CN104370942A - Cefmetazole crystal form, preparation method thereof, and pharmaceutical composition containing cefmetazole - Google Patents
Cefmetazole crystal form, preparation method thereof, and pharmaceutical composition containing cefmetazole Download PDFInfo
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- CN104370942A CN104370942A CN201310350113.XA CN201310350113A CN104370942A CN 104370942 A CN104370942 A CN 104370942A CN 201310350113 A CN201310350113 A CN 201310350113A CN 104370942 A CN104370942 A CN 104370942A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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Abstract
The invention relates to a novel cefmetazole crystal form and a preparation method thereof. The preparation method adopts a specific solvent to carry out recrystallization. Through controlling the solvent ratio, temperature decreasing speed, and stirring speed, the precipitation process of cefmetazole crystal is co-adjusted. The crystal form is like particles, the particle size is uniform, and the fluidity is good. The post production and transportation of cefmetazole products become more convenient. Furthermore, the crystal form is stable and can be preserved for a long term. The pharmaceutical composition prepared from the cefmetazole crystal form is safer as a clinical drug.
Description
Technical field
The invention belongs to the preparation field of medical compounds, particularly a kind of cefmetazole new crystal and preparation method thereof and a kind of pharmaceutical composition containing cefmetazole new crystal.
Background technology
Cefmetazole sodium, No. CAS: 56796-39-5, English name cefmetazole, chemical name (6R, 7S)-7-[[2-(cyanogen methyl sulphur) acetyl] is amino]-7-methoxyl group-3-[(1-methyl tetrazolium-5-base) thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt, molecular formula C
15h
16n
7o
5s
3na, molecular weight 493.52.
Cefmetazole sodium is the semi-synthetic cynnematin of the s-generation, and by Japan three company's exploitation altogether, product in listing in 1980, and entered China in 1992, trade(brand)name cefmotazole.It has good stability to the spectrum β-lactamase that negative bacillus produces, the negative bacillus such as intestinal bacteria, klebostiella pneumoniae, Proteus mirabilis, Shigella, Salmonella have good susceptibility to this product, S. aureus L-forms, A group Hemolytic streptococcus, catarrh do not draw Chinese bacterium extremely sensitive to this product, have good anti-microbial activity to bacteroides fragilis, enterobacter, Rhodopseudomonas, Methicillin-resistant Staphylococcus aureus, streptococcus pneumoniae, meningococcus be insensitive or resistance to this product.Clinically for the treatment by diseases such as the microbial respiratory system infection of sensitivity, biliary tract infection, peritonitis, urinary system infections.
Cefmetazole (CAS56796-20-4) is the important intermediate preparing cefmetazole sodium, in industrial production, cefmetazole sodium is many to be prepared by cefmetazole and alkaline sodium salt (as Sodium isooctanoate) salify, produce and relate to feeding intake of cefmetazole, therefore, the quality of cefmetazole determines the quality of cefmetazole sodium to a great extent.
In addition, cefmetazole also has the prospect being directly prepared into pharmaceutical composition, Chinese patent CN201110089578.5, CN200910026797.1 all disclose the technical scheme that cefmetazole and basic auxiliary are mixed with powder injection, and the every quality index of cefmetazole product directly can affect the quality of cefmetazole pharmaceutical composition.
Document: the preparation method disclosing a kind of cefmetazole in the synthesising process research (Hebei Medical University master Diplomarbeit) of cefmetazole and intermediate 7-MAC thereof, the fusing point of gained cefmetazole is 125-126 DEG C, the cefmetazole crystal formation particle diameter prepared according to this method is less, be difficult to filter, gained crystal particle diameter heterogeneity after dry, and product is fine powder state, mobility is not good.
Patent CN201110281291.2 discloses a kind of preparation method of cefmetazole, it is high that this method has productive rate, the advantages such as production cost is low, repeat through contriver, also there is the defect of particle diameter inequality in the cefmetazole crystal formation prepared according to this method, after dry, gained crystal is fine powder state, and mobility is not good, is unfavorable for subsequent production.
