CN100532383C - Cefoperazone sodium novel crystal form and its preparation method - Google Patents
Cefoperazone sodium novel crystal form and its preparation method Download PDFInfo
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- CN100532383C CN100532383C CNB2005100869501A CN200510086950A CN100532383C CN 100532383 C CN100532383 C CN 100532383C CN B2005100869501 A CNB2005100869501 A CN B2005100869501A CN 200510086950 A CN200510086950 A CN 200510086950A CN 100532383 C CN100532383 C CN 100532383C
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Abstract
The invention discloses a new stable crystal system of cefoperazone sodium, which is composed of one or more of hypotype I, II and II of crystal system A. the invention also provides the making method of three hypotypes and application in the anti-infective agent.
Description
Technical field
The present invention relates to pharmacy field, relate to a kind of stable cefoperazone sodium crystal specifically, relate to the preparation method and the application of three kinds of hypotypes of described crystal formation simultaneously.
Background technology
T-1551 (cefoperazone sodium), its chemical name is: (6R, 7R)-and 3-[[(1-methyl isophthalic acid H-tetrazolium-5 base) sulphur] methyl]-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine carbon acylamino)-2-p-hydroxybenzene-kharophen]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt.Advantages such as it belongs to third generation cephalosporin analog antibiotic, and it has has a broad antifungal spectrum, and anti-microbial effect is strong are widely used in clinically, and as cefoperazone for inj sodium, the compound preparation made from Sulbactam is a cefoperazone for inj sodium and sulbactam sodium etc.
T-1551 all has fairly large production at home and abroad at present, and for fullying understand the quality present situation of homemade cefoperazone for inj sodium, Nat'l Pharmaceutical ﹠ Biological Products Control Institute has carried out the emphasis examination at random in 2000 to it in the microbiotic chamber.The sample of this examination at random is distributed in 17 provinces from 28 manufacturing enterprises, and total lot number is 112 batches, and wherein 72 batches are directly extracted by manufacturing enterprise, account for 64.3% of total lot number; 40 batches are extracted from the circulation field, account for 35.7%.
According to Chinese Pharmacopoeia nineteen ninety-five version the sample that extracts is tested, it is as follows that the result adds up:
1, total qualification rate of inferior examination at random is 88.4%; 13 batch samples are against regulation, and disqualification rate is 11.6%.
2, from Interventions Requested, the color of proterties, clarity, solution, crystallinity are all up to specification, and the assay item is against regulation in the substandard product 8 batches (dividing 5 producers), accounts for 61.5% of defective sum; Clarity is underproof 2 batches (dividing 2 producers), accounts for 15.4%; Moisture is underproof 3 batches (1 producer), accounts for 23.1%.
3, from sample source, from have 8 batches of the field of circulation, account for 61.5% of defective sum in the substandard product, it is against regulation to be the assay item; And clarity and moisture failure all take out from production producer (totally 5 batches, account for defective sum 38.5%).
The result shows that content is defective to be to cause the underproof major cause of homemade cefoperazone for inj sodium product, and 8 batches of against regulation products of this inspection are all taken out from the circulation field.Do correlation analysis by effect phase and content to product, find that total trend is: the sample of approaching more effect phase, content are low more.The prompting T-1551 decomposes in the shelf lives gradually.
So the stability from production field raising T-1551 has great significance to its safe and effective medication.
Summary of the invention
(1) technical problem that will solve
Purpose of the present invention aims to provide a kind of stable cefoperazone sodium crystal that helps as pharmaceutical preparation, and the preparation method and the application in the preparation anti-infectives thereof of stable cefoperazone sodium crystal are provided.
(2) technical scheme
The present inventor discovers that there are two kinds of different crystal formations in T-1551 crystal type sample, and we are referred to as A crystal formation and B crystal formation respectively.The experiment of high temperature powder X-ray diffraction, thermal analysis experiment and accelerated stability test confirm that all A crystal formation T-1551 is more stable than the B crystal formation.
