CN108195973A - The detection method of isomers in a kind of Valsartan hydrocarbonylation object - Google Patents
The detection method of isomers in a kind of Valsartan hydrocarbonylation object Download PDFInfo
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- CN108195973A CN108195973A CN201810279785.9A CN201810279785A CN108195973A CN 108195973 A CN108195973 A CN 108195973A CN 201810279785 A CN201810279785 A CN 201810279785A CN 108195973 A CN108195973 A CN 108195973A
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Abstract
The present invention provides a kind of detection method of isomers in Valsartan hydrocarbonylation object, the detection method is high to the chromatographic peak separating degree of isomers in Valsartan hydrocarbonylation object, has higher system suitability, while all comply with standard in precision, quantitative limit, detection limit, repeatability, linear and range and stability.Present invention firstly provides the detection methods of isomers in Valsartan hydrocarbonylation object, have the characteristics that system suitability is good, precision is high and stability is good, while the assay method of the present invention is easy to operate, and the time used is shorter, at low cost, take short.
Description
Technical field
The present invention relates to the detection methods that a kind of HPLC methods measure isomers in Valsartan hydrocarbonylation object, belong to Pharmaceutical Analysis skill
Art field.
Background technology
Valsartan（valsartan）, it is chemical entitled：[[[1,1'- joins 2'- (1H- tetrazole -5- bases) N- valeryls-N-
Benzene] -4- bases] methyl]-Valine is a angiotensin II receptor antagonist anti-hypertension class drug, which has been
To I types (AT1) receptor blockade for making angiotensinⅡ, the raising of angiotensinⅡ blood plasma level, stimulate unclosed AT2 by
Body, while the effect for the AT1 receptors that contend with reduce blood pressure so as to achieve the effect that expand blood vessel.The chemical name of Valsartan hydrocarbonylation object
It is the key that synthesizing Xieshatan is intermediate for N- [(2'- cyano -1,1'- biphenyl -4- bases) methyl]-Valine methyl ester hydrochloride
Body, entitled N- valeryls-N- [[2'- (1H- tetrazole -5- bases) [1,1'- biphenyl] -4- bases] the methyl]-L- of chemistry of Valsartan
Valine, Valsartan are the configurations of L-type, and D configurations are the impurity wherein contained, and D configurational isomers in Valsartan hydrocarbonylation object
Content can seriously affect the content of isomers in Valsartan, therefore the isomer impurities content in accurate control Valsartan hydrocarbonylation object
It is the important step for the Valsartan bulk pharmaceutical chemicals for synthesizing high quality.There is presently no isomers in document report Valsartan hydrocarbonylation object
Detection method.Present invention firstly provides a kind of detection method of isomers in Valsartan hydrocarbonylation object, this method has precision
Good, accuracy height, high repeatability and other advantages.
Invention content
The object of the present invention is to provide a kind of detection methods of isomers in Valsartan hydrocarbonylation object, it is made to be applicable in system
Property, precision, quantitative limit, detection limit, the guidance that Chinese Pharmacopoeia method validation is complied fully in terms of the range of linearity and accuracy
Principle, the quality control available for Valsartan bulk pharmaceutical chemicals.
To achieve the above object, the present invention provides following technical solution：
The detection method of isomers, includes the following steps in a kind of Valsartan hydrocarbonylation object：
（1）Solution is prepared, prepares blank solution, positioning solution, contrast solution and test solution respectively；The blank solution is
Mobile phase solution, the positioning solution are prepared by Valsartan hydrocarbonylation object isomer control product and mobile phase solution, and the control is molten
Liquid is prepared by Valsartan hydrocarbonylation object reference substance and mobile phase solution, and the test solution is by Valsartan hydrocarbonylation object sample and flowing
Phase solution is prepared.
（2）Assay method：
The mobile phase includes n-hexane, isopropanol, trifluoroacetic acid and dimethylamine；Preferably, n-hexane in the mobile phase：It is different
Propyl alcohol：Trifluoroacetic acid：The volume ratio of dimethylamine is 70:30:0.1:0.1.Chromatographic condition：OD chromatographic columns, flow velocity：0.6±
0.2mL/min；Column temperature：30±2℃；Sample size：10 ± 2 μ l, run time：30 ± 2min, Detection wavelength：222±5nm.