Cefmetazole commercially available is at present also in finely powdered, and particle diameter pole heterogeneity, product bulk density is little, poor fluidity, to follow-up transhipment, packing, mixes, brings very big inconvenience, add equipment and human cost.In addition, when being mixed with pharmaceutical composition with basic auxiliary, mixing the uneven quality of pharmaceutical composition that also can make and being affected.
Therefore, the crystal formation finding a kind of suitable cefmetazole is particularly important.Contriver is from the deficiency solving prior art existence, first a kind of novel method preparing cefmetazole crystal formation is filtered out by great many of experiments, wonderful discovery when being furtherd investigate by the cefmetazole crystal formation obtained this method, the cefmetazole crystal formation using novel method to prepare is a kind of new crystal being different from prior art, this crystal formation is particulate state, uniform particle sizes, good fluidity, offer convenience to subsequent production and transport, the more important thing is, this crystal formation has the high advantage of stability, meets the requirement of standing storage.
Summary of the invention
First object of the present invention is the shortcoming overcoming prior art, and provide a kind of new cefmetazole crystal formation, this crystal particle shape, has the advantages such as uniform particle sizes, good fluidity, good stability.
The feature of described cefmetazole crystal formation is: represent there is peak at 4.3,7.7,10.7,13.1,18.6,19.6,21.0,22.8,25.3 and 27.1 places with 2 θ angles in the X-ray powder diffraction figure of this crystal formation, error is ± 0.2.
The feature of described cefmetazole crystal formation is: this crystal formation also has peak at 12.6,13.4,14.0,14.6,18.2,25.9,28.5 places, and error is ± 0.2.
In the DSC differential thermal analysis spectrogram of described crystal formation, between 145-170 DEG C, have exothermic peak, its peak value is 163.2 DEG C; The fusing point of described crystal formation is 148.5-149.5 DEG C; TG spectrogram shows, and described cefmetazole crystal form samples, before 160 DEG C, obvious quality change does not occur.
Another object of the present invention is to provide a kind of method preparing cefmetazole crystal formation, cefmetazole crystal formation of the present invention can be prepared according to the method.
Although recrystallization is one of Main Means of known acquisition crystal formation in field, but the cefmetazole crystal formation prepared by common recrystallization method is Powdered, mobility extreme difference, stability is not good yet, the preparation of specific cefmetazole crystal formation of the present invention, relate to concrete solvent system, specific operation steps, concrete temperature condition and stirring velocity etc.Concrete, the preparation method of described cefmetazole crystal formation comprises following steps:
1) join in solvent orange 2 A by cefmetazole, be progressively warmed up to 30-45 DEG C, stirring and dissolving, the quality-volume ratio of cefmetazole and solvent orange 2 A is 1g:3-15mL.
2) add proper amount of active carbon, stir filtered while hot after 20-30 minute and obtain cefmetazole solution, add solvent B, the volume of described solvent B is the 10%-20% of solvent orange 2 A volume.
3) be that 0.3-1.0 DEG C/min stirring is cooled to room temperature with cooling rate, place after 30 minutes, be that 1.0-2.0 DEG C/min stirring is cooled to-15 DEG C with cooling rate, temperature is kept slowly to stir one hour, filtration drying obtains cefmetazole crystal formation, described in be cooled to room temperature and be cooled to the mixing speed in-15 DEG C of stages and independently can be selected from 60-130r/min.
Above-mentioned steps 1), 2) in, solvent orange 2 A, B independently can be selected from the acetone-ol solution that volume fraction is 0-65%, and described alcohol is methyl alcohol or ethanol.