T-1551 A crystal formation is done cluster analysis, be divided into five hypotypes again, further compare the degree of crystallinity of different subtype, find the stable best of hypotype I, hypotype II and hypotype III take second place slightly, but all are better than hypotype IV and hypotype V.
Stable T-1551 provided by the invention is made up of hypotype I, the II of T-1551 A crystal formation, among the III one or more.This crystal formation is a triclinic(crystalline)system, and unit cell parameters is: a=1.5888nm, b=1.3070nm, c=1.1007nm, α=115.98, β=161.76, γ=80.60, spacer are P-1, P1.Being characterized as of each hypotype wherein:
Hypotype I:, distinguish the strong (I/I of corresponding relative diffraction peak at 10 diffractive features peak position places that 2 θ are 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1
0) parameter is 29.63 ± 3.01,26.50 ± 3.21,41.75 ± 4.50,100 ± 0,44.88 ± 5.39,39.38, ± 4.89,63.88 ± 5.99,63.88 ± 3.28,65.13 ± 3.92 and 37.88 ± 4.71 (2SD represents with mean value).
Hypotype II:, distinguish the strong (I/I of corresponding relative diffraction peak at 10 diffractive features peak position places that 2 θ are 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1
0) parameter was 31.6 ± 6.63,26.6 ± 6.42,44.8 ± 1.67,100 ± 0,57.2 ± 4.56,49.6 ± 2.28,79 ± 6.16,72.6 ± 5.02,72.8 ± 3.29 and 44.4 ± 4.15 (2SD represents with mean value).
Hypotype III:, distinguish the strong (I/I of corresponding relative diffraction peak at 10 diffractive features peak position places that 2 θ are 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1
0) parameter was 32.14 ± 2.69,27.86 ± 4.07,43.57 ± 7.29,100.0 ± 0,66.57 ± 5.52,57.57 ± 6.41,94.00 ± 7.66,83.00 ± 6.93,78.86 ± 5.35 and 50.00 ± 3.27 (2SD represents with mean value).
T-1551 A crystal formation of the present invention prepares by following step:
(1) in acetone or ethanol solution, stir adding cefoperazone acid and distilled water down, three by volume weight ratio is 1-2.5:1:1, stirs also to add the alkali salify, regulates between the pH5.0-7.0.
(2) stir 0.5-1 hour after-filtration mixture and being pressed in the aseptic crystallization still, controlled temperature 20-40 ℃, stir the acetone or the dehydrated alcohol that add down with cefoperazone acid envelope-bulk to weight ratio 0.4-0.6:1.
(3) add a small amount of T-1551 A crystal formation hypotype I, II or III crystal seed, stir, adding is carried out crystallization with the acetone of cefoperazone acid envelope-bulk to weight ratio 10-16:1 then, stirs.
(4) growing the grain 0.5-1.5 hour, filter, use the washing with acetone crystallization, drying.
Temperature is controlled at 10-30 ℃ when wherein stirring in the step (1), and used alkali is selected from one or more in yellow soda ash, sodium bicarbonate, sodium-acetate and the Sodium isooctanoate.
Mixing speed is controlled at 10-60 rev/min after wherein adding crystal seed in the step (3), add the acetone speed control the 8-16 liter/minute.
Preferred 40 ℃ of dryings 20 hours in vacuum drying oven of the crystallization of gained in the step (4) wherein.
The present invention also provides the I of T-1551 A crystal formation, II, the application of III hypotype in the preparation anti-infectives, can will be selected from above-mentioned three kinds of crystal formations one or more as effective constituent, make cefoperazone for inj sodium according to the ordinary method of this area, perhaps make the cefoperazone for inj sodium and sulbactam sodium with the Sulbactam beta-lactamase inhibitor, perhaps with clavulanic acid, beta-lactamase inhibitors such as Tazobactam Sodium are made pharmaceutically acceptable compound preparation, and the mixing ratio of T-1551 A crystal formation and beta-lactamase inhibitor is as being the weight ratio of 1:10-10:1 in the compound preparation.Such combination can further strengthen anti-infectious effect.
