CN101865894B - Method for detecting impurities in freeze-dried powder injection of nedaplatin - Google Patents
Method for detecting impurities in freeze-dried powder injection of nedaplatin Download PDFInfo
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Abstract
The invention relates to a method for detecting impurities in a freeze-dried powder injection of nedaplatin. In particular, the method comprises the following steps of: 1. adoption of a high performance liquid chromatography, wherein the chromatographic conditions are as follows: octyl chemically bonded silica is used as a bulking agent, a mobile phase is a mixture of water and acetonitrile or methanol, into which diethylamine or triethylamine is added, the detection wavelength is 205 to 222nm, the column temperature is between 20 and 45 DEG C, and the flow rate of the mobile phase is 0.5 to 2.0ml/min; 2. sample solution preparation, wherein the solution of the freeze-dried powder injection sample of nedaplatin, of which the nedaplatin content is 0.5 to 2mg/ml, is prepared by using a mixed solvent of water and methanol; and 3. measurement, wherein 5 to 20 micro liters of the sample solution is poured into a high performance liquid chromatograph, and chromatograms are recorded for analysis. By the method, the interference of skeleton excipient dextran with impurity detection is eliminated, and the impurities in nedaplatin raw materials can be easily, quickly and stably detected while the cost is lowered.
Description
Technical field
The present invention relates to the method for detecting impurities of freeze-dried powder injection of nedaplatin, say so more specifically and detect in the freeze-dried powder injection of nedaplatin production run or the method for impurity in the final finished through high performance liquid chromatography.
Background technology
Nedaplatin belongs to antineoplastic, gets permission listing first June nineteen ninety-five, is used to treat head and neck neoplasm, cellule and non-small cell lung cancer, cancer of the esophagus, carcinoma of urinary bladder, carcinoma of testis, oophoroma, cervix cancer.The toxicity spectrum of Nedaplatin (Nedaplatin) is different with cis-platinum, and its dose-limiting toxicity is the decrease of platelet due to the bone marrow suppression.But its renal toxicity and gastrointestinal side effect and cis-platinum relatively decrease, no cross resistance, and selectivity discharges medicine and good advantages such as solubility.Find in the clinical testing that Nedaplatin is effective to extensive solid tumor; To head and neck neoplasm efficient more than 40%; Be superior to cis-platinum, efficient to cancer of the esophagus greater than 50%, than cis-platinum high about 20%; Cervix cancer also there be efficient more than 40%, for these tumor patients provide new effective selection of clinical.
Active component peak retention time in traditional chromatogram checking system is very short in the freeze-dried powder injection of nedaplatin; Impurity is difficult to separately; And chromatogram checking system poor stability; The slight variation of factors such as moving phase, solvent, column temperature and chromatographic column will produce very big influence for testing result, even can not be applicable to detecting of related impurities.Simultaneously, traditional chromatogram checking system needs long equilibration time, and very big to traditional chromatographic column damage; It is bigger to expend cost; Must find out a kind of rational chromatographic system, work up easy, quick, stable foreign impurity matters test method, so that control this quality effectively.
CN200910094394.0 discloses platinum-containing anticancer drug cis-platinum, oxaliplatin, Nedaplatin etc. and has related to and produce the control method that silver iodide deposition platinum complex prepares silver in the process, not to the recommendation on improvement of above-mentioned technological deficiency.
CN200710020343.4 discloses the preparation method of the extremely low Nedaplatin of a kind of silver content, not to the recommendation on improvement of above-mentioned technological deficiency.
CN200710020326.0 discloses a kind of preparation method of freeze-dried powder injection of nedaplatin; Retention time is shorter in the chromatogram checking system that wherein adopts; Impurity separates undesirable; Chromatogram checking system stability is not good, and factors such as moving phase, solvent, column temperature and chromatographic column are bigger for the testing result influence.