For step 1), its object is to form the suitable cefmetazole solution of concentration, and there is supersaturation in subsequent steps, it should be noted that, in this step, the concentration of cefmetazole solution is unsuitable too high, while too high concentration can make product in subsequent step separate out, impurity is also together separated out, and the product of separating out contains another crystal formation a certain amount of; Too low strength of solution then can affect the speed of cefmetazole precipitation and the degree of precipitation.Contriver is found by screening, and the quality-volume ratio adding cefmetazole acid and solvent orange 2 A is 1g:3-15mL, when preferred 5-10mL, can form the cefmetazole solution of moderate concentration, and be conducive to the preparation of cefmetazole crystal formation in subsequent process steps.
For step 2), the object adding gac in this step is to slough product colour, in field, those of ordinary skill can select gac kind and add-on according to solution colour situation and decolorizing effect, it should be noted that, the kind of gac and aperture need adapt with foreign pigment, in addition, very few gac can not reach decolorizing effect, and too much gac then can affect the yield of product.Preferably, it is sugar carbon that institute adds gac, and such activated carbon pore size is large, cheap; Add the preferred 0.3-0.6g/100mL solution of amount of gac; The saturation ratio that solvent B object is cefmetazole in the hierarchy of control is added in this step, and the coring and increment of collaborative follow-up temperature-fall period co-controlling cefmetazole crystallisation process, add the kind of solvent B and volume and cefmetazole crystal formation quality closely related, found by the great many of experiments screening of contriver, when the volume adding solvent B is the 10%-20% of solvent orange 2 A volume, the crystallization object of expection can be reached.
For step 3), the cooling of this step is divided into high temperature-room temperature, two stages of room temperature-low temperature, concrete, first temperature-fall period first form appropriate crystal seed, and evenly separate out a part of cefmetazole, second temperature-fall period then separates out most of cefmetazole further, this step is by controlling cooling rate and stirring velocity control crystal precipitation rate, too fast cooling rate and stirring velocity can make crystal speed of separating out too fast, thus make crystal particle diameter too small and particle diameter is uneven, crossing slow cooling rate and stirring velocity then can make solution form partial over saturation, also crystalline uniformity can be affected, contriver is found by great many of experiments conditional filtering, when high temperature-room temperature, the mixing speed of room temperature-cold stage controls respectively at 60 ~ 130r/min, first stage cooling rate is 0.3-1.0 DEG C/min, when subordinate phase cooling rate is 1.0-2.0 DEG C/min, moderate and the uniform particle diameter of crystal speed of separating out, be conducive to obtaining described cefmetazole crystal formation.
Can find out, this programme regulates cefmetazole crystal precipitation process jointly by solvent species, solvent ratios, cooling rate, stirring velocity, technical scheme integrally, the each step of above-mentioned preparation method combines closely, each technical parameter mutually make hold up, organic unity, acting in conjunction makes cefmetazole can with same stable crystal form, homogeneous separating out from solution, and gained cefmetazole product purity can be stabilized in more than 99.4%.
A preferred implementation of the preparation method of described cefmetazole crystal formation, is that its operation steps is as follows:
1) cefmetazole being joined volume fraction is in the acetone-ethanol solution of 65%, is progressively warmed up to 30 DEG C, stirring and dissolving, and the quality-volume ratio of cefmetazole and acetone-ethanol solution is 1g:10mL;
2) add proper amount of active carbon, after stirring 20-30min, filtered while hot obtains cefmetazole saturated solution, and add ethanol, the volume of described ethanol is 20% of acetone-ethanol liquor capacity in step 1);
3) be 1.0 DEG C/min with cooling rate, rotating speed is that 100r/min stirs and is cooled to room temperature, places after 30 minutes, be 2.0 DEG C/min with cooling rate, rotating speed is that 80r/min stirring is cooled to-15 DEG C, and keep temperature slowly to stir one hour, filtration drying obtains cefmetazole crystal formation.
3rd object of the present invention is to provide a kind of pharmaceutical composition containing cefmetazole, it is characterized in that said composition contains cefmetazole crystal formation of the present invention, described pharmaceutical composition is the mixture of cefmetazole and L-arginine, and in described composition, the mass ratio of cefmetazole and L-arginine is 1:0.4.