(3) beneficial effect
Cefoperazone sodium crystal of the present invention is compared with T-1551 at present commonly used and is shown better stability.
Description of drawings
Fig. 1 is a T-1551 powder x-ray diffraction collection of illustrative plates
Fig. 2 is the high temperature powder X-ray diffraction collection of illustrative plates of T-1551 A crystal formation
Fig. 3 is the high temperature powder X-ray diffraction collection of illustrative plates of T-1551 B crystal formation
Fig. 4 is the DSC collection of illustrative plates of T-1551 A, two kinds of crystal formations of B
Fig. 5 is the influence curve figure of temperature to the stability of A, two kinds of crystal formations of B and unformed T-1551
Fig. 6 is the influence curve figure of humidity to the stability of A, two kinds of crystal formations of B and unformed T-1551
Fig. 7-9 is that the powder x-ray diffraction of T-1551 A crystal formation hypotype I, II, III sample is represented collection of illustrative plates
Figure 10-12 is the electromicroscopic photograph (8000 times) of T-1551 A crystal formation hypotype I, II, III sample
Figure 13-16 is the HPLC color atlas of T-1551 A crystal formation hypotype I, II, III, V sample
Figure 17 is the HPLC color atlas of T-1551 control sample
Embodiment
Can further be expressly understood the present invention by specific embodiments of the invention given below, but following embodiment not a limitation of the invention.
The classification of embodiment 1 T-1551 crystal type sample
112 batches of homemade cefoperazone for inj sodium of examination at random are carried out finding when powder x-ray diffraction is analyzed be all the crystal type sample but have two kinds of different diffracting spectrums, diffraction peak distributing position of the two and intensity are all inequality, see Fig. 1.Prompting T-1551 crystal type sample may have two kinds of different crystal formations, and we are referred to as A crystal formation and B crystal formation respectively.I/I with A crystal formation and B crystal formation feature top eight spectral line separately
0, 2 θ, d/n value (the d/n value is calculated by Bragg equation 2d sin θ=n λ) list in the table 1 respectively.As seen the d/n value of A crystal formation and B crystal formation is obviously different, further specifies the crystal type T-1551 and has two kinds of different crystal formations.
The powder x-ray diffraction data of the T-1551 of two kinds of different crystal forms of table 1
The comparison of embodiment 2 A crystal formations and B stable crystal form
2.1. lattice stability
2.1.1 high temperature powder X-ray diffraction experiment
Two kinds of crystal formations of T-1551 A, B are carried out the experiment of high temperature powder X-ray diffraction respectively, and when finding that the A crystal formation is heated to 120 ℃, the peak intensity of diffraction peak begins to weaken; 2 θ be 28.58,28.30 diffraction peak from acromion be merged into unimodal then have be divided into two diffraction peaks that intensity is less; During to 140 ℃, each diffraction peak position and the variation of intensity in its diffracting spectrum are all little, show that too big variation, better heat stability do not take place lattice.The high temperature powder X-ray diffraction collection of illustrative plates of T-1551 A, two kinds of crystal formations of B is seen Fig. 2 and Fig. 3.
2.1.2 thermal analysis experiment
Same a kind of medicine that crystal formation is different, fusing point often there are differences, and has only a kind of crystal formation stable on thermodynamics usually, and it is higher to show as fusing point.Two kinds of crystal formations of T-1551 A, B are carried out the DSC experiment respectively, find that the DSC curve of A crystal formation is milder, do not have tangible thermal change, show that the A crystal formation is more stable.The DSC collection of illustrative plates of T-1551 A, two kinds of crystal formations of B is relatively seen Fig. 4.
