CN108195973B - 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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- CN108195973B CN108195973B CN201810279785.9A CN201810279785A CN108195973B CN 108195973 B CN108195973 B CN 108195973B CN 201810279785 A CN201810279785 A CN 201810279785A CN 108195973 B CN108195973 B CN 108195973B
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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, system suitability with higher, while all complying 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, and the measuring method for having the characteristics that system suitability is good, precision is high and stability is good while of the invention is easy to operate, and the time used is shorter, at low cost, time-consuming short.
Description
Technical field
The present invention relates to the detection methods of isomers in a kind of HPLC method measurement Valsartan hydrocarbonylation object, belong to Pharmaceutical Analysis skill
Art field.
Background technique
Valsartan (valsartan), chemical name are as follows: N- valeryl-N- [[2'- (1H- tetrazole -5- base) [1,1'- connection
Benzene] -4- base] methyl]-Valine is a angiotensin II receptor antagonist anti-hypertension class drug, which has been
To I type (AT1) receptor blockade for making angiotensinⅡ, angiotensinⅡ blood plasma level is increased, stimulate unclosed AT2 by
Body, while the effect for the AT1 receptor that contends with, to achieve the effect that expanding blood vessel reduces blood pressure.The chemical name of Valsartan hydrocarbonylation object
It is the key that synthesizing Xieshatan is intermediate for N- [(2'- cyano -1,1'- biphenyl -4- base) methyl]-Valine methyl ester hydrochloride
Body, entitled N- valeryl-N- [[2'- (1H- tetrazole -5- base) [1,1'- biphenyl] -4- base] the methyl]-L- of chemistry of Valsartan
Valine, Valsartan are the configurations of L-type, and D configuration is the impurity wherein contained, and D configurational isomer 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 synthesizing the Valsartan bulk pharmaceutical chemicals of 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.
Summary of the invention
The object of the present invention is to provide a kind of detection method of isomers in Valsartan hydrocarbonylation object, it is applicable in it 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 can be used for the quality control of Valsartan bulk pharmaceutical chemicals.
To achieve the above object, the invention provides the following technical scheme:
The detection method of isomers in a kind of Valsartan hydrocarbonylation object, comprising the following steps:
(1) solution is prepared, prepares blank solution, positioning solution, contrast solution and test solution respectively；The blank is molten
Liquid is mobile phase solution, and the positioning solution is prepared by Valsartan hydrocarbonylation object isomer control product and mobile phase solution, described right
Prepared according to solution by Valsartan hydrocarbonylation object reference substance and mobile phase solution, the test solution by Valsartan hydrocarbonylation object sample and
Mobile phase solution is prepared.
(2) measuring method:
The mobile phase includes n-hexane, isopropanol, trifluoroacetic acid and dimethylamine；Preferably, in the mobile phase just oneself
Alkane: isopropanol: trifluoroacetic acid: the volume ratio of dimethylamine is 70:30:0.1:0.1.Chromatographic condition: OD chromatographic column, flow velocity: 0.6 ±
0.2mL/min；Column temperature: 30 ± 2 DEG C；Sample volume: 10 ± 2 μ l, runing time: 30 ± 2min, Detection wavelength: 222 ± 5nm.
Beneficial effect
From the above technical scheme, chromatographic peak of the detection method of the present invention to isomers in Valsartan hydrocarbonylation object
Separating degree is high, system suitability with higher, at the same precision, quantitative limit, detection limit, repeatability, linear and range and
Stability all complies with standard.Present invention firstly provides the detection methods of isomers in Valsartan hydrocarbonylation object, are applicable in system
The features such as property is good, precision is high and stability is good, while measuring method of the invention is easy to operate, the time used is shorter, at
This is low, time-consuming short.
Detailed description of the invention
Fig. 1 is the liquid chromatogram that Valsartan hydrocarbonylation object isomers detects blank solution；
Fig. 2 is the liquid chromatogram that Valsartan hydrocarbonylation object isomers detects 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 detection 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 detection system applicability of comparative example；
Fig. 8 is the liquid chromatogram of 2 Valsartan hydrocarbonylation object isomers detection system applicability of comparative example.
Specific embodiment
The present invention is explained further and illustrated with specific embodiment below, but do not limit the invention in any way
Range.