CN200710022407.4 discloses a kind of method of reifining Nedaplatin, not to the recommendation on improvement of above-mentioned technological deficiency.
CN200810058604.6 and CN200910094048.2 disclose antineoplastic Nedaplatin C
2H
8N
2O
3The preparation method of Pt is not to the recommendation on improvement of above-mentioned technological deficiency.
" Chinese Journal of Inorganic Chemistry " 2009 8 phases 1375～1378 pages of novel synthesis of reporting Nedaplatin, crystal structure and thermal stabilitys are not to the recommendation on improvement of above-mentioned technological deficiency.
" 2008 1 phases of Pharmaceutical Analysis journal, 131～133 pages of methods of having reported with RP-HPLC method mensuration injection Nedaplatin content and related substance; Retention time is lacked (about 4min) in the chromatogram checking system that wherein adopts; Impurity separates not ideal enough, owing to added the citric acid of more amount, the chromatogram checking system needs long equilibration time; And stability is not good, and factors such as moving phase, solvent, column temperature and chromatographic column are bigger for the testing result influence.
" Chinese Journal of Pharmaceuticals " 2000 31 volumes 10 phases, 457～458 pages of HPLC determination methods of having reported Nedaplatin are with the content of high effective liquid chromatography for measuring Nedaplatin.Adopt Spherisorb NH
2Post is a moving phase with 40mmol/L potassium dihydrogen phosphate-acetonitrile (8:2), and the detection wavelength is 210nm.Though the retention time of Nedaplatin has prolongation, Nedaplatin and related substance (being impurity) only can initial gross separations, and it is less that impurity detects number, exist objectionable impurities not detect the hidden danger that possibly bring for patient's clinical drug safety.In addition, used the higher NH of cost
2Post, simultaneously with the salt solusion of higher concentration as moving phase, the chromatogram checking system needs very long equilibration time, this moving phase and to NH
2The post damage is very big, and it is bigger to expend cost.
Reported among " Biomedical Research on Trace Elements " 1993 4 (2) interim 49～50 pages " HPLC/ICP-AES method for the simultaneous determination of cis-diammine (glycolato) platinum and its metabolite in urine " and adopted ICP-AES to measure the method for cis-platinum and metabolin thereof, not to the recommendation on improvement of above-mentioned technological deficiency.
Existing known technology is all less than the suggestion that above defective is proposed improve.
Summary of the invention
The objective of the invention is to provide a kind of method for detecting impurities of freeze-dried powder injection of nedaplatin to above weak point; Can prolong the retention time of active component peak in the chromatogram checking system in the freeze-dried powder injection of nedaplatin through this method; Impurity is better separated; Reduce of the influence of factors vary such as moving phase, solvent, column temperature and chromatographic column for testing result; Shorten chromatogram checking system equilibration time, improve the durability of chromatographic column, thereby in that reduce can easy, quick, stable detection Nedaplatin impurities in raw materials when detecting cost; So that control product quality effectively, avoided objectionable impurities not detect the hidden danger that to bring for patient's clinical drug safety.
The chemical name of Nedaplatin is: (Z)-diamino (glycolic acid-O1 ,-O2) platinum, structural formula is:
Molecular formula: C
2H
8N
2O
3Pt
Molecular weight: 303.18.
The present invention detects the impurity in the freeze-dried powder injection of nedaplatin through high performance liquid chromatography; Adopting octyl silane group silica gel is filling agent; Can prolong the retention time of active component peak in the chromatogram checking system in the freeze-dried powder injection of nedaplatin, impurity is better separated.