3.2 accelerated stability test
3.2.1 temperature effect
T-1551 is with the rising of the temperature acceleration of degrading, but temperature is to the difference that influences of different crystal forms T-1551 stability.(below 60 ℃) at a lower temperature, the more unformed sample of crystal type sample is stable, three's stability order is: the A crystal formation〉the B crystal formation〉unformed; And under the hot conditions (more than 70 ℃), the B crystal form samples is least stable, and three's stability order is: the A crystal formation〉unformed the B crystal formation, and along with the rising of temperature, the degradation speed increase of B crystal form samples is the fastest.The stability that shows T-1551 not only with whether be that crystal type is relevant, and relevant with the crystalline type, A crystal formation stable best.Temperature is relatively seen Fig. 5 to the influence of the stability of A, two kinds of crystal formations of B and unformed T-1551.
3.2.2 humidity effect
T-1551 is with the increase of humidity, and degraded is accelerated.Three's stability order is: the A crystal formation〉the B crystal formation〉unformed.Unformed stability of sample is subjected to having the greatest impact of humidity: along with the increase of humidity, and its stability decreases, degraded is accelerated.The crystal type sample is with also having this trend, but changes not obvious.Humidity is relatively seen Fig. 6 to the influence of the stability of A, two kinds of crystal formations of B and unformed T-1551.
The cluster analysis of embodiment 3 T-1551 A crystal form samples
Choose totally 24 batches of T-1551 A crystal form samples of various processes gained and carry out the powder x-ray diffraction experiment, spectrogram is analyzed with RISM.Qualitative Analysis software at random, obtain corresponding with it peak strong (I) in the average diffraction peak (2 θ) at the last 10 peak and each the sample collection of illustrative plates, the results are shown in Table 2-1, and the strong (I/I in relative peak
0), the results are shown in Table 2-2.The hierarchical clustering method that utilization SPSS software provides is classified to the A crystal form samples, and A crystal formation cefoperazone sodium sample can further be divided into 5 hypotypes: being numbered 13,14,15,6 and 7 sample is the I hypotype; Being numbered 4,17,12,19,11,8,10,1,2,3,16 and 24 sample is the II hypotype; Being numbered 5,20 and 18 sample is the III hypotype; Being numbered 9 sample is the IV hypotype; Being numbered 21,23 and 22 sample is the V hypotype.
Table 2-1 T-1551 A crystal form samples diffractive features cluster data
Table 2-2 T-1551 A crystal form samples diffractive features cluster data
Embodiment 4 T-1551 A crystal formation I, II, III hypotype characteristic parameter are measured
The sample of further choosing T-1551 A crystal formation I, II, III hypotype carries out the powder x-ray diffraction experiment, gets the strong (I/I in the relative peak of diffraction peak of each sample indescribably in diffractive features peak position (2 θ=7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5,25.1) punishment
0) as index parameter, wherein hypotype I, II, III characteristic parameter see Table 2-3, on behalf of collection of illustrative plates, the powder x-ray diffraction of sample see Fig. 7-9, and the electromicroscopic photograph of each hypotype sample (8000 times) is seen Figure 10-12.
The powder x-ray diffraction characteristic parameter of table 2-3 T-1551 A crystal formation I, II, III hypotype sample
Comparison between embodiment 5 each hypotype of T-1551 A crystal formation
5.1 the comparison of degree of crystallinity
Degree of crystallinity is defined as the per-cent of crystallising part and unformed part in the sample, and its numerical value has reflected the quality of sample crystallization degree to a certain extent.Account for the relative crystallinity of each sample of percentage calculation of total peak integral area with the diffraction peak area sum of each sample of A crystal formation T-1551, the result shows, the average crystallite degree difference of each hypotype sample, the average crystallite degree of hypotype I is the highest, hypotype II and hypotype III take second place slightly, but all are higher than hypotype IV and hypotype V.
