CN106397458A - Ceftazidime crystal compound as drug for treating infection during surgical operation - Google Patents
Ceftazidime crystal compound as drug for treating infection during surgical operation Download PDFInfo
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- CN106397458A CN106397458A CN201610845669.XA CN201610845669A CN106397458A CN 106397458 A CN106397458 A CN 106397458A CN 201610845669 A CN201610845669 A CN 201610845669A CN 106397458 A CN106397458 A CN 106397458A
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- cefotaxime
- crystal compound
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- pyridine
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicines and discloses a ceftazidime crystal compound as a drug for treating the infection during the surgical operation. The structural formula of the ceftazidime crystal compound is shown in a formula (I). The ceftazidime crystal compound is measured through the powder X-ray diffraction measurement method, and the X-ray powder diffraction pattern of the ceftazidime crystal compound, at a diffraction angle of 2 theta +/- 0.2 degree, is shown in a figure 1. The ceftazidime crystal compound is high in purity and good in stability, and the content of pyridine and polymer in the ceftazidime crystal compound is low. Meanwhile, the ceftazidime crystal compound is less prone to moisture absorption, good in fluidity and greatly improved in solubility.
Description
Technical field
The invention belongs to pharmaceutical technology field is and in particular to a kind of medicine cefotaxime crystal treating Postoperative infection
Compound.
Background technology
Ceftazidime pentahydrate is anti Bacillus pyocyaneu Flugge effect in the third generation cephalosporin that GlaxoSmithKline PLC company is formulated
Antibiotic the strongest, for the septicemia caused by sensitive gram negative bacilli, ALRI, abdominal cavity and infection of biliary tract, again
Polygamy urinary tract infections and serious skin soft tissue infection etc..For the immune deficiency person being caused by multiple resistance gram negative bacillis
Caused by infection, inside-hospital infection and gram negative bacilli or pseudomonas aeruginosa, central nervous system infection is especially suitable.Its
Structural formula is：
In order to ensure human administration's safety, NF specifies, for cefotaxime antibiotic it is desirable to ceftazidime pentahydrate
Content be not less than 95%, impurity pyridine content is not higher than 0.12%, and the content of polymer is not higher than 0.3%, other total miscellaneous contents
Not higher than 2.0%, its color and luster is not higher than No. 6 colors.Beta-Lactam antibiotic, such as penicillin medicine and Cephalosporins, by
In the less stable of parent nucleus, it is susceptible to reset, decomposes and polymerisation, the polymer product being formed and anaphylactic shock
There is close relationship.In penicillin, averagely in 21.44 μ g/g, allergic reaction incidence is 0.2% to polymeric impurities；Polymer
Averagely in 51.24 μ g/g, allergic reaction incidence is 0.43% to impurity；During polymeric impurities average out to 76.7 μ g/g, allergy
Rate is 0.74%.Though cynnematin allergic reaction is so serious not as good as penicillin, when polymer is high, human body mistake equally can be caused
Quick reaction.
Cefotaxime chance light, heat, water, oxidation etc. are unstable, are also easy to produce catabolite, particularly suffer from high temperature (50 DEG C of ＞)
In the case of, tend to occur degraded and polymerisation, generate cefotaxime dimer, trimer and polymer etc. polymer,
Thus leading to active constituents of medicine content to reduce, color and luster is strengthened, and polymeric impurities content raises.In addition, expired cefotaxime
Antibiotic, because the resting period is long, also usually makes active constituents of medicine content reduce, darkens, polymer content liter
High.Further, in some cases, because controlling of production process is improper, obtained ceftazidime pentahydrate, cefotaxime
Dimer, trimer and polymer etc. polymer content is especially high.And polymer content high when, easily make human body produce allergy anti-
Should.So for the high ceftazidime pentahydrate of this kind of polymeric impurities content or cefotaxime pharmaceutical preparation it is necessary to enter
One step is purified, ceftazidime pentahydrate crystal that obtain high-quality, that purity is high.
