CN106093263A - A kind of ceftriaxone sodium for injection method of quality control - Google Patents
A kind of ceftriaxone sodium for injection method of quality control Download PDFInfo
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- CN106093263A CN106093263A CN201610517884.7A CN201610517884A CN106093263A CN 106093263 A CN106093263 A CN 106093263A CN 201610517884 A CN201610517884 A CN 201610517884A CN 106093263 A CN106093263 A CN 106093263A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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Abstract
The present invention provides a kind of ceftriaxone sodium for injection method of quality control, and the method includes preparing ammonium bromide acetonitrile solution, phosphate buffer, citrate buffer respectively, adds water dilute filtration for flowing phase.With octadecylsilane chemically bonded silica as filler；Detection wavelength is 254nm；Flow velocity is 1.5ml/min.The method is meeting outside impurity A, the impurity C separation requirement with adjacent peak, the separation of other each impurity is also more easy to reach requirement, there is the features such as reliable, accurate, stable, method specificity is strong, highly sensitive, reproducible, be highly suitable in commercial production and daily defects inspecting.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of ceftriaxone sodium for injection method of quality control.
Background technology
Ceftriaxone sodium is that third generation water-soluble semi synthesizes Cephalosporins antibiotic, is recorded by multinational pharmacopeia.This medicine
Product are long-acting, broad-spectrum cephalosporin, by suppressing the synthetically produced antibacterial action of cell wall, to gram-positive bacteria and negative bacterium
There is stronger bactericidal action.Beta-lactamase including and cephalosporinase mould include penicillin there is high stability.Main
It is applicable to this product sensitivity is caused a disease microbial pneumonia, otorhinolaryngology infection, urinary system infection, septicemia, meningitis, bone
With the infection of joint, skin soft-tissue infection, peritonitis, biliary tract and gastrointestinal infection, genital system infection including gonorrhea
Deng it can also be used to preoperative prevention infect.
In the industrial production, owing to the production technology of ceftriaxone sodium is more complicated, medicine nature is not sufficiently stable,
Produce and storage easily produces impurity, and dopant species and the way of production is more, impurity content is low, study to its impurity
Bring certain difficulty.This medicine easily hydrolyzes generation impurity C (triazine ring) and hydroxy-containing compounds, and the former is also that synthesis cephalo is bent
The initiation material of pine sodium, the latter's easily condensation formation lactone under conditions of slant acidity；Ceftriaxone sodium holds under illumination condition
It is easily formed impurity A (trans ceftriaxone)；Initiation material 7-ACA, triazine ring and the AE active ester of reaction and intermediate 7-
ACT is also likely to be occurred in the final product.The existence of these impurity, not only makes drug effect reduce, and antibacterial activity weakens, very
To human body being produced harm.Zhongqi Pharmaceutical Technology (Shijiazhuang) Co. Ltd. of Shiyao Group and Chinese Academy of Medical Sciences's medicine
Biotechnology research used zebrafish embryo toxicity test finds 10-3Impurity A under mol/L concentration, impurity C and 7-ACA can
Causing zebrafish embryo lopsided and dead, wherein the impurity A of low dosage can cause zebrafish embryo toxic reaction, and toxicity is three
Plant in impurity maximum.In order to ensure drug quality and clinical application safe and effective, it is necessary to likely occurring in product
Impurity is analyzed research.
The existing relevant substance detecting method of ceftriaxone sodium for injection, each intermediate and the separating degree of degradation impurity, special
It not that impurity A, impurity C are bad with the separating effect of adjacent peak.For making the separating degree of each impurity reach requirement, it is more suitable for relevant thing
The detection of matter, from defects inspecting accurately, method detection feasible etc. from the standpoint of, it is bent that we establish a new injection cephalo
Pine sodium method of quality control so that impurity A, impurity C meet the requirements with the separating degree of adjacent peak, also makes other each impurity simultaneously
Separating degree meets the requirements, and system suitability is good.
Summary of the invention
We use common high performance liquid chromatography, by optimizing the indexs such as flowing phase, flow velocity, detection wavelength and using
Known impurities positions, the Self-control method of the correction up factor, focuses on ceftriaxone sodium for injection impurity A and the control of impurity C,
Establish a kind of new detection method.The method can make that impurity A, impurity C are more preferable with adjacent peak must be separated, and also makes other each impurity
Separate is more preferable, is more suitable for the detection having related substance.
For achieving the above object, the present invention is by the following technical solutions:
The present invention provides a kind of ceftriaxone sodium for injection method of quality control, it is characterised in that:
1, chromatographic condition:
Preparation ammonium bromide acetonitrile solution, phosphate buffer, citrate buffer respectively, adds water dilute filtration for flowing phase.