5.2 the comparison of chemical stability
Choose the representative sample of each hypotype of A crystal formation T-1551, carry out the mensuration of content and related substance with the HPLC method after room temperature is placed certain hour, relatively the chemical stability of each hypotype sample the results are shown in Figure 13-16.Because IV hypotype sample size is few, points out it not to be of universal significance, therefore do not do further discussion.
In Figure 13-16, with respect to the relative retention time (RRT) of T-1551 main peak is that 0.31,0.88 and 1.48 impurity peaks (1,2, No. 3 chromatographic peak in the corresponding collection of illustrative plates respectively) peak area is bigger, be the related substance that mainly contains in the sample, wherein RRT is that 0.88 No. 2 impurity structures are known, is cefoperazone degradation product B.
With a collection of without the A crystal formation cefoperazone sodium sample of placing in contrast, the difference of different subtype sample content and related substance changing conditions after room temperature is placed certain hour relatively, color atlas is seen Figure 17, data results sees Table 3.
The chemical stability of each hypotype sample of table 3 A crystal formation T-1551 relatively
The result shows that T-1551 can be degraded in put procedure, content reduces, related substance increases.By comparing and can infer with control sample, be the degraded product except that known No. 2 impurity of structure in the sample, No. 1 and No. 3 impurity also should mainly be produced by degraded.On the other hand, by each hypotype sample relatively after the identical time places content reduction value and the related substance increased value as can be known, the chemical stability difference of each hypotype sample, wherein the stability of hypotype I, II, III better.
5.3 degree of crystallinity and sample chemical stability relationship
Crystal type medicine crystal formation is identical but not necessarily have identical chemical stability.By to each hypotype sample room degree of crystallinity of A crystal formation T-1551 and chemical stability more as can be seen, the chemical stability of sample and its degree of crystallinity are proportionate, along with reducing of degree of crystallinity, stability reduces.In 5 hypotypes, hypotype I's is stable best, and hypotype II and hypotype III take second place slightly, but all is better than hypotype IV and hypotype V.With regard to stability with regard to, experimental result shows, the average crystallite degree difference of each hypotype sample of A crystal formation T-1551, and degree of crystallinity high chemical stability is good more more.And the difference of prepared just preparation of the mass discrepancy of T-1551 and compound formulation.
The preparation of embodiment 6 T-1551 A crystal formation hypotype I
(1) add 45L acetone in reactor, open and stir the acid of adding 25kg cefoperazone, add 25L distilled water then, stirred 15 minutes, temperature is controlled at 20 ℃, under agitation slowly adds sodium bicarbonate then, regulates pH5.0;
(2) stirring was pressed in the sterilisable chamber intercrystalline still by sterile filtration sheet frame and 0.22 μ m folder filter after 1 hour, and Tc is controlled at 20 ℃, opened to stir to add 15L acetone;
(3) add a small amount of T-1551 A crystal formation hypotype I, continue to stir 0.5 hour, add the crystallization of 400L acetone, mixing speed is controlled at 20 rev/mins, adds the acetone speed control at 8 liters/minute;
(4) stirred down growing the grain 1 hour, filter, use washing with acetone again, filter is done the back 40 ℃ of vacuum drying oven inner dryings 20 hours.
Obtain the 23.2kg T-1551, the result is A crystal formation hypotype I through the x-ray diffraction analysis.
The preparation of embodiment 7 T-1551 A crystal formation hypotype I
(1) add 62L acetone in reactor, open and stir the acid of adding 25kg cefoperazone, add 25L distilled water then, stirred 15 minutes, temperature is controlled at 30 ℃, under agitation slowly adds sodium bicarbonate then, regulates pH7.0;
(2) stirring was pressed in the sterilisable chamber intercrystalline still by sterile filtration sheet frame and 0.22 μ m folder filter after 0.5 hour, and Tc is controlled at 40 ℃, opened to stir to add 12L acetone;
(3) add a small amount of T-1551 A crystal formation hypotype I, continue to stir 0.5 hour, add the crystallization of 250L acetone, mixing speed is controlled at 50 rev/mins, adds the acetone speed control at 15 liters/minute;
(4) stirred down growing the grain 0.5 hour, filter, use washing with acetone again, filter is done the back 40 ℃ of vacuum drying oven inner dryings 20 hours.