CN102924483B discloses a kind of cefotaxime crystalline compounds, its preparation method and its no bacterium mix powder form
Pharmaceutical composition, the preparation method of cefotaxime crystalline compounds comprises the steps：1) prepare crude product solution：By cephalo he
Pyridine crude product adds in the mixed solvent being formulated by dimethyl sulfoxide and oxolane, is stirred to dissolve, and adds activated carbon decolorizing,
Filter, obtain crude product solution, standby；2) prepare recrystallisation solvent：By acetone and ethyl acetate by volume 1-2.5: 11.5 ratio
Example prepares recrystallisation solvent, and described recrystallisation solvent volume is 6-14 times of cefotaxime crude product weight；3) crystallize：Under stirring, to
Step 1) gained crude product solution in stream plus step 2) gained recrystallisation solvent, have solid separate out；After completion of dropping, continue stirring
Mix lower dropping ethanol, separate out to there being crystal；Standing 3-6h, filter, wash with dimethyl sulfoxide, be dried, obtain described in cephalo he
Acridine compound.Compared with prior art, the invention has the advantages that：(1) cefotaxime crystal chemical combination provided by the present invention
Thing purity is high, and has preferable heat endurance, and substantially non-hygroscopic；
(2) the preparation method process is simple of cefotaxime provided by the present invention, high income, repeatability is strong, is suitable for industrializing
Produce；(3) the pharmaceutical composition stability containing this cefotaxime crystalline compounds provided by the present invention is fine, thus improving
Drug safety and validity, reduce the incidence of bad reaction.This cefotaxime crystalline compounds uses Cu-K alpha ray
Measure the X-ray powder diffraction spectrogram obtaining as shown in Figure 3.
CN103864819A discloses a kind of cefotaxime compound and its pharmaceutical composition, the system of cefotaxime compound
Preparation Method comprises the steps：1）Preparation crude product solution：Cefotaxime crude product is added and is formulated with methyl alcohol by dimethyl sulfoxide
Mixed solvent in, control temperature 20-30 DEG C, add activated carbon decolorizing, filter, obtain cefotaxime crude product solution, standby；2）
Nucleus generating process：In the range of 20-30 DEG C, in this solution, stream adds the temperature controlling cefotaxime crude product solution under agitation
Deionized water, has muddy appearance, obtains turbid solution；3）Crystal growing process：By step 2）The turbid solution of gained is placed in super
Under sound field, control 20-30 DEG C of solution temperature, drip chloroform thereto, separate out crystal；Close ultrasonic field, be cooled to 0-5
DEG C, filter, filter cake is washed with deionized, vacuum drying obtains described cefotaxime compound.The present invention has excellent as follows
Point：（1）Cefotaxime compound provided by the present invention has preferable heat endurance, and polymer content change is little；（2）This
Bright provided cefotaxime has preferable mobility, is conducive to improving the accuracy of packing, and mixes with other compositions
When, be easily mixed uniformly；（3）Cefotaxime provided by the present invention has preferable bioavilability.This cefotaxime compound
The X-ray powder diffraction spectrogram being obtained using Cu-K alpha ray measurement is as shown in Figure 4.
Although above-mentioned purification process to some extent solves its purity problem, through further investigation revealed that, by
In cefotaxime during depositing, particularly under conditions of high temperature (50 DEG C of ＞), tend to occur degraded and polymerisation, with
The prolongation of resting period, its high polymer content increases, so that the risk that human body produces allergic reaction is increased.
Cefotaxime is clinically typically used in the form of ceftazidime for injection aseptic powdery.Injection head
His pyridine of spore is usually cefotaxime and pharmaceutic adjuvant mixing is aseptic subpackaged forms, and has that grain diameter is larger, and mixing is uneven, dress
Amount difference is big, and during leading to use, effective active composition cefotaxime is not easy accurate quantitative analysis.Simultaneously because cefotaxime
Purity is different so that ceftazidime for injection has the various problems such as color and luster, degraded, polymerization and stability, bad reaction wind
Danger increases.