Moving phase has very big influence to separate impurities degree and peak shape in the experimental result, and in traditional colour spectral test system, the slight variation of moving phase ratio or pH value will produce very big influence for testing result, even can not be applicable to detecting of related impurities.Through inventor's research experiment, find that (volume ratio is that 60:40～99:1) is that the impurity effect of moving phase detection freeze-dried powder injection of nedaplatin is fine with water and acetonitrile or methanol mixture.Research experiment is further found; When the volume ratio of water and acetonitrile or carbinol mixture is that 70:30～99:1) is the moving phase better effects if; Adding diethylamine or triethylamine can improve the separate impurities degree and improve peak shape in moving phase, and diethylamine or the triethylamine measured with interpolation moving phase cumulative volume 0.005%～0.1% are good.Adopt such chromatographic condition; Factors vary such as moving phase, solvent, column temperature and chromatographic column are minimum for the influence of testing result; Chromatogram checking system equilibration time is shortened greatly; Improved the durability of chromatographic column simultaneously, can be easy, quick when reduce detecting cost, the impurity in the stable detection freeze-dried powder injection of nedaplatin.
The Nedaplatin stability of solution is relatively poor, adopts traditional colour spectral test system, adopts water or moving phase as solvent no matter be; Along with the prolongation impurity of standing time obviously increases, even if preservation also is so under 2～8 ℃ cryogenic conditions, in addition; Used dextran as the skeleton agent in the freeze-dried powder injection of nedaplatin, dextran is the blended polymer in the certain molecular weight scope, in chromatographic detection system, shows as a plurality of assorted peaks; And the dextran of different batches goes out the peak position and difference in size is bigger, is difficult to separate with the main peak and the impurity peaks of freeze-dried powder injection of nedaplatin, in order to guarantee the accuracy of testing result; Through inventor's research experiment; Find to adopt water of the present invention and methanol mixed solvent (volume ratio is 50:50, and with the phosphoric acid adjusting pH to 5.6 of 0.05mol/L) that the freeze-dried powder injection of nedaplatin sample ligand is processed the Nedaplatin solution of debita spissitudo, concrete is exactly to contain the solution that Nedaplatin concentration is 0.5～2mg/ml; Filter and put under 2～8 ℃ of conditions and keep in Dark Place; Since filtering be insoluble to the auxiliary material of this mixed solvent, can well eliminate skeleton agent dextran to the interference that impurity detects, significantly improved its stability simultaneously; Impurity does not have obvious increase; This provides convenience for continuous detecting of a large amount of samples, such as can adopting the auto injection liquid chromatographic system that can control sample temperature, thereby realizes a large amount of sample continuous sample introductions under the unmanned.
The method for detecting impurities of a kind of freeze-dried powder injection of nedaplatin provided by the invention, specific as follows:
1) adopt high performance liquid chromatography, its chromatographic condition is: with octyl silane group silica gel is filling agent; Moving phase is water and the acetonitrile or the methanol mixture of having added diethylamine or triethylamine; The volume ratio of water and acetonitrile or methyl alcohol is 60:40～99:1, and the addition of diethylamine or triethylamine is 0.005%～0.1% of water and acetonitrile or a carbinol mixture cumulative volume; The detection wavelength is 205～222nm; Column temperature is 20～45 ℃; Flow rate of mobile phase is 0.5～2.0ml/min;
2) preparation of sample solution: adopt water and methanol mixed solvent (volume ratio is 50:50, and regulates pH to 5.6 with the phosphoric acid of 0.05mol/L) that sample ligand is made for the solution that contains Nedaplatin 0.5～2mg/ml, filter and put under 2～8 ℃ of conditions and keep in Dark Place;
3) measure: the sample solution of 5 μ L～20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, the volume ratio of said moving phase water and acetonitrile or methyl alcohol is 70:30～99:1.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said moving phase have added the diethylamine or the triethylamine of water and acetonitrile or carbinol mixture cumulative volume 0.01%～0.1%.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said detection wavelength is 210～222nm.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said detection wavelength is 220nm.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said column temperature are 30～45 ℃.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said column temperature are 40 ℃.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said flow rate of mobile phase are 0.8～1.2ml/min.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin, said flow rate of mobile phase are 1.0ml/min.
