CN106432277A - Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition - Google Patents
Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition Download PDFInfo
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Abstract
The invention discloses a cefoperazone sodium compound and a sulbactam sodium compound. The cefoperazone sodium compound and the sulbactam sodium compound are both prepared with a strong-field coupling crystallization technology, specifically, ultrasonic out-field strengthened crystals are added in the compound crystallization process, and the high-purity compounds are prepared. 'Research & Development of the Industrialization Project of High-end Medicine Product Refining Crystallization Technologies' wins the 2015 national scientific and technological progress second prize, and the high-field coupling crystallization technology belongs to one of high-end medicine product refining crystallization technologies. The two compounds have the characteristics of high purity and good stability. Besides, the invention further discloses cefoperazone sodium and sulbactam sodium medicinal composition. The cefoperazone sodium and sulbactam sodium medicinal composition is prepared from components in parts by weight as follows: 0.25-2 parts of cefoperazone sodium (on the basis of C25H27N9O8S2) and 0.25-2 parts of sulbactam sodium (on the basis of C8H11NO5S).
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of cefoperazone of employing high field coupling crystallization technique preparation
Sodium compound and sulbactam sodium compound and combinations thereof preparation.
Background technology
The high-end medical product essence of the unit such as one of the present inventor University Of Tianjin and Xi'an Lijun pharmaceutical Co., Ltd
The research and development of crystallization technique processed and Industrialization Projects, obtain national science technological progress second prize in 2015.
High field coupling crystallization technique belongs to one in high-end medical product refining crystallization technology, and which is intended to break through both at home and abroad
Related pharmaceutical product crystal formation and its crystallization technique patent are blocked, it is achieved that high-end medical product research and development and crystallization technique level jump
Rise, the leading level in the world has been reached, has promoted China's pharmaceutical industries scientific and technological progress.
Cefoperazone sodium is the third generation cephalosporin that Japan folic hill chemical industrial company develops, and lists within 1981.
It also has to gram positive bacteria, Bacteroidess anti-to having very strong antibacterial activity including the gram-negative bacteria including bacillus pyocyaneus
Bacterium activity；Strong to beta-lactamase toleration, the ability that induction produces beta-lactamase is extremely low, is difficult Induction of bacterial and produces drug resistance
Property, it is respectively provided with good therapeutic effect and safety to the various infection symptoms such as respiratory tract, biliary tract, department of obstetrics and gynecology, surgery.Shu Ba
Smooth is to be developed by Pfizer research department of the U.S. for 1978, and proves the sulbactam with Inhibitory activity.Since nineteen ninety-two, moral
The country such as state and France have approved sulbactam single preparations of ephedrine in succession, and trade name is respectively Betamaze and Combactam, and can be
Clinically neatly combine for treating serious drug-fast bacteria infection with suitable beta-lactam antibiotic.Cefoperazone sodium be β-
Lactam antibioticses, are easily decomposed by the beta-lactamase that pathogenic bacterium produce, and easily occur drug resistance after clinical practice.Sulbactam sodium
For beta-lactamase inhibitor, both share very strong synergetic antibacterial effect.The compound preparation of both compositions has very high
Social benefit and economic benefit.
Cefoperazone sodium in the market and sulbactam sodium crude drug all have that purity is poor, the problem of stability difference,
Have impact on its quality of the pharmaceutical preparations.The reason for there is problem above be probably crystallize in be mingled with partial impurities, residual solvent etc. in crystal formation
Reason.Solve this problem and novel crystallization production technology must be researched and developed, waited with optimizing solvent, temperature, response time, additive
Journey technological parameter, makes crystallization carry out under the suitable conditions, so as to ensure the quality of product.
Present invention is generally directed to problem above, the factor such as solvent, temperature, external force, additive during crystal formation is filled
Divide on the basis of investigating, purity height, the cefoperazone sodium of good stability and sulbactam have been obtained using high field coupling crystallization technique
Sodium, adds ultrasonic external field reinforcing crystallization specially during compound crystal, prepares highly purified compound.In actual industrial
In application, ultrasonic field energy consumption is relatively low, and the impact for temperature is less, and the cavitation effect of ultrasonic field can effectively be accelerated mass transfer and divide
From process, and other impurities will not be introduced, detached material is not significantly affected.The more conventional crystallization of the present invention
Process steps are simpler, are suitable to industrial-scale production.The injection cephalo that is made using heretofore described two kinds of compounds
Piperazine ketone sodium and sulbactam sodium, more conventional preparation has more preferable stability.