The present inventor, with existing cefotaxime crude product as raw material, through lot of experiments, has been obtained one kind and has been different from existing skill
The cefotaxime compound of the novel crystal forms of art, and by test, surprisingly find this crystalline compounds purity height, pyridine and polymerization
Thing content is low, good stability, and is difficult moisture absorption, good fluidity, substantially increases its dissolubility.Made using this crystalline compounds
Capsule dissolubility is high, impurity content is low, good stability.
Content of the invention
It is an object of the invention to provide a kind of medicine cefotaxime crystalline compounds treating Postoperative infection, this crystalline substance
Not only purity is high for body compound, and pyridine and polymer content are low, good stability, and it is difficult moisture absorption, mobility, dissolubility etc.
It is substantially better than prior art.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that：
A kind of medicine cefotaxime crystalline compounds treating Postoperative infection, the knot of described cefotaxime crystalline compounds
Shown in structure formula such as formula (I), this crystalline compounds is measured with powder x-ray diffraction determination method, the X being represented with the 2 θ ± 0.2 ° angles of diffraction
Ray powder diffraction as shown in figure 1,
Formula（）.
The present invention also provides the preparation method of the medicine cefotaxime crystalline compounds of above-mentioned treatment Postoperative infection, should
Method comprises the steps：
Take cefotaxime bulk drug, in the methyl alcohol of addition uniform temperature, the mixed solvent A of dimethylformamide, obtain solution；So
Afterwards in the horizontal direction of the liquid level of resulting solution apply stationary magnetic field, and under conditions of this stationary magnetic field to solution in drip
Acetone, ethyl acetate, the mixed solvent B of ether；After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, vacuum is done
Dry 3 hours, obtain described cefotaxime crystalline compounds.
Described cefotaxime bulk drug can be the head as disclosed in CN102391289A for the method using prior art
Ceftazidime pentahydrate or commercially available ceftazidime pentahydrate raw material that the synthetic method of his pyridine of spore prepares
Medicine.
In above-mentioned preparation method, wherein, described uniform temperature is 35-45 DEG C.The volume of described mixed solvent A（ml）For head
His pyridine weight of spore（g/ml）6-8 times, methyl alcohol and dimethylformamide volume ratio are 1:2.5.Described magnetic field intensity is 0.8T-
1.5T.The volume of described mixed solvent B（ml）For cefotaxime weight（g/ml）8-10 times, acetone, ethyl acetate and ether
Volume ratio is 2:3:5.
The present invention also provides a kind of cefotaxime capsule, and described capsule contains cefotaxime crystal provided by the present invention
The cefotaxime crystalline compounds that compound or above-mentioned preparation method are obtained.
Described cefotaxime capsule, in parts by weight, by the cefotaxime crystalline compounds of 100-200 weight portion, 80-
The microcrystalline cellulose of 100 weight portions, the Ac-Di-Sol of 8-12 weight portion, the superfine silica gel powder composition of 2-4 weight portion.
Preferably, described cefotaxime capsule, in parts by weight, by the cefotaxime crystalline compounds of 150 weight portions,
The microcrystalline cellulose of 90 weight portions, the Ac-Di-Sol of 9 weight portions, the superfine silica gel powder composition of 3 weight portions.
Described cefotaxime capsule, is prepared from by following preparation method：
1）Feedstock treating：With vibration screen-dividing machine, cefotaxime is crossed 80 mesh sieves, standby；
2）Microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, superfine silica gel powder are crossed respectively 60 mesh sieves, standby；
3）Weigh：Carry out weighing supplementary material according to prescription；
4）Premix：Cross-linked carboxymethyl cellulose sodium of the microcrystalline cellulose of recipe quantity, superfine silica gel powder and 1/3 recipe quantity is added to mixed
In conjunction machine, motor rotation frequency 200r/min is set, opens mixer and mix 30 minutes；
5）Always mix：Cross-linked carboxymethyl cellulose sodium of the cefotaxime of recipe quantity and 2/3 recipe quantity is added in mixer, setting
Motor rotation frequency 200r/min, opens mixer and mixes 10 minutes；It is subsequently adding pre- mixed microcrystalline cellulose, superfine silica gel powder
And 1/3 recipe quantity cross-linked carboxymethyl cellulose sodium, arrange motor rotation frequency 150r/min, open mixer mix 20 minutes；
6）Autocapsulefillingmachine is filling；
7）Packaging.
