10 by volume ratio of ethyl acetate preparation recrystallisation solvent, described recrystallisation solvent volume is 12 times of ceftazime crude product weight;
3) crystallization: under stirring, to step 1) stream adds step 2 in the crude product solution of gained) the gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip ethanol, to there being crystal to separate out; Leave standstill 5h, filter, with the methyl-sulphoxide washing, drying obtains described ceftazime crystalline compounds.Yield 92%, content are 98.8%, and the content of polymkeric substance is 0.01%.
The ceftazime crystalline compounds that obtains is measured with the powder x-ray diffraction assay method, locate to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 5.7 °, 7.6 °, 9.1 °, 11.8 °, 12.2 °, 12.6 °, 13.3 °, 15.5 °, 16.7 °, 18.4 °, 20.5 °, 25.8 °, 26.3 ° and 31.8 °, as shown in Figure 1.
The preparation of [embodiment 2～9] ceftazime crystalline compounds
Below be embodiments of the invention 2-9, step is with embodiment 1, and the concrete technology parameter sees Table 1:
Table 1, embodiment 2-9
The resulting ceftazime crystalline compounds of embodiment 2-9 is measured with the powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates that represents with 2 θ ± 0.2 ° diffraction angle is with embodiment 1.
[example of formulations 1] ceftazime aseptic powder injection
The preparation method:
1, interior packaging material is processed
Antibiotic glass bottle, plug, aluminium lid routinely technique clean, dry, sterilize, and be for subsequent use;
2, concrete steps
(1) takes by weighing the prepared ceftazime crystal of the anhydrous sodium carbonate of recipe quantity and embodiment 1, in sterile chamber, mix;
(2) product check in the middle of;
(3) undertaken aseptic subpackaged by specification;
(4) vacuumize, tamponade, roll lid;
(5) packing, full inspection, warehouse-in.
[example of formulations 2] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 2.
[example of formulations 3] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 3.
[example of formulations 4] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 4.
[example of formulations 5] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 5.
[example of formulations 6] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 6.
[example of formulations 7] ceftazime aseptic powder injection
The preparation method: with example of formulations 1, difference is that used ceftazime is the prepared ceftazime crystal of embodiment 7.
Comparative example 1
Degraded and polyreaction particularly under the condition of high temperature (＞50 ℃), often occur, thereby cause the active constituents of medicine content in depositing process in ceftazime, and color and luster is strengthened, and polymeric impurities content raises.This comparative example is used for investigating the prepared ceftazime crystalline compounds of the present invention and the thermal stability difference of ceftazime of the prior art.
Each sample is numbered in this comparative example:
Trial target 1: the ceftazime crystalline compounds that the embodiment of the invention 1 is prepared;
Trial target 2: the ceftazime crystalline compounds that the embodiment of the invention 6 is prepared;
Reference substance 1: according to the method for CN1775784A embodiment 1 ceftazidime pentahydrate is carried out the ceftazidime pentahydrate that obtains behind the purifying;
Reference substance 2: the ceftazidime pentahydrate crystal that obtains according to the method for CN101607966A embodiment 1.
With each sample be exposed to respectively that relative humidity is 75%, temperature is under 60 ℃ the environment, (high performance liquid chromatography and size exclusive chromatography are according to second one of pharmacopeia in 2005 to adopt the content of ceftazime behind the high performance liquid chromatography test different time and the content that size exclusive chromatography is measured high molecular polymer, the relevant condition of appendix VD and appendix VH is measured), the results are shown in Table 2.
Table 2, thermostability comparative result
As can be seen from the above table, adopt the thermostability of the ceftazime crystalline compounds that method of the present invention makes significantly to be better than adopting the method for prior art to carry out the ceftazidime pentahydrate crystal that obtains behind the purifying.
Ceftazime crystalline compounds to other embodiment of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Comparative example 2
High wet test
The purification process that this comparative example is used for investigating the prepared ceftazime compound of the present invention and adopt prior art is processed the water absorbability difference of the ceftazidime pentahydrate crystal that obtains.
The compound of sample 1-4 numbering representative is with comparative example 1.
Each sample opening is put in the clean culture dish, spread out into≤thin layer that 5mm is thick, each two parts, put into respectively the constant humidity encloses container, placed 10 days under respectively at the condition of relative humidity 75% and 92.5% at 25 ℃, took a sample in the 5th day and the 10th day, by the moisture content of each sample of weight loss on drying experiment measuring, test-results and comparison in 0 day, test-results sees Table 3.
Table 3, high humidity test-results
As can be seen from the above table, the ceftazime crystalline compounds of the present invention's preparation is substantially non-hygroscopic under high humidity, and its stability under high humidity environment obviously is better than adopting the purification process of prior art to process the ceftazidime pentahydrate crystal that obtains.
Ceftazime crystalline compounds to other embodiment of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Comparative example 3
Stability test
With the sample of example of formulations 2 preparations of the present invention and (Shanghai Xinxianfeng Pharmaceutical Co., Ltd.'s production of the ceftazime powder injection of listing, specification 1.0g/ bottle) influence factor test investigation was carried out in placement in 10 days under 60 ℃ of high temperature, illumination 4500Lx condition, the results are shown in Table 4; Under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, placed 6 months, carry out accelerated test and investigate, the results are shown in Table 5; Under 25 ℃ of high temperature, relative humidity 60% ± 10% condition, placed 18 months, and carried out test of long duration and investigate, detect the variation of every quality index, the results are shown in Table 4, table 5 and table 6.