Content of the invention
The first object of the present invention is to provide a kind of cefoperazone sodium compound, and the compound is using high field coupling crystallization
Technology is prepared, have the characteristics that purity height, good stability.
Cefoperazone sodium compound of the present invention is prepared and is comprised the following steps：
(1) cefoperazone acid is dissolved in the mixed solvent of water and organic solvent, at a certain temperature by material dissolution；
(2) salt forming agent is soluble in water, controlling reaction temperature, salt forming agent is slowly added in material liquid, stirring reaction, extremely
Suitable ph；
(3) filter, filtrate is poured in crystallizer, reduce temperature, dissolved agent is slowly added to, internal or outer in crystallizer
Ultrasonic field is laid in face, carries out the ultrasonic field reinforcing of crystallization process, filters, dissolved agent washing filter cake, and drying under reduced pressure obtains cefoperazone
Sodium
Preferably, in above-mentioned preparation method, the organic solvent described in step (1) is methanol, ethanol, chloroform, second
Any one in ether, the volume ratio of described water and organic solvent is 1：(1-1.5), described material dissolution temperature is 30-40
℃.
Preferably, in above-mentioned preparation method, the salt forming agent sodium lactate described in step (2), sodium acetate, Sodium isooctanoate., carbon
Any one in sour sodium, sodium bicarbonate, Feldalat NM, Sodium ethylate, described reaction temperature is controlled to 30-40 DEG C, and described becomes salt
It is pH value after agent for 6.0-6.7.
Preferably, in above-mentioned preparation method, dissolved agent described in step (3) is acetone, any one in ethyl acetate,
Described mixing speed is 250rpm, described reduction temperature to 15-20 DEG C, the frequency of described ultrasonic field is 20-100kHz,
Power is 5-15W/ solution, and described ultrasonic field is arranged on outside crystallization reactor or inside crystallization reactor.
The powder x-ray diffraction collection of illustrative plates of cefoperazone sodium of the present invention is 9.22 ± 0.2 ° in 2 θ of the angle of diffraction,
11.48 ± 0.2 °, 12.93 ± 0.2 °, 18.62 ± 0.2 °, 19.38 ± 0.2 °, 24.53 ± 0.2 °, at 28.40 ± 0.2 °, there is spy
Diffraction maximum is levied, as shown in Figure 1.
Cefoperazone sodium compound of the present invention, its Fourier transform infrared spectroscopy wave number be 1752.32 ±
2cm-1, 1727.61 ± 2cm-1, 1679.33 ± 2cm-1, 1611.26 ± 2cm-1, 1543.73 ± 2cm-1, 1390.06 ± 2cm-1,
1348.77±2cm-1, 1247.64 ± 2cm-1, 1052.29 ± 2cm-1There is characteristic absorption peak at place, as shown in Figure 2.
Cefoperazone sodium compound of the present invention, its DTA analysis result shows there is fusion and decomposition at 135.2 ± 1 DEG C
Endothermic peak, has decomposition endothermic peak at 245.7 ± 1 DEG C, as shown in Figure 3.
The second object of the present invention is to provide a kind of sulbactam sodium compound, and the compound is using high field coupling crystallization skill
Art is prepared, have the characteristics that purity height, good stability.
Sulbactam sodium compound of the present invention is prepared from using following methods：
(1) 6,6- dibromo sulbactam is dissolved in the mixed solvent of water and organic solvent, at a certain temperature by original
Material dissolving；
(2) salt forming agent is soluble in water, controlling reaction temperature, salt forming agent is slowly added in material liquid, stirring reaction, extremely
Suitable ph；
(3) charcoal absorption, filters, filtrate is poured in crystallizer, reduces temperature, is slowly added to dissolved agent, in crystallizer
Ultrasonic field is laid in portion or outside, carries out the ultrasonic field reinforcing of crystallization process, filters, dissolved agent washing filter cake, and drying under reduced pressure is obtained
Sulbactam sodium.