Compared with prior art, the invention has the advantages that：
（1）Not only purity is high for cefotaxime crystalline compounds provided by the present invention, and pyridine and polymer content are low, stability
Good, and it is difficult moisture absorption, and mobility, dissolubility etc. are substantially better than prior art；
（2）The preparation method process is simple of cefotaxime provided by the present invention, high income, repeatability is strong, is suitable for industrializing
Produce；
（3）Capsule dissolubility containing this cefotaxime crystalline compounds provided by the present invention is high, impurity content is low, stability
Good.
Brief description
Fig. 1 is the X-ray powder diffraction figure of cefotaxime crystalline compounds of the present invention；
Fig. 2 is the heat analysis collection of illustrative plates of cefotaxime crystalline compounds of the present invention；
Fig. 3 is the X-ray powder diffraction collection of the cefotaxime crystallization of patent CN102924483B embodiment preparation；
Fig. 4 is the X-ray powder diffraction collection of the cefotaxime crystallization of patent CN103864819A embodiment preparation.
Specific embodiment
With embodiment, technical scheme is described in detail below, it will help the technical side to the present invention
The advantage of case, effect have and further understand, embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determining.
The preparation of embodiment 1 cefotaxime crystalline compounds
Take cefotaxime bulk drug, the volume adding 35 DEG C is the methyl alcohol of 6 times of cefotaxime weight, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then in the level side of the liquid level of resulting solution
Upwards apply magnetic field intensity be 0.8T stationary magnetic field, and under conditions of this stationary magnetic field to solution in dropping volume be cephalo
He is 8 times of acetone of pyridine weight, ethyl acetate, the mixed solvent B of ether, and the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, be vacuum dried 3 hours, obtain described cefotaxime crystal
Compound.
Measured with powder x-ray diffraction determination method, the X-ray powder diffraction collection being represented with the 2 θ ± 0.2 ° angles of diffraction is such as
Show feature at 3.1 °, 4.0 °, 6.0 °, 6.7 °, 9.5 °, 14.1 °, 22.1 °, 24.5 °, 36.1 °, 37.9 ° shown in Fig. 1 to spread out
Penetrate peak.
Measuring moisture using Ka Shi aquametry is 14.13 wt%, substantially identical with theoretical value.
Measured using thermogravimetric analysis, result is as shown in Fig. 2 crystal water content is 14.15wt%, substantially identical with theoretical value.
The preparation of embodiment 2 cefotaxime crystalline compounds
Take cefotaxime bulk drug, the volume adding 40 DEG C is the methyl alcohol of 7 times of cefotaxime weight, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then in the level side of the liquid level of resulting solution
Upwards apply magnetic field intensity be 1.1T stationary magnetic field, and under conditions of this stationary magnetic field to solution in dropping volume be cephalo
He is 9 times of acetone of pyridine weight, ethyl acetate, the mixed solvent B of ether, and the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, be vacuum dried 3 hours, obtain described cefotaxime crystal
Compound.
Measured with powder x-ray diffraction determination method, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 3 cefotaxime crystalline compounds
Take cefotaxime bulk drug, the volume adding 45 DEG C is the methyl alcohol of 8 times of cefotaxime weight, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then in the level side of the liquid level of resulting solution
Upwards apply magnetic field intensity be 1.5T stationary magnetic field, and under conditions of this stationary magnetic field to solution in dropping volume be cephalo
He is 10 times of acetone of pyridine weight, ethyl acetate, the mixed solvent B of ether, and the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, be vacuum dried 3 hours, obtain described cefotaxime crystal
Compound.