A kind of method for detecting impurities of freeze-dried powder injection of nedaplatin is made as the solution that contains Nedaplatin 1mg/ml with the freeze-dried powder injection of nedaplatin sample ligand, filters and put under 2～8 ℃ of conditions to keep in Dark Place.
The method for detecting impurities of a kind of freeze-dried powder injection of nedaplatin of the present invention; Can prolong the retention time of active component peak in the chromatogram checking system in the freeze-dried powder injection of nedaplatin through this method; Well eliminate of the interference of skeleton agent dextran to impurity is detected; Can impurity better be separated, reduce of the influence of factors vary such as moving phase, solvent, column temperature and chromatographic column, shorten chromatogram checking system equilibration time for testing result; Improve the durability of chromatographic column; Thereby can be easy, quick when reduce detecting cost, the impurity in the stable detection freeze-dried powder injection of nedaplatin, so that control product quality effectively, avoided objectionable impurities not detect the hidden danger that possibly bring for patient's clinical drug safety.
Description of drawings
Fig. 1: carry out the high-efficient liquid phase chromatogram that freeze-dried powder injection of nedaplatin impurity detects according to embodiment 1.
Embodiment
Further specify the present invention through embodiment below.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the present invention and requires the scope protected.
Detecting used freeze-dried powder injection of nedaplatin sample in following examples provides by Jiangsu Aosaikang Pharmaceutical Co., Ltd, and lot number is 20080501S.
Embodiment 1:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.1% with water-acetonitrile (volume ratio 80:20) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 0.5ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and chromatogram is seen Fig. 1.It is good that testing result shows that each item impurity separates.
Embodiment 2:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.005% with water-acetonitrile (volume ratio 90:10) preparating mixture;
Column temperature: 40 ℃;
Flow velocity: 1.0ml/min;
Detect wavelength: 210nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 0.5mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 3:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.05% with water-methanol (volume ratio 70:30) preparating mixture;
Column temperature: 30 ℃;
Flow velocity: 0.8ml/min;
Detect wavelength: 205nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 2mg/ml, filter and put under 2 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 4:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.05% with water-acetonitrile (volume ratio 70:30) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 2.0ml/min;
Detect wavelength: 222nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 2mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 5:
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.005% with water-methanol (volume ratio 65:35) preparating mixture;
Column temperature: 35 ℃;
Flow velocity: 1.0ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 6:
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.005% with water-acetonitrile (volume ratio 60:40) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 1.2ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 6 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 10 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 7:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.1% with water-methanol (volume ratio 80:20) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 2.0ml/min;
Detect wavelength: 222nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1.5mg/ml, filter and put under 4 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 10 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 8:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.1% with water-methanol (volume ratio 60:40) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 1.2ml/min;
Detect wavelength: 210nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 2mg/ml, filter and put under 6 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 9:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.01% with water-methanol (volume ratio 80:20) preparating mixture;
Column temperature: 20 ℃;
Flow velocity: 0.5ml/min;
Detect wavelength: 215nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 10 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 10:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.01% with water-acetonitrile (volume ratio 99:1) preparating mixture;
Column temperature: 30 ℃;
Flow velocity: 0.8ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 0.5mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 11:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.01% with water-acetonitrile (volume ratio 70:30) preparating mixture;
Column temperature: 45 ℃;
Flow velocity: 2.0ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 4 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 5 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 12:
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.05% with water-methanol (volume ratio 80:20) preparating mixture;
Column temperature: 40 ℃;
Flow velocity: 2.0ml/min;
Detect wavelength: 222nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 0.8mg/ml, filter and put under 4 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 10 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 13:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.01% with water-methanol (volume ratio 60:40) preparating mixture;
Column temperature: 25 ℃;
Flow velocity: 0.5ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 6 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 14:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.05% with water-acetonitrile (volume ratio 85:15) preparating mixture;
Column temperature: 20 ℃;
Flow velocity: 0.5ml/min;
Detect wavelength: 222nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 0.8mg/ml, filter and put under 6 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 15:
Instrument: SHIMADZU LC-20AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the triethylamine of potpourri cumulative volume 0.1% with water-acetonitrile (volume ratio 60:40) preparating mixture;
Column temperature: 30 ℃;
Flow velocity: 0.5ml/min;
Detect wavelength: 215nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 0.5mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 16:
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: octyl silane group silicagel column (4.6 * 250mm, 5 μ m);
Moving phase:, in potpourri, add the diethylamine of potpourri cumulative volume 0.005% with water-methanol (volume ratio 99:1) preparating mixture;
Column temperature: 30 ℃;
Flow velocity: 1.0ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: (volume ratio is 50:50 to adopt water and methanol mixed solvent; And regulate pH to 5.6 with the phosphoric acid of 0.05mol/L) the freeze-dried powder injection of nedaplatin sample ligand is made for the solution that contains Nedaplatin 1mg/ml, filter and put under 8 ℃ of conditions and keep in Dark Place;
Measure: the sample solution of 10 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and it is good that testing result shows that each item impurity separates.
