CN103245741B - The detection method of impurity in Meropenem - Google Patents
The detection method of impurity in Meropenem Download PDFInfo
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- CN103245741B CN103245741B CN201310156719.XA CN201310156719A CN103245741B CN 103245741 B CN103245741 B CN 103245741B CN 201310156719 A CN201310156719 A CN 201310156719A CN 103245741 B CN103245741 B CN 103245741B
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Abstract
The invention provides the detection method of impurity in Meropenem, comprise following operation steps: (1) gets Meropenem sample, the dilution that is dissolved in water is for sample solution; (2) extracting sample solution, injects high performance liquid chromatograph and detects; Wherein, chromatographic condition is as follows: chromatographic column: with the spherical silica gel chemical bonding hydrophilic compounds of rigidity for filler; Mobile phase: phosphate buffer, its pH=6.00 ± 0.05, isocratic elution; UV detect wavelength: 220 ± 2nm.Detection method provided by the invention, can be separated effectively by each impurity in Meropenem, and degree of separation is good, thus can calculate the content of different impurities more accurately, for the further monitoring of Meropenem polymeric impurities, research provide possibility.
Description
Technical field
The present invention relates to a kind of detection method to impurity in Meropenem.
Background technology
Meropenem, is the wide spectrum carbapenem antibiotic of Prof. Du Yucang, produces antibacterial action by the synthesis of anti-bacteria cell membrane.The hydrolytic action of Meropenem to most of beta-lactamase has stronger stability.Its preparation is meropenem for injection, within 1994, in Italy's listing, within 1999, in Discussion on Chinese Listed, is the medication of national medical insurance Class B, is used for the treatment of the inflammation such as pneumonia, gynecological infection, urinary tract infections, meningitis, skin soft-tissue infection, septicemia.
Use said preparation to occur allergic reaction sometimes, and research finds, allergic reaction is relevant with the Meropenem polymeric impurities in meropenem for injection.Therefore, there is allergic reaction for reducing, the amount of Meropenem polymkeric substance in meropenem for injection need be reduced, meanwhile, also need to monitor Meropenem polymer content in product.
At present, multinational pharmacopeia is all adopt octadecyl silane to be chromatographic column, monitors, and fail effectively to detect the impurity such as Meropenem polymkeric substance to Meropenem opened loop compound content.There is researchist to find, with sephadex chromatography post, Meropenem polymkeric substance is detected, achieve the compartment analysis (Wang Xijun etc., the polymkeric substance in gel chromatography Meropenem, Contemporary Chinese medicine, 19 volume 11 phases in 2012) to polymkeric substance.
But inventor tests discovery, multiple polymers magazins' layout cannot be opened by existing exclusion chromatography, hinders the further monitoring to Meropenem polymeric impurities, research.Inventor's inference, the not good reason of polymeric impurities degree of separation may be that Meropenem polymkeric substance mostly is dipolymer, and Meropenem impurity B is the isomers of dipolymer, and therefore, Meropenem polymkeric substance can not effectively be separated with impurity B by existing method well.
Summary of the invention
Based on the problems referred to above, the object of the present invention is to provide the analytical approach of impurity in a kind of Meropenem, the content of multiple Meropenem impurity can be monitored more accurately.
The invention provides the detection method of impurity in Meropenem, comprise following operation steps:
(1) get Meropenem sample, the dilution that is dissolved in water is for sample solution;
(2) extracting sample solution, injects high performance liquid chromatograph and detects; Wherein, chromatographic condition is as follows:
Chromatographic column: the gel chromatographic columns being filler with the silica gel chemical bonding hydrophilic compounds that rigidity is spherical; Mobile phase: phosphate buffer, its pH=6.00 ± 0.05, isocratic elution; UV detect wavelength: 220 ± 2nm.
Find in the present invention's experiment, when pH of buffer is 6.00, magazins' layout degree is best, not overlapping between each impurity, effectively can detect the limitation of each impurity.