Measured with powder x-ray diffraction determination method, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 4 cefotaxime crystalline compounds
Take cefotaxime bulk drug, the volume adding 35 DEG C is the methyl alcohol of 7 times of cefotaxime weight, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then in the level side of the liquid level of resulting solution
Upwards apply magnetic field intensity be 1.1T stationary magnetic field, and under conditions of this stationary magnetic field to solution in dropping volume be cephalo
He is 10 times of acetone of pyridine weight, ethyl acetate, the mixed solvent B of ether, and the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, be vacuum dried 3 hours, obtain described cefotaxime crystal
Compound.
Measured with powder x-ray diffraction determination method, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
The preparation of embodiment 5 cefotaxime crystalline compounds
Take cefotaxime bulk drug, the volume adding 45 DEG C is the methyl alcohol of 6 times of cefotaxime weight, the mixing of dimethylformamide
In solvent orange 2 A, methyl alcohol and dimethylformamide volume ratio are 1:2.5, obtain solution；Then in the level side of the liquid level of resulting solution
Upwards apply magnetic field intensity be 0.8T stationary magnetic field, and under conditions of this stationary magnetic field to solution in dropping volume be cephalo
He is 8 times of acetone of pyridine weight, ethyl acetate, the mixed solvent B of ether, and the volume ratio of acetone, ethyl acetate and ether is 2:3:5；
After being added dropwise to complete, stand 4 hours, filter, filter cake is washed with ethanol, be vacuum dried 3 hours, obtain described cefotaxime crystal
Compound.
Measured with powder x-ray diffraction determination method, same with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction represent
Embodiment 1.
【Example of formulations 1】Cefotaxime capsule
In parts by weight, prescription composition is as follows：100 parts of cefotaxime, 80 parts of microcrystalline cellulose, Ac-Di-Sol 8
Part, 2 parts of superfine silica gel powder.
Cefotaxime is the cefotaxime crystalline compounds that the embodiment of the present invention 1 is obtained.
Preparation method：
1）Feedstock treating：With vibration screen-dividing machine, cefotaxime is crossed 80 mesh sieves, standby；
2）Microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, superfine silica gel powder are crossed respectively 60 mesh sieves, standby；
3）Weigh：Carry out weighing supplementary material according to prescription；
4）Premix：Cross-linked carboxymethyl cellulose sodium of the microcrystalline cellulose of recipe quantity, superfine silica gel powder and 1/3 recipe quantity is added to mixed
In conjunction machine, motor rotation frequency 200r/min is set, opens mixer and mix 30 minutes；
5）Always mix：Cross-linked carboxymethyl cellulose sodium of the cefotaxime of recipe quantity and 2/3 recipe quantity is added in mixer, setting
Motor rotation frequency 200r/min, opens mixer and mixes 10 minutes；It is subsequently adding pre- mixed microcrystalline cellulose, superfine silica gel powder
And 1/3 recipe quantity cross-linked carboxymethyl cellulose sodium, arrange motor rotation frequency 150r/min, open mixer mix 20 minutes；
6）Autocapsulefillingmachine is filling；
7）Packaging.
【Example of formulations 2】Cefotaxime capsule
In parts by weight, prescription composition is as follows：100 parts of cefotaxime, 90 parts of microcrystalline cellulose, Ac-Di-Sol 12
Part, 2 parts of superfine silica gel powder.
Preparation method：With example of formulations 1, except that cefotaxime used is the cephalo prepared by embodiment 2
His pyridine crystalline compounds.
【Example of formulations 3】Cefotaxime capsule
In parts by weight, prescription composition is as follows：150 parts of cefotaxime, 90 parts of microcrystalline cellulose, Ac-Di-Sol 9
Part, 3 parts of superfine silica gel powder.