Preferably, in above-mentioned preparation method, the organic solvent described in step (1) is methanol, ethanol, chloroform, second
Any one in ether, the volume ratio of described water and organic solvent is 1：(1.5-2), described material dissolution temperature is 25-35
℃.
Preferably, in above-mentioned preparation method, the salt forming agent sodium lactate described in step (2), sodium acetate, sodium carbonate, carbonic acid
Any one in hydrogen sodium, Feldalat NM, Sodium ethylate, described reaction temperature is controlled to 25-35 DEG C, after described addition salt forming agent is
PH value is 4.5-5.5.
Preferably, in above-mentioned preparation method, dissolved agent described in step (3) is acetone, any one in ethyl acetate,
The temperature of described charcoal absorption is 20-30 DEG C, and described reduction temperature is to 5-10 DEG C, and the frequency of described ultrasonic field is 20-
100kHz, power are 5-15W/L solution, and described ultrasonic field is arranged on outside crystallization reactor or inside crystallization reactor.
Sulbactam sodium compound of the present invention, its powder x-ray diffraction collection of illustrative plates 2 θ of the angle of diffraction be 11.50 ±
0.2 °, 12.55 ± 0.2 °, 12.96 ± 0.2 °, 15.31 ± 0.2 °, 18.66 ± 0.2 °, at 24.58 ± 0.2 °, there is feature diffraction
Peak, as shown in Figure 4.X-ray powder diffraction test condition：EMPYREAN (sharp shadow) X of Dutch Panalytical company is penetrated
Line diffractometer, CuK α is radiated, light tube voltage 40kV, heater current 300mA, continuous scanning, 0.02 ° of step-length, 8 ° of scanning speed/
Min, sweep limitss are 2～50 °.
Sulbactam sodium compound of the present invention, its Fourier transform infrared spectroscopy is 1599.06 ± 2cm in wave number-1,
1453.71±2cm-1, 1256.69 ± 2cm-1, 1223.41 ± 2cm-1, 1159.66 ± 2cm-1, 1150.71 ± 2cm-1,
1146.31±2cm-1, 561.24 ± 2cm-1, 549.36 ± 2cm-1There is characteristic absorption peak at place, as shown in Figure 5.Fourier transformation
Examination of infrared spectrum condition：Nicolet, Nexus470, pressing potassium bromide troche.
Sulbactam sodium compound of the present invention, its DTA analysis result shows, has melting heat absorption at 190.3 ± 1 DEG C
, there is decomposition endothermic peak at peak in 260.4.1 ± 1 DEG C.As shown in Figure 6.DSC data by differential scanning calorimeter (DSC1/500, auspicious
Scholar Mettler Toledo company) analysis obtain, analysis condition is：Sample 5～10mg sample is placed in 40 μ L aluminum crucibles, high-purity
Nitrogen does reaction gas and shielding gas, and flow is respectively 50ml/min and 20ml/min.10 DEG C/min of heating rate, temperature range 25
～300 DEG C.
The 3rd purpose of the present invention is to provide one kind comprising cefoperazone sodium compound of the present invention and sulbactam sodium
The pharmaceutical composition of compound, which includes the component of following weight portion：0.25-2 part cefoperazone sodium is (with C25H27N9O8S2Meter)
With 0.25-2 part sulbactam sodium (with C8H11NO5S is counted).The pharmaceutical composition preparation process is simple to operate, and more conventional product has
More preferable stability.
Cefoperazone sodium of the present invention/sulbactam sodium medicine composition is prepared and is comprised the following steps：
(1) get the raw materials ready：After crude drug content and moisture conversion, cefoperazone sodium and sulbactam sodium is weighed by recipe quantity；
(2) mix：Above two raw material is mixed to uniform, intermediate inspection content in mixer；
(2) subpackage, total head plug：Mixed powder is sub-packed in injection bottles made of glass tubes, pressure is complete to fill in；
(3) lid is rolled.