With octadecylsilane chemically bonded silica as filler；Detection wavelength is 254nm；Flow velocity is 1.5ml/min；Column temperature is 30 DEG C.
2, system suitability experiment:
Weigh 5mg ceftriaxone reference substance, 5mg impurity A reference substance and 5mg impurity C reference substance respectively, to 100ml measuring bottle, add
Flowing phased soln is also diluted to scale, shakes up.
Measuring 20 μ l, inject chromatograph of liquid, record chromatogram, impurity A peak, impurity C peak are relative with ceftriaxone peak
Retention time respectively may be about 1.3,0.5, and the separating degree between ceftriaxone peak and impurity A peak should be not less than 3.0.
3, need testing solution:
Take the content under content uniformity item appropriate, accurately weighed, add flowing phased soln and dilution make in every 1ml containing about
The solution of 0.3mg, as need testing solution；Precision measures 1.0ml, puts in 100ml measuring bottle, add flowing phase dilution to scale, shake
Even, as contrast solution.
4, this method has also carried out the serial of methods checkings such as specificity, linearity and range, method precision, all conforms to
Ask.
In sum, the present invention provides a kind of ceftriaxone sodium for injection method of quality control, is meeting impurity A, impurity C
Outside with the separation requirement of adjacent peak, the separation of other each impurity is also more easy to reach requirement, have accurate, reliable, stable, method is special
The features such as attribute is strong, highly sensitive, reproducible, are highly suitable in commercial production and daily defects inspecting.
Detailed description of the invention
The detailed description of the invention of the present invention is further elucidated below, but embodiments of the present invention are not limited to this, any right
The unsubstantiality that the enforcement of the present invention is made simply changes or replaces, and is intended to be included in the scope of the present invention.
Embodiment 1
High performance liquid chromatograph: Shimadzu LC-20AT/SPD-20A；Chromatographic column: Dalian Yi Lite ODS2(C18 post), column length
250mm, internal diameter 4.6mm, particle diameter 5 m；UV detector: wavelength 254nm；Flow velocity: 1.5ml/min；Sample size: 20 l；Column temperature: 30
℃。
Flowing phase: ammonium bromide acetonitrile solution-water-phosphate buffer-citrate buffer.
System suitability:
Weigh 5mg ceftriaxone reference substance, 5mg ceftriaxone impurity A reference substance and 5mg ceftriaxone impurity C reference substance respectively,
Put in 100ml measuring bottle, add flowing phased soln and be diluted to scale, shaking up, as system suitability solution, measure 20 μ l and inject liquid
Chromatography, records the relative retention time at chromatogram, ceftriaxone impurity A peak, ceftriaxone impurity C peak and ceftriaxone peak
Respectively may be about 1.3,0.5, the separating degree between ceftriaxone peak and ceftriaxone impurity A peak should be not less than 3.0.
Need testing solution:
Taking the content under content uniformity item, mix homogeneously, precision weighs in right amount (about 30mg), puts in 100ml measuring bottle, adds flowing
Phased soln is also diluted to scale, shakes up, as need testing solution.
Contrast solution:
Precision pipettes above-mentioned need testing solution 1.0ml, puts in 100ml measuring bottle, with flowing phase dilution to scale, shakes up.
Algoscopy:
Precision measures and takes contrast solution 20 μ l, injects chromatograph of liquid, regulates detection sensitivity, makes the peak height of main constituent chromatographic peak
It is about the 25% of full scale；Precision measures need testing solution and each 20 μ l of contrast solution, is injected separately into chromatograph of liquid, records color
Spectrogram is to 2 times of main constituent peak retention time.
Limit:
Impurity peaks in need testing solution chromatogram, ceftriaxone impurity A (is multiplied by correction factor by the calculated by peak area after correction
1.2) cannot be greater than 0.5 times (0.5%) of contrast solution main peak area, impurity C peak area cannot be greater than contrast solution main peak area
0.8 times (0.8%), other single impurity peak area cannot be greater than 0.2 times (0.2%) of contrast solution main peak area, each impurity
Peak area and cannot be greater than contrast solution main peak area (1.0%), any less than contrast solution master in need testing solution chromatogram
The peak of peak area 0.05 times (0.05%) is negligible, and its peak sequence is followed successively by: lactone, 7-ACA, impurity C (triazine ring),
7-ACT, ceftriaxone, impurity A (ceftriaxone transisomer), see liquid chromatograph Fig. 1.
Computing formula:
Impurity C and other single contaminants are calculated as follows:
X is miscellaneous=(A miscellaneous/A to) × 1%
Impurity A is calculated as follows:
X is miscellaneous=(A miscellaneous × f/A to) × 1%
Total impurities is calculated as follows:
X is miscellaneous=and (the miscellaneous A of A × 1.2 mono-miscellaneous+A of+A impurity C+A ...)/A is right × and 1%.