Obtain the 23.2kg T-1551, the result is A crystal formation hypotype I through the x-ray diffraction analysis.
The preparation of embodiment 8 T-1551 A crystal formation hypotype II
(1) add 25L acetone in reactor, open and stir the acid of adding 25kg cefoperazone, add 25L distilled water then, stirred 15 minutes, temperature is controlled at 10 ℃, under agitation slowly adds Sodium isooctanoate and sodium-acetate then, regulates pH6.0;
(2) stirring was pressed in the sterilisable chamber intercrystalline still by sterile filtration sheet frame and 0.22 μ m folder filter after 0.5 hour, and Tc is controlled at 30 ℃, opened to stir to add the 10L dehydrated alcohol;
(3) add a small amount of T-1551 A crystal formation hypotype II, continue to stir 0.5 hour, add the crystallization of 300L acetone, mixing speed is controlled at 60 rev/mins, adds the acetone speed control at 10 liters/minute;
(4) stirred down growing the grain 1.5 hours, filter, use washing with acetone again, filter is done the back 40 ℃ of vacuum drying oven inner dryings 20 hours.
Obtain the 23.0kg T-1551, the result is A crystal formation hypotype II through the x-ray diffraction analysis.
The preparation of embodiment 9 T-1551 A crystal formation hypotype III
(1) add 45L acetone in reactor, open and stir the acid of adding 25kg cefoperazone, add 25L distilled water then, stirred 15 minutes, temperature is controlled at 20 ℃, under agitation slowly adds sodium bicarbonate then, regulates pH5.0;
(2) stirring was pressed in the sterilisable chamber intercrystalline still by sterile filtration sheet frame and 0.22 μ m folder filter after 1 hour, and Tc is controlled at 20 ℃, opened to stir to add 15L acetone;
(3) add a small amount of T-1551 A crystal formation hypotype III, continue to stir 0.5 hour, add the crystallization of 350L acetone, mixing speed is controlled at 30 rev/mins, adds the acetone speed control at 13 liters/minute;
(4) stirred down growing the grain 1.5 hours, filter, use washing with acetone again, filter is done the back 40 ℃ of vacuum drying oven inner dryings 20 hours.
Obtain the 23.1kg T-1551, the result is A type the 3rd a class crystal formation through the x-ray diffraction analysis.
Each hypotype packing under aseptic condition respectively with embodiment 4-6 gained T-1551 A crystal formation promptly gets cefoperazone for inj sodium.
Each hypotype of embodiment 4-6 gained T-1551 A crystal formation is mixed with arbitrary proportion, mix powder with the weight ratio of 1:1, promptly get the cefoperazone for inj sodium and sulbactam sodium after aseptic subpackaged with sulbactam.
Claims (10)
1, a kind of T-1551 A crystal formation is characterized in that this crystal formation is a triclinic(crystalline)system, and unit cell parameters is: a=1.5888nm, b=1.3070nm, c=1.1007nm, α=115.98, β=161.76, γ=80.60, spacer are P-1, P1.