Description of the drawings
The X-ray powder diffraction spectrogram of Fig. 1 cefoperazone sodium compound；
Fourier transform infrared spectroscopy (FT-IR) figure of Fig. 2 cefoperazone sodium compound；
Differential thermal analyses (DTA) figure of Fig. 3 cefoperazone sodium compound；
The X-ray powder diffraction spectrogram of Fig. 4 sulbactam sodium compound；
Fourier transform infrared spectroscopy (FT-IR) figure of Fig. 5 sulbactam sodium compound；
Differential thermal analyses (DTA) figure of Fig. 6 sulbactam sodium compound；
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but therefore do not limit the present invention to institute
In the scope of embodiments that states, it should be understood by those skilled in the art that the equivalent done by present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Embodiment 1：The preparation of cefoperazone sodium compound
(1) 500g cefoperazone acid is dissolved in the mixed solvent of 500ml water and 500ml ethanol, 30 DEG C of control temperature will
Material dissolution；
(2) 65.12g sodium bicarbonate is dissolved in 500ml water, 30 DEG C of controlling reaction temperature, by the aqueous solution of sodium bicarbonate
It is slowly added in material liquid, stirring reaction, to pH value 6.0；
(3) filter, filtrate is poured in crystallizer, reduce temperature to 15 DEG C, 2L acetone is slowly added to, inside crystallizer
Lay ultrasonic field, carry out the ultrasonic field reinforcing of cefoperazone sodium crystallization process, the frequency of ultrasonic field is 100kHz, power be
L solution, filters, washing with acetone filter cake, drying under reduced pressure, obtains cefoperazone sodium 453g.
The X-ray powder diffraction collection of product is 9.22 °, 11.48 ° in 2 θ of the angle of diffraction, 12.93 °, 18.62 °,
19.38 °, 24.53 °, at 28.40 °, there is characteristic peak.Solid Fourier transform infrared spectroscopy is 1752.32cm in wave number-1,
1727.61cm-1, 1679.33cm-1, 1611.26cm-1, 1543.73cm-1, 1390.06cm-1, 1348.77cm-1,
1247.64cm-1, 1052.29cm-1There is characteristic peak at place.Its DTA decomposition temperature is 245.1 DEG C.Placement ten days under 60 DEG C of high temperature, still
For white crystalline powder.60 DEG C of heat stabilization test results show, the weight rate 1.0% of 10 days, and heat stability is good.
Embodiment 2：The preparation of cefoperazone sodium compound
(1) 500g cefoperazone acid is dissolved in the mixed solvent of 500ml water and 750ml chloroform, controls temperature 40
DEG C by material dissolution；
(2) 104g sodium lactate is dissolved in 600ml water, 40 DEG C of controlling reaction temperature, will be slow for the aqueous solution for becoming sodium lactate
Add in material liquid, stirring reaction, to pH value 6.7；
(3) filter, filtrate is poured in crystallizer, reduce temperature to 20 DEG C, 2L ethyl acetate is slowly added to, in crystallizer
The internal ultrasonic field reinforcing that lays ultrasonic field, carry out cefoperazone sodium crystallization process, the frequency of ultrasonic field is 20kHz, power is
5W/L solution, filter, ethyl acetate washing filter cake, drying under reduced pressure, obtain cefoperazone sodium 442g.
The X-ray powder diffraction collection of product is 9.3 °, 11.52 ° in 2 θ of the angle of diffraction, 12.91 °, 18.54 °, 19.32 °,
24.42 °, at 28.37 °, there is characteristic peak.Solid Fourier transform infrared spectroscopy is 1751.51cm in wave number-1, 1726.39cm-1,
1678.51cm-1, 1612.39cm-1, 1544.58cm-1, 1391.42cm-1, 1349.41cm-1, 1248.23cm-1,
1053.44cm-1There is characteristic peak at place.Its DTA decomposition temperature is 244.9 DEG C.Place ten days under 60 DEG C of high temperature, be still white crystalline
Powder.60 DEG C of heat stabilization test results show, the weight rate 1.1% of 10 days, and heat stability is good.