In formula: the miscellaneous peak area for impurity peaks each in need testing solution of A.
F is the correction factor of impurity peaks.
A is to the peak area for contrast solution main peak.
Accompanying drawing explanation
Fig. 1 is liquid chromatogram.
Claims (3)
1. a ceftriaxone sodium for injection method of quality control, it is characterised in that:
1) chromatographic condition:
Preparation ammonium bromide acetonitrile solution, phosphate buffer, citrate buffer respectively, adding water dilute filtration is flowing phase,
With octadecylsilane chemically bonded silica as filler, detection wavelength is 254nm, and flow velocity is 1.5ml/min, and column temperature is 30 DEG C；
2) system suitability experiment:
Weigh 5mg ceftriaxone reference substance, 5mg impurity A reference substance and 5mg impurity C reference substance respectively, to 100ml measuring bottle, add
Flowing phased soln is also diluted to scale, shakes up, and measures 20 μ l, injects chromatograph of liquid, records chromatogram, impurity A peak, impurity C
Peak respectively may be about 1.3,0.5 with the relative retention time at ceftriaxone peak, and the separating degree between ceftriaxone peak and impurity A peak should
Not less than 3.0；
3) need testing solution:
Take the content under content uniformity item appropriate, accurately weighed, add flowing phased soln and dilution make in every 1ml containing about
The solution of 0.3mg, as need testing solution；Precision measures 1.0ml, puts in 100ml measuring bottle, add flowing phase dilution to scale, shake
Even, as contrast solution.
The most according to claim 1, with ammonium bromide acetonitrile solution-water-phosphate buffer-citrate buffer for flowing
Phase, it is characterised in that the volume ratio of corresponding component is 400～480:460～500:58～61:5～6.
The most according to claim 1, the percentage composition of ammonium bromide acetonitrile solution is 0.833%～1%；In phosphate buffer, phosphorus
The ratio of acid disodium hydrogen and potassium dihydrogen phosphate volume is 1:1, adjusts pH to 7.0 ± 0.2；The percentage composition of citrate buffer is 2%
～2.05%, regulate pH to 5.0 ± 0.2.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112798705A (en) * | 2020-12-28 | 2021-05-14 | 北京悦康科创医药科技股份有限公司 | Method for detecting impurities of ceftriaxone sodium polymer |
| CN114113359A (en) * | 2021-05-07 | 2022-03-01 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
| CN114414714A (en) * | 2022-01-24 | 2022-04-29 | 武汉九州钰民医药科技有限公司 | Detection method of ceftriaxone sodium related substances, ceftriaxone sodium dimer, and preparation method and application thereof |
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| US20050059156A1 (en) * | 2003-08-06 | 2005-03-17 | Pharmacia Italia S.P.A. | Method for detecting contaminants in pharmaceutical products |
| CN104407063A (en) * | 2014-09-21 | 2015-03-11 | 四川制药制剂有限公司 | Method for determining content of ceftriaxone sodium for injection |
| CN105017243A (en) * | 2015-06-29 | 2015-11-04 | 苏州东瑞制药有限公司 | Ceftriaxone sodium photodecomposition product, and preparation method and analysis and detection method thereof |
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2016
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Patent Citations (3)
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| US20050059156A1 (en) * | 2003-08-06 | 2005-03-17 | Pharmacia Italia S.P.A. | Method for detecting contaminants in pharmaceutical products |
| CN104407063A (en) * | 2014-09-21 | 2015-03-11 | 四川制药制剂有限公司 | Method for determining content of ceftriaxone sodium for injection |
| CN105017243A (en) * | 2015-06-29 | 2015-11-04 | 苏州东瑞制药有限公司 | Ceftriaxone sodium photodecomposition product, and preparation method and analysis and detection method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112798705A (en) * | 2020-12-28 | 2021-05-14 | 北京悦康科创医药科技股份有限公司 | Method for detecting impurities of ceftriaxone sodium polymer |
| CN114113359A (en) * | 2021-05-07 | 2022-03-01 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
| CN114113359B (en) * | 2021-05-07 | 2024-02-20 | 佛山市南海北沙制药有限公司 | Central control detection method of 7-ACA derivative |
| CN114414714A (en) * | 2022-01-24 | 2022-04-29 | 武汉九州钰民医药科技有限公司 | Detection method of ceftriaxone sodium related substances, ceftriaxone sodium dimer, and preparation method and application thereof |
| CN114414714B (en) * | 2022-01-24 | 2024-03-12 | 武汉九州钰民医药科技有限公司 | Cefadrone sodium related substance detection method, ceftriaxone sodium dimer, preparation method and application thereof |
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