Advantageous effect
By above technical scheme it is found that detection method of the present invention detaches the chromatographic peak of isomers in Valsartan hydrocarbonylation object
Degree is high, has higher system suitability, while in precision, quantitative limit, detection limit, repeatability, linear and range and stabilization
Property all complies with standard.Present invention firstly provides the detection method of isomers in Valsartan hydrocarbonylation object, have system suitability it is good,
The features such as precision height and good stability, while the assay method of the present invention is easy to operate, the time used is shorter, at low cost,
It takes short.
Description of the drawings
Fig. 1 is the liquid chromatogram that Valsartan hydrocarbonylation object isomers detects blank solution；
Fig. 2 is that Valsartan hydrocarbonylation object isomers detects the liquid chromatogram that enantiomter positions solution；
Fig. 3 is the liquid chromatogram that Valsartan hydrocarbonylation object isomers detects contrast solution；
Fig. 4 is the liquid chromatogram that Valsartan hydrocarbonylation object isomers detects test solution；
Fig. 5 is the liquid chromatogram of Valsartan hydrocarbonylation object isomers detecting system applicability；
Fig. 6 is the linear relationship chart of Valsartan hydrocarbonylation object isomers；
Fig. 7 is the liquid chromatogram of 1 Valsartan hydrocarbonylation object isomers detecting system applicability of comparative example；
Fig. 8 is the liquid chromatogram of 2 Valsartan hydrocarbonylation object isomers detecting system applicability of comparative example.
Specific embodiment
It is explained further with specific embodiment below and is illustrated the present invention, but do not limit the invention in any way
Range.
Embodiment 1
1) experiment material and instrument condition
High performance liquid chromatograph：Shimadzu LC-15C；Chromatographic column：5 μm, 4.6 × 250 mm, OD columns；Chromatographic condition：Flow velocity：
0.6mL/min；Column temperature：30℃；Sample size：10μl；Run time：30min；Detection wavelength：222nm；Mobile phase：N-hexane：
Isopropanol：Trifluoroacetic acid：The volume ratio of dimethylamine is 70:30:0.1:0.1.
2）Experimental procedure
Prepare blank solution：Mobile phase.
Prepare enantiomter positioning solution：Precision weighs Valsartan hydrocarbonylation object isomer control product 5.29mg, puts 10ml
In volumetric flask, add flowing phased soln and be diluted to scale, shake up.
Prepare contrast solution：Precision weighs Valsartan hydrocarbonylation object reference substance 12.51mg, puts in 25ml volumetric flasks, adds flowing
Phased soln is simultaneously diluted to scale, shakes up.
Prepare test solution：Valsartan hydrocarbonylation object sample 12.84mg is taken, puts in 25ml volumetric flasks, adds flowing phase dilution
It to scale, shakes up, as test solution.
Assay method：Precision measures blank solution, enantiomter positioning solution, contrast solution and test solution each 10
µl；Liquid chromatograph is injected, records chromatogram, as shown in Figure 1, Figure 2, Fig. 3 and Fig. 4.Valsartan is calculated by peak area external standard method
The content of enantiomter is 0.08% in hydrocarbonylation object, is met《Chinese Pharmacopoeia》In about isomers as defined in drug standard
Impurity should be not more than 0.20% regulation.
2 detection method system suitability of the present invention of embodiment
Blank solution, enantiomter positioning solution, contrast solution and test solution are prepared as described in Example 1, then will be right
It reflects isomers positioning solution and dilutes 100 times, then accurate measurement 2mL, 10mL is diluted, as system suitability solution.
After system balancing, respectively into above-mentioned each solution, chromatogram is recorded, obtains system suitability collection of illustrative plates as shown in figure 5, institute
Obtaining system suitability, the results are shown in Table 1.