Embodiment 3：The preparation of sulbactam sodium compound
(1) 650g 6,6- dibromo sulbactam is dissolved in the mixed solvent of 500ml water and 750ml methanol, 25 DEG C of temperature
Lower by material dissolution；
(2) will be soluble in water for 285g Sodium isooctanoate., 25 DEG C of controlling reaction temperature, the aqueous solution of Sodium isooctanoate. is slowly added to
In material liquid, stirring reaction, to pH value 4.5；
(3) temperature control is carried out charcoal absorption at 20 DEG C, filters, filtrate is poured in crystallizer, reduce temperature to 5 DEG C,
Acetone is slowly added to, inside crystallizer, ultrasonic field is laid, the ultrasonic field reinforcing of sulbactam sodium crystallization process is carried out, ultrasonic field
Frequency is 20kHz, power is 5W/L solution, to filter, washing with acetone filter cake, and drying under reduced pressure obtains sulbactam sodium 542g.
The X-ray powder diffraction collection of product is 11.50 °, 12.55 ° in 2 θ of the angle of diffraction, 12.96 °, 15.31 °,
18.66 °, at 24.58 °, there is characteristic peak.Solid Fourier transform infrared spectroscopy is 1599.06cm in wave number-1, 1453.71cm-1,
1256.69cm-1, 1223.41cm-1, 1159.66cm-1, 1150.71cm-1, 1146.31cm-1, 561.24cm-1, 549.36cm-1
There is characteristic peak at place.DTA decomposition temperature is 260.1 DEG C.Place ten days under 60 DEG C of high temperature, be still white crystalline powder.60 DEG C of heat
Stability test result shows, the weight rate 0.9% of 10 days, and heat stability is good.
Embodiment 4：The preparation of sulbactam sodium compound
(1) 650g 6,6- dibromo sulbactam is dissolved in the mixed solvent of 500ml water and 1L ether, at a temperature of 35 DEG C
By material dissolution；
(2) will be soluble in water for 250g Feldalat NM, 35 DEG C of controlling reaction temperature, the aqueous solution of Feldalat NM is slowly added to raw material
In liquid, stirring reaction, to pH value 5.5；
(3) temperature control is carried out charcoal absorption at 30 DEG C, filters, filtrate is poured in crystallizer, reduce temperature to 10 DEG C,
Ethyl acetate is slowly added to, and ultrasonic field is laid in the internal or outside of crystallizer, is carried out the ultrasonic field of sulbactam sodium crystallization process
Reinforcing, the frequency of ultrasonic field is 50kHz, power is 10W/L solution, to filter, washing with acetone filter cake, and drying under reduced pressure obtains sulbactam
Sodium 535g.
The X-ray powder diffraction collection of product in 11.61 ± 0.2 ° of the angle of diffraction, 12.59 ± 0.2 °, 12.87 ± 0.2 °,
15.26 ± 0.2 °, 18.75 ± 0.2 °, at 24.69 ± 0.2 °, there is characteristic peak.Solid Fourier transform infrared spectroscopy in wave number is
1598.24±2cm-1, 1452.66 ± 2cm-1, 1255.17 ± 2cm-1, 1221.93 ± 2cm-1, 1158.26 ± 2cm-1,
1151.21±2cm-1, 1147.14 ± 2cm-1, 560.25 ± 2cm-1, 548.12 ± 2cm-1There is characteristic peak at place.DTA decomposition temperature
For 259.7 DEG C.Place ten days under 60 DEG C of high temperature, be still white crystalline powder.60 DEG C of heat stabilization test results show, 10 days
Weight rate 0.9%, heat stability is good.
Embodiment 5：The preparation of cefoperazone sodium and sulbactam sodium for injection
The step of according to embodiment 1 and embodiment 3, prepares cefoperazone sodium and sulbactam sodium compound, using this raw material system
Standby cefoperazone sodium and sulbactam sodium for injection, specification 0.5g.Wherein cefoperazone sodium is (with C25H27N9O8S2Meter) 0.25g and easypro bar
Smooth sodium is (with C8H11NO5S is counted) 0.25g.
Prescription：
Preparation process：
(1) get the raw materials ready：After crude drug content and moisture conversion, cefoperazone sodium and sulbactam sodium is weighed by recipe quantity；
(2) mix：Above two raw material is mixed 1h, mix homogeneously, intermediate inspection content in mixer；
(2) subpackage, total head plug：Mixed powder is sub-packed in injection bottles made of glass tubes, pressure is complete to fill in；
(3) lid is rolled.