Further, in step (2), the concentration of described phosphate buffer is 0.02 ~ 0.03mol/L.
Further, described phosphate buffer is phosphate sodium dihydrogen buffer solution, potassium phosphate buffer, sodium hydrogen phosphate damping fluid or dipotassium hydrogen phosphate damping fluid, preferably phosphoric acid sodium dihydrogen damping fluid.
Further, in step (2), the model of described chromatographic column is 5 μm, 7.8 × 300mm.
Described chromatographic column is TSK-GEL-G2000SWXL further.
Further, in step (2), the flow velocity of mobile phase is 0.6 ~ 1.0ml/min; The column temperature of chromatographic column is 20 ~ 30 DEG C.
Preferably, in step (2), the flow velocity of mobile phase is 0.6ml/min.Under this flow conditions, between each impurity, impurity and the peak-to-peak degree of separation of Meropenem master best, be more convenient for the integral and calculating of peak area.
Further, in step (1), described Meropenem is meropenem for injection.
Detection method provided by the invention, can be separated effectively by each impurity in Meropenem, and degree of separation is good, thus can calculate the content of different impurities more accurately, for the further monitoring of Meropenem polymeric impurities, research provide possibility.
Accompanying drawing explanation
Fig. 1 is the chromatogram under embodiment 1 condition: a, b, c are Meropenem impurity, and d is Meropenem.
Fig. 2 is the chromatogram under embodiment 2 condition.
Fig. 3 is the chromatogram under embodiment 3 condition.
Fig. 4 is the chromatogram under embodiment 4 condition.
Fig. 5 is the chromatogram under embodiment 5 condition.
Fig. 6 is the chromatogram under comparative example 1 condition.
Fig. 7 is the chromatogram under comparative example 2 condition.
Embodiment
Below in conjunction with specific embodiment and comparative example, the present invention is described in further detail.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on content of the present invention all belong to scope of the present invention.
Test equipment and reagent:
Test apparatus: Alltech200HPLC(is difficult to understand safe, pump:Alltech426HPLC pump; Det:Linear UVIS2000); Chromatographic column: TSK-GEL-G2000SWXL, 5 μm, 7.8 × 300mm(I.D.); Determined wavelength: 220nm(error range is 2nm, and namely determined wavelength is at 218 ~ 222nm, all falls into scope); Column temperature: 20 ~ 30 DEG C; Sampling volume: 20ul; The peak area of Meropenem impurity in chromatogram and the ratio of the peak total area are drawn the relative content of each impurity in Meropenem.
Embodiment 1 detection method
Mobile phase: 0.025mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.00 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.8ml/min.
Determination step:
Take meropenem for injection sample 13.65mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 1, isolates a, b, c tri-impurity in Meropenem sample, and wherein, the total content of a, b is 0.43%.
Embodiment 2 detection method
Mobile phase: 0.02mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.00 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.8ml/min.
Determination step:
Take meropenem for injection sample 13.45mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 2, isolates a, b, c tri-impurity in Meropenem sample, and wherein, the total content of a, b is 0.55%.
Embodiment 3 detection method
Mobile phase: 0.03mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.00 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.8ml/min.
Determination step:
Take meropenem for injection sample 13.67mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 3, isolates a, b, c tri-impurity in Meropenem sample, and wherein, the total content of a, b is 0.57%.
Embodiment 4 detection method
Mobile phase: 0.025mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.00 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.6ml/min.
Determination step:
Take meropenem for injection sample 13.43mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 4, isolates a, b, c tri-impurity in Meropenem sample, and wherein, the total content of a, b is 0.33%.
Embodiment 5 detection method
Mobile phase: 0.025mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.00 ± 0.05 with 0.5mol/L sodium hydroxide solution); Flow velocity: 1.0ml/min.
Determination step:
Take meropenem for injection sample 13.52mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 5, isolates a, b, c tri-impurity in Meropenem sample, and wherein, the total content of a, b is 0.25%.