Embodiment 17:
The Nedaplatin method for detecting impurities that CN200710020326.0 provides.
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: octadecylsilane chemically bonded silica post (4.6 * 250mm, 5 μ m);
Moving phase: with methyl alcohol-0.01mol/L citric acid soln (volume ratio 30:70) (regulating pH value to 6.0 with triethylamine) is moving phase;
Column temperature: 40 ℃;
Flow velocity: 1.0ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: adopt moving phase the freeze-dried powder injection of nedaplatin sample ligand to be made for the solution that contains Nedaplatin 1mg/ml;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph; The record chromatogram is also analyzed; Find in the detection that the Nedaplatin retention time is shorter; Impurity separates undesirable, and chromatogram checking system stability is not good, and factors such as moving phase, solvent, column temperature and chromatographic column are bigger for the testing result influence.
Embodiment 18:
" 2008 1 phases of Pharmaceutical Analysis journal, 131～133 pages of methods that provide with RP-HPLC method mensuration Nedaplatin impurity.
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: the stainless steel column of Shim-pack CLC-ODS (4.6 * 150mm, 5 μ m);
Moving phase: with methyl alcohol-0.01mol/L citric acid soln (volume ratio 30:70) (regulating pH value to 6.0 with triethylamine) is moving phase;
Column temperature: 30 ℃;
Flow velocity: 0.7ml/min;
Detect wavelength: 220nm.
The preparation of sample solution: adopt moving phase the freeze-dried powder injection of nedaplatin sample ligand to be made for the solution that contains Nedaplatin 1mg/ml;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, and discovery Nedaplatin retention time is lacked (about 4min) in the detection; Impurity separates not ideal enough; Owing to added the citric acid of more amount, the chromatogram checking system needs long equilibration time, and balance needs 2 hours; And stability is not good, and factors such as moving phase, solvent, column temperature and chromatographic column are bigger for the testing result influence.
Embodiment 19:
The method of the mensuration Nedaplatin impurity that " Chinese Journal of Pharmaceuticals " 2000 31 10 phases 457～458 of volume provide.
Instrument: SHIMADZU LC-10AT high performance liquid chromatograph;
Chromatographic column: Spherisorb NH2 post (4.0 * 300mm, 10 μ m);
Moving phase: with 40mmol/L potassium dihydrogen phosphate-acetonitrile (volume ratio 8:2) is moving phase;
Column temperature: 30 ℃;
Flow velocity: 0.8ml/min;
Detect wavelength: 210nm.
The preparation of sample solution: adopt moving phase the freeze-dried powder injection of nedaplatin sample ligand to be made for the solution that contains Nedaplatin 20 μ g/ml;
Measure: the sample solution of 20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed, though find the retention time of Nedaplatin in the detection prolongation is arranged; But Nedaplatin and related substance (being impurity) only can initial gross separations; It is less that impurity detects number, and the chromatogram checking system needs very long equilibration time, and balance needs 3 hours; This moving phase and very big to the damage of NH2 post, it is bigger to expend cost.