The preparation of 1 cefoperazone sodium compound of comparative example
Using with embodiment identical technique, but parameter is different.
(1) 500g cefoperazone acid is dissolved in the mixed solvent of 100ml water and 500ml ethanol, 10 DEG C of control temperature will
Material dissolution；
(2) 65.12g sodium bicarbonate is dissolved in 500ml water, 10 DEG C of controlling reaction temperature, by the aqueous solution of sodium bicarbonate
It is slowly added in material liquid, stirring reaction, to pH value 5.5；
(3) filter, filtrate is poured in crystallizer, reduce temperature to 0 DEG C, be slowly added to 2L acetone, 400rpm stirring knot
Crystalline substance, filters, washing with acetone filter cake, drying under reduced pressure, obtains cefoperazone sodium 266g.
Comparative example 2：The preparation of sulbactam sodium compound
Using with embodiment identical technique, but parameter is different.
(1) 650g 6,6- dibromo sulbactam is dissolved in the mixed solvent of 500ml water and 500ml ether, 45 DEG C of temperature
Lower by material dissolution；
(2) will be soluble in water for 250g Feldalat NM, 45 DEG C of controlling reaction temperature, the aqueous solution of Feldalat NM is slowly added to raw material
In liquid, stirring reaction, to pH value 6.0；
(3) temperature control is carried out charcoal absorption at 40 DEG C, filters, filtrate is poured in crystallizer, reduce temperature to 20 DEG C,
It is slowly added to ethyl acetate, 300rpm stirred crystallization, filters, washing with acetone filter cake, drying under reduced pressure, obtains sulbactam sodium 352g.Right
Ratio 3：The preparation of cefoperazone sodium and sulbactam sodium for injection
The step of according to comparative example 1 and comparative example 2, prepares cefoperazone sodium and sulbactam sodium compound, using this raw material system
Standby cefoperazone sodium and sulbactam sodium for injection, specification 0.5g.Wherein cefoperazone sodium is (with C25H27N9O8S2Meter) 0.25g and easypro bar
Smooth sodium is (with C8H11NO5S is counted) 0.25g.
Prescription：
Preparation process：
(1) get the raw materials ready：After crude drug content and moisture conversion, cefoperazone sodium and sulbactam sodium is weighed by recipe quantity；
(2) mix：Above two raw material is mixed 1h, mix homogeneously, intermediate inspection content in mixer；
(2) subpackage, total head plug：Mixed powder is sub-packed in injection bottles made of glass tubes, pressure is complete to fill in；
(3) lid is rolled.
Test example 1：
To the embodiment of the present invention 1 and prepared by comparative example 1, cefoperazone sodium compound has carried out purity detecting to the present inventor.
Purity detecting result：
As a result：The cefoperazone sodium that cefoperazone sodium compound purity prepared by the present invention is prepared apparently higher than prior art
Compound.Test example 2：
The present inventor takes funnel method to determine angle of repose to the embodiment of the present invention 1 and cefoperazone sodium prepared by comparative example 1,
The mobility of cefoperazone sodium is studied.
Angle of repose testing result:
| Embodiment | Angle of repose θ |
| Embodiment 1 | 29.1° |
| Comparative example 1 | 33.8° |
As a result：The mobility of cefoperazone sodium compound prepared by the present invention is significantly better than the cefoperazone sodium of prior art
Compound, can meet the needs of different preparations preparation.
Test example 3：
To the embodiment of the present invention 3 and prepared by comparative example 2, sulbactam sodium compound has carried out purity detecting to the present inventor.
Purity detecting result：
As a result：The sulbactam sodium chemical combination that sulbactam sodium compound purity prepared by the present invention is prepared apparently higher than prior art
Thing.
Test example 4：
The present inventor takes funnel method to determine angle of repose to the embodiment of the present invention 3 and sulbactam sodium prepared by comparative example 2, right
The mobility of sulbactam sodium is studied.
Angle of repose testing result:
| Embodiment | Angle of repose θ |
| Embodiment 1 | 28.2° |
| Comparative example 1 | 34.5° |
As a result：The mobility of sulbactam sodium compound prepared by the present invention is significantly better than the sulbactam sodium chemical combination of prior art
Thing, can meet the needs of different preparations preparation.