Table 1- system suitability results
3 detection method limiting test of the present invention of embodiment
Prepare quantitative limit solution：The enantiomter positioning solution 1mL that the embodiment 1 is prepared is taken, with flowing phase dilution 100
Again, then the accurate 3mL that measures adds mobile phase to be diluted in 25mL measuring bottles, then the accurate 1mL that measures adds mobile phase to be diluted to 10mL, system
.
Prepare detection limit solution：Precision measures quantitative limit solution 3mL, then is diluted to 10mL with mobile phase, is made.
Assay method and as a result, chromatographic condition measures as described in Example 1, obtains that the results are shown in Table 2.
Table 2- limiting test results
4 detection method linear relationship of the present invention of embodiment is investigated
Valsartan hydrocarbonylation object isomer control product 5.29mg is taken, it is accurately weighed, add flowing phase dilution that concentration is made to be respectively
0.06348 μ g/ml, 0.5290 μ g/ml, 0.7935 μ g/ml, 1.0580 μ g/ml, 1.5870 μ g/ml, 2.1160 μ g/ml it is molten
Liquid, precision measure above-mentioned each 10 μ l of solution, are injected separately into liquid chromatograph, record chromatogram, are done linearly with peak area and concentration
It returns.Linear equation y=58816x+742.37；г=0.9999 (R2=0.9999), x are sample concentration, and г is related coefficient.Experiment
As a result：In the range of isomer concentration is the μ g/ml of 0.06348 μ g/ml ~ 2.1160, concentration is with peak area in good linear
Relationship.Linear relationship chart is as shown in fig. 6, the results are shown in Table 3.
Table 3- linear relationships investigate result
5 detection method Intermediate precision of the present invention of embodiment is tested
Valsartan hydrocarbonylation object isomer control product 5.29mg is taken, it is accurately weighed, add flowing phase dilution that a concentration of 1.0580 μ g/ are made
The solution of ml, repeats sample introduction 6 times, and measure is repeated 6 times respectively at second day.
Result of the test：Under the conditions of the assay method, precision meets the requirements under the related substance item of each sample.As a result
It is shown in Table 4.Table 4- precision measurement results
The stability test of 6 solution of the present invention of embodiment
Precision weighs Valsartan hydrocarbonylation object sample 12.61mg, puts in 25ml volumetric flasks, adds flowing phased soln and is diluted to scale,
It shakes up, as sample solution.Respectively at 0,2,4,8 hour sample introduction, chromatogram is recorded.
Result of the test：Sample solution was relatively stablized in 8 hours, and enantiomter testing result is without significant change.As a result see
Table 5.
Table 5- stabilities of solution investigate result
The repetitive test of 7 detection method of the present invention of embodiment
Precision weighs Valsartan hydrocarbonylation object sample about 12.5mg, puts in 25ml measuring bottles, adds flowing phased soln and is diluted to 0.5mg/
The solution of ml, shakes up, as sample solution.Precision measures 10 μ l injection liquid chromatographs, records chromatogram.Replication 6 times.
Result of the test：Under the conditions of the assay method, repeatability meets the requirements under each sample enantiomter item, the results are shown in Table 6.
Table 6- repeatability investigates result
Comparative example 1
（1）Solution is prepared：Mobile phase in embodiment 1 is adjusted to n-hexane：Isopropanol：Trifluoroacetic acid is 70 by volume:
30:0.1, it is used using the mobile phase of above-mentioned n-hexane, isopropanol and trifluoroacetic acid composition as experimental solutions are prepared in embodiment 1
Blank solution, enantiomter positioning solution, contrast solution and test solution, then enantiomter positioning solution is diluted
100 times, then accurate measurement 2mL, 10mL is diluted, as system suitability solution.
（2）Chromatographic condition and assay method：High performance liquid chromatograph：Shimadzu LC-15C；Chromatographic column：5μm , 4.6×250
Mm, OD column；Chromatographic condition：Flow velocity：0.6mL/min；Column temperature：30℃；Sample size：10μl；Run time：30min；Detect wave
It is long：222nm；Mobile phase：N-hexane：Isopropanol：Trifluoroacetic acid is 70 by volume:30:0.1.After system balancing, respectively into
Above-mentioned each solution records chromatogram, it is as shown in Figure 7 to obtain system suitability collection of illustrative plates.Do not gone out using above-mentioned system as can be seen from Figure 7
Peak, it is impossible to be used in measure the measure of isomers in Valsartan hydrocarbonylation object.