Aforementioned pharmaceutical compositions includes but not limited to that injection comprises injection liquid, aseptic powder needle for injection agent, concentrated solution for injection etc.; Oral preparation is as tablet, granule, capsule, oral liquid, pill, suspensoid etc.; External preparation is as suppository, drops etc.; Described preparation optimizing injection, more preferably injectable sterile powder.
Cefmetazole crystal described in this programme comparatively prior art has uniform particle sizes, good fluidity, stability high, therefore its be presented as in follow-up production process feed intake, packing precision is high, the mixing of gained pharmaceutical composition is homogeneous, stability is also better than prior art products, improves drug safety.
It is as follows that goal of the invention of the present invention and each goal of the invention have following beneficial effect relative to prior art:
1, provide a kind of new cefmetazole crystal formation, it is particulate state, has that purity is high, uniform particle sizes, good fluidity, stability advantages of higher;
2, a kind of method preparing cefmetazole crystal formation is provided, by the regulating and controlling cefmetazole crystal precipitation process to solvent species, solvent ratios, cooling rate, stirring velocity, make cefmetazole can with same stable crystal form, homogeneous separating out from solution, and gained cefmetazole product purity be more than 99.4%.
3, provide a kind of pharmaceutical composition containing cefmetazole, it is characterized in that: containing cefmetazole crystal formation of the present invention, the mixing of this pharmaceutical composition is homogeneous, and stability is better than prior art products, improves drug safety.
Accompanying drawing explanation
Accompanying drawing 1 is the X-ray powder diffractogram of crystal formation of the present invention
Accompanying drawing 2 is the differential thermal analysis spectrogram of crystal formation of the present invention
Accompanying drawing 3 is the thermogravimetric analysis spectrogram of crystal formation of the present invention
Accompanying drawing 4 is the HPLC spectrogram of crystal formation of the present invention
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but working of an invention mode is not limited thereto.
Instrument and testing conditions
X-ray powder diffraction
Sharp shadow (Empyrean) X-ray diffractometer
Cu target K α
1ray, voltage 40Kv, power supply 40mA, divergent slit 1/32 °, antiscatter slits 1/16 °, the narrow 7.5mm of anti-scatter, 2 θ scopes: 3 °-50 °, step-length 0.02 °, often walks residence time 40s.
Differential thermal analysis
Germany NETZSCH company DSC204F1 differential scan calorimeter
Thermogravimetric analysis
Germany NETZSCH company's T G209 thermogravimetric analyzer
Embodiment 1
Cefmetazole 10g is added in reaction flask, add the acetone-ethanol solution that 100mL volume fraction is 65%, progressively be warmed up to 30 DEG C, add 0.5g gac after stirring and dissolving and stir filtered while hot after 20-30 minute, after adding 20mL ethanol, with 100r/min stirring and to be cooled to room temperature with 1 DEG C/min, keep room temperature 30min, stir with 80r/min and be cooled to-15 DEG C with 2 DEG C/min, stir about one hour, solid is separated out rear filtration drying completely and is obtained cefmetazole product, filtration drying obtains cefmetazole crystal formation, fusing point 148.5-149.5 DEG C, this product crystal formation has X-ray diffraction spectrogram as shown in Figure 1, differential thermal analysis spectrogram as shown in Figure 2, thermogravimetric spectrogram as shown in Figure 3, HPLC testing product purity is 99.62%, spectrogram as shown in Figure 4.
Embodiment 2
Cefmetazole 10g is added in reaction flask, add the acetone-methanol solution that 80mL volume fraction is 20%, progressively be warmed up to 40 DEG C, add 0.4g gac after stirring and dissolving and stir filtered while hot after 20-30 minute, after adding 15mL ethanol, stir with 80r/min and be cooled to room temperature with 0.5 DEG C/min, keep room temperature 30min, stir with 60r/min and be cooled to-15 DEG C with 1 DEG C/min, stir about one hour, solid is separated out rear filtration drying completely and is obtained the cefmetazole product identical with embodiment 1.