Embodiment 20:
Embodiment 1～embodiment 20 testing results are relatively seen table 1.
Table 1 embodiment 1～embodiment 20 testing result comparison sheets
Can find out that from table 1 technical scheme of the present invention (embodiment 1～16) is longer than prior art (embodiment 17～19) retention time, thereby is more conducive to separate impurities, detect at impurity on the stability of number and detected level and have clear superiority.Add up from the time of process of the test, technical scheme of the present invention (embodiment 1～16) is short a lot of than prior art (embodiment 17～19) chromatographic system equilibration time, more helps the fast and stable test sample.
Claims (10)
1. the method for detecting impurities of a freeze-dried powder injection of nedaplatin, specific as follows:
1) adopt high performance liquid chromatography, its chromatographic condition is: with octyl silane group silica gel is filling agent; Moving phase is water and the acetonitrile or the methanol mixture of having added diethylamine or triethylamine; The volume ratio of water and acetonitrile or water and methyl alcohol is 60:40～99:1, and the addition of diethylamine or triethylamine is 0.005%～0.1% of water and acetonitrile or a carbinol mixture cumulative volume; The detection wavelength is 205～222nm; Column temperature is 20～45 ℃; Flow rate of mobile phase is 0.5～2.0ml/min;
2) preparation of sample solution: adopt water and methanol mixed solvent the freeze-dried powder injection of nedaplatin sample ligand to be made for the solution that contains Nedaplatin 0.5～2mg/ml; Filter and put under 2～8 ℃ of conditions and keep in Dark Place; The volume ratio of water and methanol mixed solvent is 50:50, and regulates pH to 5.6 with the phosphoric acid of 0.05mol/L;
3) measure: the sample solution of 5 μ L～20 μ L is injected high performance liquid chromatograph, and the record chromatogram is also analyzed.
2. method according to claim 1, the volume ratio that it is characterized in that said moving phase water and acetonitrile or methyl alcohol is 70:30～99:1.
3. method according to claim 1 is characterized in that said moving phase added the diethylamine or the triethylamine of potpourri cumulative volume 0.01%～0.1%.
4. method according to claim 1, it is characterized in that detecting wavelength is 210～222nm.
5. method according to claim 4, it is characterized in that detecting wavelength is 220nm.
6. method according to claim 1 is characterized in that column temperature is 30～45 ℃.
7. method according to claim 6 is characterized in that column temperature is 40 ℃.
8. method according to claim 1 is characterized in that flow rate of mobile phase is 0.8～1.2ml/min.
9. method according to claim 8 is characterized in that flow rate of mobile phase is 1.0ml/min.
10. method according to claim 1 is characterized in that the freeze-dried powder injection of nedaplatin sample ligand is made as the solution that contains Nedaplatin 1mg/ml, filters and puts under 2～8 ℃ of conditions and keep in Dark Place.
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| CN108241032B (en) * | 2016-12-23 | 2020-10-16 | 江苏奥赛康药业有限公司 | Method for analyzing nedaplatin |
| CN110759948B (en) * | 2018-07-27 | 2021-08-13 | 上海医药工业研究院 | Platinum-containing compound, preparation method, separation method and application thereof |
| CN111122740B (en) * | 2019-12-31 | 2022-06-14 | 辰欣药业股份有限公司 | Method for separating and determining related substances of oxaliplatin based on C18 bonded phase chromatographic column |
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| RP-HPLC法测定注射用奈达铂含量及有关物质;陈祥峰, 袁玉;《药物分析杂志》;20080131;第28卷(第1期);全文 * |
| 奈达铂的HPLC测定法;毕同香 等;《中国医药工业杂志》;20001031;第31卷(第10期);457-458 * |
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