Preparation method：With example of formulations 1, except that cefotaxime used is the cephalo prepared by embodiment 3
His pyridine crystalline compounds.
【Example of formulations 4】Cefotaxime capsule
In parts by weight, prescription composition is as follows：200 parts of cefotaxime, 80 parts of microcrystalline cellulose, Ac-Di-Sol 12
Part, 2 parts of superfine silica gel powder.
Preparation method：With example of formulations 1, except that cefotaxime used is the cephalo prepared by embodiment 4
His pyridine crystalline compounds.
【Example of formulations 5】Cefotaxime capsule
In parts by weight, prescription composition is as follows：200 parts of cefotaxime, 100 parts of microcrystalline cellulose, Ac-Di-Sol
12 parts, 4 parts of superfine silica gel powder.
Preparation method：With example of formulations 1, except that cefotaxime used is the cephalo prepared by embodiment 5
His pyridine crystalline compounds.
Trial target 1：Cefotaxime crystalline compounds prepared by the embodiment of the present invention 1；
Trial target 2：Cefotaxime crystalline compounds prepared by the embodiment of the present invention 3；
Reference substance 1：Method according to CN102924483B embodiment 1 is obtained cefotaxime crystalline compounds；
Reference substance 2：Method according to CN103864819A embodiment 1 is obtained cefotaxime compound；
Reference substance 3：Method according to CN105560194A embodiment 1 is obtained cefotaxime；
Reference substance 4：Method according to CN105585582A embodiment 1 is obtained cefotaxime.
Experimental example 1：Heat stabilization test
It is, in the environment of 75%, temperature is 60 DEG C, to have according in CN105560194A that each sample is respectively exposed to relative humidity
Pass material, impurity pyridine, the detection method of polymer detect to items, the results are shown in Table 1：
Table 1 heat stabilization test result
Pyridine is two class noxious materials, and pyridine can stimulate human eye, skin and respiratory tract, to human central nervous system, liver,
Kidney, stomach and intestine all have an impact, and consciousness of personality can be caused to reduce.If pyridine residual quantity is high, more serious impact can be produced on human body.Logical
Cross the security test to cefotaxime medicine, pyridine residual limit of safety in cefotaxime medicine not can exceed that
0.12%.Contain pyridine groups due in cefotaxime structure, medicine, in placement process, can gradually decompose impurity pyridine and go out
Come, particularly the cefotaxime of stability difference, in placement process, pyridine residual quantity can increase comparatively fast, and this has relatively to human body
Big harm.
The height of drug quality is directly connected to the health of millions upon millions of working people's bodies, is also related to China's economic construction
Effect, the consolidation of national defence and nationality flourishing；It has been far from the thing of medical industry enterprise scope itself, but entirely
The national, major issue in the world.Those skilled in the art all clearly know, in the present age that pharmaceutical technology is flourishing, drug safety standard quilt
Constantly lifted, the purity also more and more higher of prepared medicine, be effectively reduced impurity content, even the several percentage of zero point
Point it is also possible to effectively reduce the generation of bad reaction, therefore impurity content to drug quality and people's drug safety to closing weight
Will.Medicine needs to store and transport just can cure the sickness to save the patient from production to the process of circulation, therefore, medicine in storage and transportation
Quality be particularly important, stability is the key determining drug quality quality, in medicine storage and transportation, stable
Property bad, impurity change directly affect greatly people's drug safety.
As can be seen from the above table, the relevant material of cefotaxime crystalline compounds of the present invention, pyridine, polymer equal size are equal
Very low, and heat endurance is significantly better than the cefotaxime being obtained after purification using the method for prior art, is effectively lifted
The stability of drug safety and storage, reduces the generation of bad reaction.
Above-mentioned test is also carried out to the cefotaxime crystalline compounds of other embodiments of the present invention, its result phase obtaining
Seemingly.