Embodiment 3
Cefmetazole 10g is added in reaction flask, add 50mL methyl alcohol, progressively be warmed up to 45 DEG C, after stirring and dissolving, add 0.3g gac, stir filtered while hot after 30 minutes, after adding the methyl alcohol of 10ml, stir with 80r/min and be cooled to room temperature with 0.5 DEG C/min, keeping room temperature 30min, then stir with 60r/min and be cooled to-15 DEG C with 1 DEG C/min, stir about one hour, solid is separated out rear filtration drying completely and is obtained the cefmetazole product identical with embodiment 1.
Embodiment 4
Detect the slope of repose (GB/T11986-1989) of embodiment 1,2,3 gained cefmetazole crystal, loose density, tap density (ASTM D7481-2009), counter intensity of compression, and compare with commercially available cefmetazole product, concrete data are as shown in the table:
From above data, the slope of repose of embodiment 1-3 gained cefmetazole crystal and intensity of compression, all much smaller than commercially available prod, can be found out, the mobility of embodiment 1-3 gained cefmetazole crystal is much better than commercially available prod.
Embodiment 5
Investigated the stability of embodiment 1,2,3 gained cefmetazole crystal further by Acceleration study (temperature 60 C, humidity 75%), concrete data are as shown in the table:
In Acceleration study, product list is assorted not to change substantially with situation of always mixing, and can find out, the stability of embodiment 1-3 gained cefmetazole crystal is better, is applicable to standing storage.
Embodiment 6
The aseptic cefmetazole crystal prepared according to method described in embodiment 1 and sterile L-arginine are pulverized rear mistake 80 mesh sieve respectively.10 kilograms, cefmetazole crystal and L-arginine 4 kilograms are added in V-type mixing drum, mix, namely packing after the assay was approved obtains cefmetazole pharmaceutical composition.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. a cefmetazole crystal formation, it is characterized in that representing there is peak at 4.3,7.7,10.7,13.1,18.6,19.6,21.0,22.8,25.3 and 27.1 places with 2 θ angles in the X-ray powder diffraction figure of this crystal formation, error is ± 0.2.
2. cefmetazole crystal formation according to claim 1, it is characterized in that this crystal formation also has peak at 12.6,13.4,14.0,14.6,18.2,25.9,28.5 places, error is ± 0.2.
3. the cefmetazole crystal formation according to claim 1 or 2 any one, it is characterized in that the DSC differential thermal analysis spectrogram of this crystal formation has exothermic peak between 145-170 DEG C, its peak value is 163.2 DEG C.
4. the cefmetazole crystal formation according to claim 1-3 any one, is characterized in that the fusing point of described crystal formation is 148.5-149.5 DEG C.
5. the cefmetazole crystal formation according to claim 1-4 any one, it is characterized in that the TG spectrogram display of described crystal formation, there is not obvious quality change in described cefmetazole crystal formation before 160 DEG C.
6. the cefmetazole crystal formation according to claim 1-5 any one, is characterized in that the purity of described crystal formation is greater than 99.4%.
7. a preparation method for cefmetazole crystal formation described in claim 1-6 any one, comprises following steps:
1) join in solvent orange 2 A by cefmetazole, be progressively warmed up to 30-45 DEG C, stirring and dissolving, the quality-volume ratio of cefmetazole and solvent orange 2 A is 1g:3-15mL.
2) add proper amount of active carbon, stir filtered while hot after 20-30 minute and obtain cefmetazole saturated solution, add solvent B, the volume of described solvent B is the 10%-20% of solvent orange 2 A volume.