2, T-1551 A crystal formation as claimed in claim 1 is characterized in that it forms by being selected from the following hypotype one or more:
Hypotype I: at 2 θ is 10 diffractive features peak position places of 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1, and the Dui Ying strong parameter of relative diffraction peak is 29.63 ± 3.01,26.50 ± 3.21,41.75 ± 4.50,100 ± 0,44.88 ± 5.39,39.38 ± 4.89,63.88 ± 5.99,63.88 ± 3.28,65.13 ± 3.92 and 37.88 ± 4.71 respectively;
Hypotype II: at 2 θ is 10 diffractive features peak position places of 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1, and the Dui Ying strong parameter of relative diffraction peak is 31.6 ± 6.63,26.6 ± 6.42,44.8 ± 1.67,100 ± 0,57.2 ± 4.56,49.6 ± 2.28,79 ± 6.16,72.6 ± 5.02,72.8 ± 3.29 and 44.4 ± 4.15 respectively;
Hypotype III: at 2 θ is 10 diffractive features peak position places of 7.5,10.1,13.9,14.4,18.0,18.6,19.8,20.4,21.5 and 25.1, and the Dui Ying strong parameter of relative diffraction peak is 32.14 ± 2.69,27.86 ± 4.07,43.57 ± 7.29,100.0 ± 0,66.57 ± 5.52,57.57 ± 6.41,94.00 ± 7.66,83.00 ± 6.93,78.86 ± 5.35 and 50.00 ± 3.27 respectively.
3, the preparation method of T-1551 A crystal formation as claimed in claim 2 is characterized in that it may further comprise the steps:
(1) in acetone or dehydrated alcohol, stir adding cefoperazone acid and distilled water down, three by volume weight ratio is 1-2.5:1:1, adds the alkali salify, regulates between the pH5.0-7.0;
(2) stir 0.5-1 hour after-filtration mixture and being pressed in the aseptic crystallization still, controlled temperature 20-40 ℃, stir the acetone or the dehydrated alcohol that add down with cefoperazone acid envelope-bulk to weight ratio 0.4-0.6:1;
(3) add a small amount of T-1551 A crystal formation hypotype I, II or III crystal seed, stir, adding is carried out crystallization with the acetone of cefoperazone acid envelope-bulk to weight ratio 10-16:1 then, stirs;
(4) growing the grain 0.5-1.5 hour, filter, use the washing with acetone crystallization, drying.
4, preparation method as claimed in claim 3, temperature is 10-30 ℃ when it is characterized in that wherein stirring in the step (1), used alkali is selected from one or more in yellow soda ash, sodium bicarbonate, sodium-acetate and the Sodium isooctanoate.
5, preparation method as claimed in claim 3, mixing speed is controlled at 10-60 rev/min after it is characterized in that wherein adding crystal seed in the step (3), add the acetone speed control the 8-16 liter/minute.
6, the application of T-1551 A crystal formation as claimed in claim 1 or 2 in the preparation anti-infectives.
7, application as claimed in claim 6 is characterized in that making injection with the T-1551 A crystal formation of significant quantity.
8, application as claimed in claim 6 is characterized in that the T-1551 A crystal formation and the sulbactam of significant quantity are made injection.
9, application as claimed in claim 6 is characterized in that the T-1551 A crystal formation and the beta-lactamase inhibitor of significant quantity are made pharmaceutically acceptable compound formulation.
10, application as claimed in claim 9 is characterized in that described beta-lactamase inhibitor is clavulanic acid or Tazobactam Sodium.
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| CN104470933A (en) * | 2012-07-17 | 2015-03-25 | 中化帝斯曼制药有限公司荷兰公司 | A new crystal form of cefoperazone sodium |
| CN103951679B (en) * | 2014-04-29 | 2016-04-27 | 悦康药业集团有限公司 | A kind of cefoperazone sodium compound and pharmaceutical composition thereof |
| CN104650115A (en) * | 2015-01-22 | 2015-05-27 | 杭州长典医药科技有限公司 | Cefoperazone sodium, special superfine compound powder preparation thereof and preparation method of special superfine compound powder preparation |
| CN106432273A (en) * | 2016-09-07 | 2017-02-22 | 陕西顿斯制药有限公司 | Cefoperazone sodium compound prepared by using fluid mechanics principle and preparation comprising cefoperazone sodium compound |
| CN106432277A (en) * | 2016-09-21 | 2017-02-22 | 陕西顿斯制药有限公司 | Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition |
| CN109134507A (en) * | 2017-07-24 | 2019-01-04 | 郑心 | A kind of 1/5 water cefoperazone sodium compound |
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