Comparative example 2
（1）Solution is prepared：Mobile phase in embodiment 1 is adjusted to n-hexane：Isopropanol：Trifluoroacetic acid：Diethylamine presses volume
Than being 70:30:0.1:0.1, using the mobile phase of above-mentioned n-hexane, isopropanol, trifluoroacetic acid and diethylamine composition using strictly according to the facts
It applies in example 1 experimental solutions and prepares blank solution, enantiomter positioning solution, contrast solution and test solution, then by mapping
Isomers positioning solution dilutes 100 times, then accurate measurement 2mL, 10mL is diluted, as system suitability solution.
（2）Chromatographic condition and assay method：High performance liquid chromatograph：Shimadzu LC-15C；Chromatographic column：5μm , 4.6×250
Mm, AD column；Chromatographic condition：Flow velocity：0.6mL/min；Column temperature：30℃；Sample size：10μl；Run time：30min；Detect wave
It is long：222nm；Mobile phase：Hexane：Isopropanol：Trifluoroacetic acid：Diethylamine is 70 by volume:30:0.1:0.1.Treat system balancing
Afterwards, chromatogram is recorded, it is as shown in Figure 8 to obtain system suitability collection of illustrative plates into above-mentioned each solution respectively.As can be seen from Figure 8 using upper
The system isomers of stating fails to be kept completely separate with Valsartan hydrocarbonylation object, is not suitable for the measure of isomers in Valsartan hydrocarbonylation object.
Table 7- system suitability results
Above example is only the preferred embodiments of the invention, it is noted that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications should also regard
For protection scope of the present invention.
Claims (3)
1. the detection method of isomers, includes the following steps in a kind of Valsartan hydrocarbonylation object：
（1）Solution is prepared, prepares blank solution, positioning solution, contrast solution and test solution respectively；The blank solution is
Mobile phase solution, the positioning solution are prepared by Valsartan hydrocarbonylation object isomer control product and mobile phase solution, and the control is molten
Liquid is prepared by Valsartan hydrocarbonylation object reference substance and mobile phase solution, and the test solution is by Valsartan hydrocarbonylation object sample and flowing
Phase solution is prepared；
（2）Assay method：
Using high performance liquid chromatograph, OD chromatographic columns, chromatographic condition：Flow velocity：0.6±0.2mL/min；Column temperature：30±2℃；Into
Sample amount：10 ± 2 μ l, run time：30 ± 2min, Detection wavelength：222 ± 5nm, the mobile phase include n-hexane, isopropanol,
Trifluoroacetic acid and dimethylamine.
2. the detection method of isomers in Valsartan hydrocarbonylation object according to claim 1, it is characterised in that：The mobile phase
Middle n-hexane：Isopropanol：Trifluoroacetic acid：The volume ratio of dimethylamine is 70:30:0.1:0.1.
3. the detection method of isomers in Valsartan hydrocarbonylation object according to claim 1, it is characterised in that：The chromatostrip
Part is：Flow velocity：0.6mL/min；Column temperature：30℃；Sample size：10 μ l, run time：30min, Detection wavelength：222nm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111044622A (en) * | 2018-10-12 | 2020-04-21 | 珠海润都制药股份有限公司 | Method for detecting valsartan related substance A in Sacubitril valsartan sodium |
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| CN1556800A (en) * | 2001-09-24 | 2004-12-22 | ҩ�ﻯѧ��������˾ | Process for the preparation of citalopram |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1556800A (en) * | 2001-09-24 | 2004-12-22 | ҩ�ﻯѧ��������˾ | Process for the preparation of citalopram |
| CN101560190A (en) * | 2009-06-01 | 2009-10-21 | 北京赛科药业有限责任公司 | Method for researching and controlling impurity E in valsartan |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111044622A (en) * | 2018-10-12 | 2020-04-21 | 珠海润都制药股份有限公司 | Method for detecting valsartan related substance A in Sacubitril valsartan sodium |
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