Table 4, influence factor result
Table 5, accelerated test result
Table 6, long-term test results
Be found that by above accelerated test March, June, the ceftazime aseptic powder injection clarity that test of long duration was gone on the market in the time of 18 months is against regulation, the pH value descends larger, and content is obvious, and related substance raises; And the sample appearance proterties of the present invention's preparation does not have considerable change, redissolves well, and clarity, pH value, content and related substance significantly do not change yet.The sample stable quality after long time storage that the present invention's preparation is described is better.
Ceftazime aseptic powder injection to other example of formulations of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. ceftazime crystalline compounds, it is characterized in that, the structural formula of described ceftazime crystalline compounds is suc as formula shown in (I), this crystalline compounds is measured with the powder x-ray diffraction assay method, locate to demonstrate characteristic diffraction peak with the X-ray powder diffraction collection of illustrative plates that 2 θ ± 0.2 ° diffraction angle represents at 5.7 °, 7.6 °, 9.1 °, 11.8 °, 12.2 °, 12.6 °, 13.3 °, 15.5 °, 16.7 °, 18.4 °, 20.5 °, 25.8 °, 26.3 ° and 31.8 °
Formula (I).
2. the preparation method of a ceftazime crystalline compounds claimed in claim 1 is characterized in that, the method comprises and comprising the steps:
1) preparation crude product solution: the ceftazime crude product is added by in the formulated mixed solvent of methyl-sulphoxide and tetrahydrofuran (THF), stir and make dissolving, add activated carbon decolorizing, filtration obtains crude product solution, and is for subsequent use;
2) preparation recrystallisation solvent: with acetone and ethyl acetate by volume 1～2.5: 11.5 ratio prepare recrystallisation solvent, described recrystallisation solvent volume is 6～14 times of ceftazime crude product weight;
3) crystallization: under stirring, to step 1) stream adds step 2 in the crude product solution of gained) the gained recrystallisation solvent, there is solid to separate out; After dropwising, continue under agitation to drip ethanol, to there being crystal to separate out; Leave standstill 3～6h, filter, with the methyl-sulphoxide washing, drying obtains described ceftazime compound.
3. preparation method according to claim 2 is characterized in that step 1) described in the weightmeasurement ratio of ceftazime crude product and described mixed solvent be 1: 5～11.
4. preparation method according to claim 3 is characterized in that, the volume ratio of methyl-sulphoxide and tetrahydrofuran (THF) is 2.5～7.5: 1 in the described mixed solvent.
5. preparation method according to claim 2 is characterized in that step 3) in stream add step 2) stirring velocity during the gained recrystallisation solvent is 880～1000r/min; Stirring velocity when dripping ethanol is 400～600r/min.
6. preparation method according to claim 5 is characterized in that, the speed that described stream adds is 10～15ml/min; The speed of described dropping is 3～7ml/min.
7. a ceftazime is without the pharmaceutical composition of bacterium mix powder form, it is characterized in that described pharmaceutical composition contains the ceftazime crystalline compounds that ceftazime crystalline compounds claimed in claim 1 or the described preparation method of claim 2-6 any one make.
8. pharmaceutical composition according to claim 7 is characterized in that, described pharmaceutical composition also contains anhydrous sodium carbonate.
9. pharmaceutical composition according to claim 8 is characterized in that, the mol ratio of ceftazime crystalline compounds and anhydrous sodium carbonate is 1: 0.64～0.70 in the described pharmaceutical composition.
10. pharmaceutical composition according to claim 9 is characterized in that, described pharmaceutical composition is that ceftazime crystalline compounds and anhydrous sodium carbonate are made aseptic powder injection by described mixed in molar ratio by after aseptic subpackaged.
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| CN103864819A (en) * | 2014-03-31 | 2014-06-18 | 悦康药业集团有限公司 | Ceftazidime compound and pharmaceutical composition thereof |
| CN106167498A (en) * | 2016-06-23 | 2016-11-30 | 石药集团中诺药业（石家庄）有限公司 | A kind of new ceftazidime compound |
| CN106317081A (en) * | 2016-08-22 | 2017-01-11 | 山东罗欣药业集团恒欣药业有限公司 | Anti-inflection pharmaceutical ceftazidime crystal compound and ceftazidime pharmaceutical composition |
| CN106317080A (en) * | 2016-08-17 | 2017-01-11 | 陕西顿斯制药有限公司 | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof |
| CN106397458A (en) * | 2016-09-23 | 2017-02-15 | 临沂草之美医药科技有限公司 | Ceftazidime crystal compound as drug for treating infection during surgical operation |
| CN106432280A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Medicine ceftazidime crystalline compound for treating surgical operation infection |
| CN106420619A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Drug ceftazidime dry suspension for treating surgery infection |
| CN106432281A (en) * | 2016-09-23 | 2017-02-22 | 临沂草之美医药科技有限公司 | Preparation method of pharmaceutical ceftazidime crystal compound for treating surgical infection |
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| CN103864819A (en) * | 2014-03-31 | 2014-06-18 | 悦康药业集团有限公司 | Ceftazidime compound and pharmaceutical composition thereof |
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| CN106317080A (en) * | 2016-08-17 | 2017-01-11 | 陕西顿斯制药有限公司 | Ceftazidime compound prepared by adopting coupling crystallization technology and preparation thereof |
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