Test example 5：
To the embodiment of the present invention 5 and prepared by comparative example 3, cefoperazone sodium and sulbactam sodium for injection is carried out the present inventor
Accelerated stability investigates test.Investigation condition is 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%.Place 6 months, respectively at
0th, 1,2,3,6 the end of month sampling.Inspection target is character, the clarity of solution and color, acidity, content and relevant material.Accelerate
Experiment investigation result：
As a result：Embodiment 5 is placed 6 months at the conditions of the experiments described above with 3 product of comparative example, content and relevant material and its
His indices all meet regulation, and 5 content of embodiment and relevant material change little compared with comparative example 3, and quality is good.
Brief summary：By each result of the test above-mentioned, cefoperazone sodium compound, the sulbactam sodium compound of the present invention are described
And combinations thereof preparation through indices inspection and accelerated test investigate show good stability, reliable in quality.
The measure of 5 bioavailability of test example
24 1 years old or so beasle dogs are randomly divided into 2 groups, vein gives embodiment 1 and commercially available spore piperazine ketone sodium/sulbactam
Composition of sodium (0.5g), after administration terminates, 0,0.25,0.5,1,1.5,2.5,3.5,5.5 and 7.5h gathers venous blood 1ml, injection
Take in blood vessel, be centrifuged at a high speed serum, the accurate 190 μ L of blood serum sample that draws is placed in 1.5mL Eppendorf microcentrifugal tube
In, 10 μ L internal standard saturation methotrexate solution are added, adds 400 μ L of methanol, vortex mixed 1min, 16000rpm high speed centrifugation
5min, takes 200 μ L of supernatant and adds 200 μ L water, and 2500rpm vortex 30s is mixed, and is carried out HPLC-MS analysis, is used WinNonline
Version5.2 program carries out pharmacokinetic data available process.Result of the test such as following table：
Relevant pharmacokinetic parameters：
As can be seen from the above experimental data, the spore piperazine ketone sodium/sulbactam sodium composition and city that prepared by the embodiment of the present invention
Sell product to compare, bioavailability is greatly improved, absolutely proved that pharmaceutical composition prepared by the present invention has higher biology
Availability, obtains unexpected technical effect.
Claims (9)
1. the cefoperazone sodium compound that prepared by a kind of employing high field coupling crystallization technique, structural formula is as follows：
Characterized in that, the X-ray powder diffraction pattern for being represented with the 2 θ angles of diffraction is at 9.22 ± 0.2 °, 11.48 ± 0.2 °,
12.93 ± 0.2 °, 18.62 ± 0.2 °, 19.38 ± 0.2 °, 24.53 ± 0.2 °, at 28.40 ± 0.2 °, show characteristic diffraction peak,
Its Fourier transform infrared spectroscopy is 1752.32 ± 2cm in wave number-1, 1727.61 ± 2cm-1, 1679.33 ± 2cm-1,
1611.26±2cm-1, 1543.73 ± 2cm-1, 1390.06 ± 2cm-1, 1348.77 ± 2cm-1, 1247.64 ± 2cm-1,
1052.29±2cm-1, there is characteristic absorption peak at place；Its DTA has melting endothermic peak at 135.2 ± 1 DEG C, has decomposition at 245.7 ± 1 DEG C
Endothermic peak.
2. cefoperazone sodium compound as claimed in claim 1, it is characterised in that preparation process includes：
(1) cefoperazone acid is dissolved in the mixed solvent of water and organic solvent, at a certain temperature by material dissolution；
(2) salt forming agent is soluble in water, controlling reaction temperature, salt forming agent is slowly added in material liquid, stirring reaction, to suitable
PH value；
(3) filter, filtrate is poured in crystallizer, reduce temperature, dissolved agent is slowly added to, keeping temperature, inside crystallizer
The ultrasonic field reinforcing of crystallization process or ultrasonic field is laid in outside, is carried out, is filtered, dissolved agent washing filter cake, drying under reduced pressure, obtain head
Spore piperazine ketone sodium.
3. preparation method as claimed in claim 2, it is characterised in that the organic solvent described in step (1) be
Any one in alcohol, chloroform, ether, the volume ratio of described water and organic solvent is 1：(1-1.5), described raw material is molten
Solution temperature is 30-40 DEG C.