3) be that 0.3-1.0 DEG C/min stirring is cooled to room temperature with cooling rate, place after 30 minutes, be that 1.0-2.0 DEG C/min stirring is cooled to-15 DEG C with cooling rate, temperature is kept slowly to stir one hour, filtration drying obtains cefmetazole crystal formation, described in be cooled to room temperature and to be cooled to the mixing speed in-15 DEG C of stages be 60-130r/min.
Above-mentioned steps 1), 2) in, the acetone-ol solution of solvent orange 2 A, B to be volume fraction be 0-65%, described alcohol is methyl alcohol or ethanol.
8. preparation method according to claim 7, is characterized in that the quality-volume ratio of cefmetazole and solvent orange 2 A in described step 1) is 1g:5-10mL, described step 2) in the consumption of gac be 0.3-0.6g/100mL solution.
9. preparation method according to claim 7, is characterized in that preparation process is as follows:
1) cefmetazole being joined volume fraction is in the acetone-ethanol solution of 65%, is progressively warmed up to 30 DEG C, stirring and dissolving, and the quality-volume ratio of cefmetazole and acetone-ethanol solution is 1g:10mL;
2) add gac, after stirring 20-30min, filtered while hot obtains cefmetazole saturated solution, and add ethanol, the volume of described ethanol is 20% of acetone-ethanol liquor capacity in step 1), and the amount of described gac is 0.5g/100mL solution;
3) be 1.0 DEG C/min with cooling rate, rotating speed is that 100r/min stirs and is cooled to room temperature, places after 30 minutes, be 2.0 DEG C/min with cooling rate, rotating speed is that 80r/min stirring is cooled to-15 DEG C, and keep temperature to stir one hour, filtration drying obtains cefmetazole crystal formation.
10. a pharmaceutical composition for cefmetazole, is that the cefmetazole of 1:0.4 and L-arginine form by mass ratio, it is characterized in that described cefmetazole is for the cefmetazole crystal formation described in claim 1-6 any one.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541871A (en) * | 2015-12-24 | 2016-05-04 | 国药集团致君（深圳）制药有限公司 | Cefmetazole crystal-form compound and preparation method thereof |
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| JPH01242588A (en) * | 1988-03-25 | 1989-09-27 | Chiba Gosei Kenkyusho:Kk | Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof |
| CN101574351A (en) * | 2009-05-12 | 2009-11-11 | 张轶伦 | Cefmetazole preparation used for injection and preparation method thereof |
| CN101623285A (en) * | 2009-08-14 | 2010-01-13 | 山东罗欣药业股份有限公司 | Cefmetazole sodium medicament and preparation method thereof |
| CN101787040A (en) * | 2010-03-02 | 2010-07-28 | 哈药集团制药总厂 | Method for preparing cefmetazole sodium |
| CN102127095A (en) * | 2010-12-24 | 2011-07-20 | 山东鲁抗医药股份有限公司 | Method for preparing cefmetazole sodium |
| CN102391291A (en) * | 2011-09-21 | 2012-03-28 | 河北九派制药有限公司 | Cefmetazole acid preparation method |
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2013
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| JPH01242588A (en) * | 1988-03-25 | 1989-09-27 | Chiba Gosei Kenkyusho:Kk | Crystal of 7-cyanomethylthioacetamide-7alpha-methoxy-3-(1-methyl-1h-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid and production thereof |
| CN101574351A (en) * | 2009-05-12 | 2009-11-11 | 张轶伦 | Cefmetazole preparation used for injection and preparation method thereof |
| CN101623285A (en) * | 2009-08-14 | 2010-01-13 | 山东罗欣药业股份有限公司 | Cefmetazole sodium medicament and preparation method thereof |
| CN101787040A (en) * | 2010-03-02 | 2010-07-28 | 哈药集团制药总厂 | Method for preparing cefmetazole sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105541871A (en) * | 2015-12-24 | 2016-05-04 | 国药集团致君（深圳）制药有限公司 | Cefmetazole crystal-form compound and preparation method thereof |
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