Embodiment 6 detection method
Mobile phase: 0.025mol/L potassium phosphate buffer (adjusting pH=6.00 ± 0.05 with 0.5mol/L sodium hydroxide solution); Flow velocity: 1.0ml/min.
Determination step:
Take meropenem for injection sample 13.70mg, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition.
Detection method under comparative example 1 condition of different pH
Mobile phase: 0.025mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=5.80 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.8ml/min.
Determination step:
Get meropenem for injection sample 13mg, accurate Cheng Ding, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out high performance liquid chromatography by above-mentioned condition, and result, as Fig. 6, only isolates 2 impurity, and under showing this chromatographic condition, degree of separation is not good.
Detection method under comparative example 2 condition of different pH
Mobile phase: 0.025mol/L phosphate sodium dihydrogen buffer solution (adjusting pH=6.20 with 0.5mol/L sodium hydroxide solution); Flow velocity: 0.8ml/min.
Determination step:
Get meropenem for injection sample 13mg, accurate Cheng Ding, be placed in 10ml volumetric flask, add water-soluble solution and be settled to scale, as sample solution.Extracting sample solution carries out efficient liquid phase chromatographic analysis by above-mentioned condition, and result, as Fig. 7, only isolates 2 impurity, and under showing this chromatographic condition, degree of separation is not good.
Conclusion:
(1) from embodiment and comparative example relatively, when pH of buffer is 6.00, magazins' layout degree is best, not overlapping between each impurity, effectively can detect the limitation of each impurity, and therefore, in the error range allowed, it is 6.00 ± 0.05 that the present invention limits pH of buffer.
(2) from embodiment 1-5 relatively, when the flow velocity of mobile phase is 0.6ml/min, between each impurity, impurity and the peak-to-peak degree of separation of Meropenem master best, be more convenient for the integral and calculating of peak area.
In sum, detection method provided by the invention, each impurity in Meropenem can be separated effectively, and degree of separation is good, thus the content of different impurities can be calculated more accurately, for Meropenem polymeric impurities further monitoring, research provide possibility.
Claims (2)
1. the detection method of impurity in Meropenem, is characterized in that: comprise following operation steps:
(1) get Meropenem sample, the dilution that is dissolved in water is for sample solution; Described Meropenem is meropenem for injection
(2) extracting sample solution, injects high performance liquid chromatograph and detects; Wherein, chromatographic condition is as follows:
Chromatographic column: TSK-GEL-G2000SWXL; Mobile phase: phosphate buffer, its pH=6.00 ± 0.05, isocratic elution; UV detect wavelength: 220 ± 2nm; The flow velocity of mobile phase is 0.6ml/min; The column temperature of chromatographic column is 20 ~ 30 DEG C, and the concentration of described phosphate buffer is 0.02 ~ 0.03mol/L.
2. detection method according to claim 1, is characterized in that: described phosphate buffer is phosphate sodium dihydrogen buffer solution, potassium phosphate buffer, sodium hydrogen phosphate damping fluid or dipotassium hydrogen phosphate damping fluid.
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| CN111198232A (en) * | 2018-11-19 | 2020-05-26 | 浙江长典医药有限公司 | Detection method of meropenem for injection |
| CN109521115A (en) * | 2018-12-03 | 2019-03-26 | 瀚晖制药有限公司 | A kind of detection method of polymer contained by meropenem for injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731504A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of meropenem |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731504A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of meropenem |
Non-Patent Citations (3)
| Title |
|---|
| Chromatographic determination of polymerized impurities in meropenem;Shan-Ying Cai等;《Journal of Pharmaceutical and Biomedical Analysis》;20050309;第37卷(第3期);第586页第2.2节和第589页第3.3节 * |
| β-内酰胺抗生素在Superdex peptide凝胶过滤色谱柱上的色谱行为;蔡姗英;《中国抗生素杂志》;20020331;第27卷(第3期);第157-161,192页 * |
| 凝胶色谱法测定美罗培南中的聚合物;王喜军等;《中国当代医药》;20120430;第19卷(第11期);第55-56页 * |
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