4. preparation method as claimed in claim 2, it is characterised in that the salt forming agent sodium lactate described in step (2), acetic acid
Any one in sodium, Sodium isooctanoate., sodium carbonate, sodium bicarbonate, Feldalat NM, Sodium ethylate, described reaction temperature is controlled to 30-40
DEG C, it is pH value after described addition salt forming agent for 6.0-6.7.
5. preparation method as claimed in claim 2, it is characterised in that the dissolved agent described in step (3) be
Any one in ester, the frequency of described ultrasonic field is 20-100kHz, power is that 5-15W/L solution, described ultrasonic field is arranged
Outside crystallization reactor or inside crystallization reactor, described reduction temperature is to 15-20 DEG C.
6. the sulbactam sodium compound that prepared by a kind of employing high field coupling crystallization technique, structural formula is as follows：
Characterized in that, the X-ray powder diffraction pattern for being represented with the 2 θ angles of diffraction is at 11.50 ± 0.2 °, 12.55 ± 0.2 °,
12.96 ± 0.2 °, 15.31 ± 0.2 °, 18.66 ± 0.2 °, at 24.58 ± 0.2 °, show characteristic diffraction peak, its Fourier transformation
Infrared spectrum is 1599.06 ± 2cm in wave number-1, 1453.71 ± 2cm-1, 1256.69 ± 2cm-1, 1223.41 ± 2cm-1,
1159.66±2cm-1, 1150.71 ± 2cm-1, 1146.31 ± 2cm-1, 561.24 ± 2cm-1, 549.36 ± 2cm-1There is feature at place
Absworption peak, its DTA has melting endothermic peak at 190.3 ± 1 DEG C, has decomposition endothermic peak at 260.4 ± 1 DEG C.
7. sulbactam sodium compound as claimed in claim 6, it is characterised in that preparation process includes：
(1) 6,6- dibromo sulbactam is dissolved in the mixed solvent of water and organic solvent, at a certain temperature that raw material is molten
Solution；
(2) salt forming agent is soluble in water, controlling reaction temperature, salt forming agent is slowly added in material liquid, stirring reaction, to suitable
PH value；
(3) charcoal absorption, filters, filtrate is poured in crystallizer, reduces temperature, is slowly added to dissolved agent, crystallizer internal or
Ultrasonic field being laid outside person, being carried out the ultrasonic field reinforcing of crystallization process, filter, filter cake, drying under reduced pressure, get Shu Ba are washed in dissolved agent
Smooth sodium.
8. preparation method as claimed in claim 6, it is characterised in that
Organic solvent described in step (1) is methanol, ethanol, chloroform, any one in ether, described water and organic
The volume ratio of solvent is 1：(1.5-2), described material dissolution temperature is 25-35 DEG C；
Arbitrary in salt forming agent sodium lactate, sodium acetate, sodium carbonate, sodium bicarbonate, Feldalat NM, Sodium ethylate described in step (2)
Kind, described reaction temperature is controlled to 25-35 DEG C, after described addition salt forming agent be pH value be 4.5-5.5；
Dissolved agent described in step (3) is acetone, any one in ethyl acetate, and the temperature of described charcoal absorption is 20-30
DEG C, described reduction temperature is to 5-10 DEG C, and the frequency of described ultrasonic field is 20-100kHz, power is 5-15W/L solution, institute
The ultrasonic field that states is arranged on outside crystallization reactor or inside crystallization reactor.
9. a kind of cefoperazone sodium sulbactam sodium pharmaceutical composition, it is characterised in which is injectable powder and containing claim 1 institute
Cefoperazone sodium compound obtained in preparation method described in the cefoperazone sodium compound that states or claim 1-5 any one
With the bar that relaxes obtained in the sulbactam sodium compound described in claim 6 or the preparation method described in claim 7-8 any one
Smooth sodium compound, described cefoperazone sodium sulbactam sodium pharmaceutical composition includes the component of following weight portion：0.25-2 part head
Spore piperazine ketone sodium is (with C25H27N9O8S2Meter) and 0.25-2 part sulbactam sodium (with C8H11NO5S is counted).
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