Experimental example 2：Fluidity test
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and concrete grammar is as follows：Take sample particle, from
Flow in fixing little funnel in the surface plate of circle, until obtaining highest cone, measure cone height H and radius R,
Calculate angle of repose α by tan α=H/R, the results are shown in Table 2, angle of repose is bigger, mobility is poorer.
Table 2 fluidity test result
As known from Table 2, compared with cefotaxime of the prior art, the cefotaxime compound flow prepared by the present invention shows
Write and improve, be conducive to improving the accuracy of packing, and be easily mixed when mixing with other compositions uniformly.
Experimental example 3：Dissolubility test
Add appropriate distilled water in the low capacity bottle with constant temperature jacket, add cefotaxime at 20 DEG C to not re-dissolved
Till, start magnetic stirrer, continuously stirred under constant temperature, system is in the state of two-phase coexistent all the time in experimentation, 70
In the liquid phase of system after minute, the concentration of cefotaxime is the solubility at a temperature of this.It is sampled after 2 hours analyzing, take
The close mean value of adjacent two times result as measured value of experiment, before sampling, in order that solid-liquid is sufficiently separated, stop stirring after,
Not molten cefotaxime is deposited to the bottom of low capacity bottle, extracts a small amount of upper clear supernate with syringe, with 0.45 micron of filter
Filter, take sample from filtrate, measure the content of cefotaxime by HPLC（Concentration（mg/ml））.The results are shown in Table 3.
Under table 3 room temperature, cefotaxime crystal compound of the present invention and the water-soluble of prior art crystal formation contrast
From table 3 it can be seen that the water solubility of cefotaxime crystal compound of the present invention is compared with prior art, has and significantly carry
High.
Experimental example 4：Wettability test
Each sample opening is put in clean culture dish, spreads out into≤thick the thin layer of 5mm, each two parts, be respectively put into constant humidity closed container
In, place 10 days under conditions of relative humidity 75% and 92.5% at 25 DEG C, sampled in the 5th day and the 10th day, pass through
The moisture of loss on drying experiment measurement each sample, result of the test was compared with 0 day, and experimental result is shown in Table 4.
Table 4 hygroscopicity test results
As can be seen from the above table, the cefotaxime crystalline compounds of present invention preparation are substantially non-hygroscopic under high humidity conditions, its
Stability under high humidity environment is substantially better than the cefotaxime obtaining using the purification process process of prior art.
Experimental example 5：Prescription screening is tested（Using capsule preparation method thereof of the present invention preparation）
Table 5a prescription screening experimental result
Table 5b prescription screening experimental result
As can be seen from the above table, the cefotaxime capsule that the present invention is obtained（Prescription 11）Not only mobility, dissolution rate are good, and
Polymer, always miscellaneous content significantly reduce.
Experimental example 6：Preparation influence factor is tested
Formulation test product 1：Cefotaxime capsule prepared by invention formulation embodiment 1.
Formulation test product 2：Cefotaxime capsule prepared by invention formulation embodiment 3.
By formulation test product simulation listing packaging, in 60 DEG C of high temperature, illumination 4500Lx, high humidity（RH90%±5%）Under the conditions of
Place 10 days, detected by stability high spot reviews project, compare with 0 day sample, the results are shown in Table 6.
Table 6 preparation influence factor result of the test
Found by result above, the capsule dissolubility containing this cefotaxime crystalline compounds prepared by the present invention is high, impurity
Content is low, good stability.
Above-mentioned test is also carried out to the cefotaxime capsule of present invention other example of formulations, its result phase obtaining
Seemingly.
Claims (1)
1. a kind of medicine cefotaxime crystalline compounds treating Postoperative infection it is characterised in that：Described cefotaxime
Shown in the structural formula of crystalline compounds such as formula (I), this crystalline compounds is measured with powder x-ray diffraction determination method, with 2 θ ±
X-ray powder diffraction pattern that 0.2 ° of angle of diffraction represents as shown in figure 1,
Formula（）.
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Application publication date: 20170215 |