Embodiment 1
1) experimental material and instrument condition
High performance liquid chromatograph: Shimadzu LC-15C；Chromatographic column: 5 μm, 4.6 × 250 mm, OD column；Chromatographic condition: stream
Speed: 0.6mL/min；Column temperature: 30 DEG C；Sample volume: 10 μ l；Runing time: 30min；Detection wavelength: 222nm；Mobile phase: just oneself
Alkane: 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 and position solution: precision weighs Valsartan hydrocarbonylation object isomer control product 5.29mg, sets 10ml
In volumetric flask, adds flowing phased soln and be diluted to scale, shake up.
Prepare contrast solution: precision weighs Valsartan hydrocarbonylation object reference substance 12.51mg, sets in 25ml volumetric flask, adds flowing
Phased soln is simultaneously diluted to scale, shakes up.
It prepares test solution: taking Valsartan hydrocarbonylation object sample 12.84mg, set in 25ml volumetric flask, add flowing phase dilution
It to scale, shakes up, as test solution.
Measuring method: it is each that precision measures blank solution, enantiomter positioning solution, contrast solution and test solution
10µl；Liquid chromatograph is injected, chromatogram, as shown in Figure 1, Figure 2, Fig. 3 and Fig. 4 are recorded.Figured silk fabrics sand is calculated by peak area external standard method
The content of enantiomter is 0.08% in smooth hydrocarbonylation object, meets the isomery as defined in drug standard in " Chinese Pharmacopoeia "
The impurity of body should be not more than 0.20% regulation.
The detection method system suitability of the present invention of embodiment 2
Blank solution, enantiomter positioning solution, contrast solution and test solution are prepared as described in Example 1, then
Enantiomter positioning solution is diluted into 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 map as shown in figure 5, institute
Obtaining system suitability, the results are shown in Table 1.
Table 1- system suitability result
The detection method limiting test of the present invention of embodiment 3
Prepare quantitative limit solution: the enantiomter positioning solution 1mL for taking the embodiment 1 to prepare, with flowing phase dilution
100 times, then the accurate 3mL that measures adds mobile phase to be diluted in 25mL measuring bottle, then the accurate 1mL that measures adds mobile phase to be diluted to 10mL,
It is made.
Prepare detection limit solution: precision measures quantitative limit solution 3mL, then is diluted to 10mL with mobile phase, is made.
Measuring method and as a result, chromatographic condition measurement as described in Example 1, obtains that the results are shown in Table 2.
Table 2- limiting test result
The detection method linear relationship of the present invention of embodiment 4 is investigated
Valsartan hydrocarbonylation object isomer control product 5.29mg is taken, it is accurately weighed, add flowing phase dilution 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.Test
As a result: being within the scope of 0.06348 μ of μ g/ml ~ 2.1160 g/ml in isomer concentration, concentration and peak area are in good linear
Relationship.Linear relationship chart is as shown in fig. 6, the results are shown in Table 3.
Table 3- linear relationship investigates result
The test of the detection method Intermediate precision of the present invention of embodiment 5
Valsartan hydrocarbonylation object isomer control product 5.29mg is taken, it is accurately weighed, add flowing phase dilution concentration is made to be
The solution of 1.0580 μ g/ml repeats sample introduction 6 times, repeats measurement 6 times respectively at second day.
Test result: under the conditions of the measuring 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 result
The stability test of the solution of the present invention of embodiment 6
Precision weighs Valsartan hydrocarbonylation object sample 12.61mg, sets in 25ml volumetric flask, adds flowing phased soln and is diluted to quarter
Degree, shakes up, as sample solution.Respectively at 0,2,4,8 hour sample introduction, chromatogram is recorded.
Test result: sample solution is more stable in 8 hours, and enantiomter testing result is without significant change.As a result see
Table 5.
Table 5- stability of solution investigates result
The repetitive test of the detection method of the present invention of embodiment 7
Precision weighs Valsartan hydrocarbonylation object sample about 12.5mg, sets in 25ml measuring bottle, adds flowing phased soln and is diluted to
The solution of 0.5mg/ml, shakes up, as sample solution.Precision measures 10 μ l and injects liquid chromatograph, records chromatogram.It repeats to survey
It is 6 times fixed.Test result: under the conditions of the measuring method, repeatability meets the requirements under each sample enantiomter item, as a result
It is shown in Table 6.
Table 6- repeatability investigates result
Comparative example 1
(1) solution is prepared: the mobile phase in embodiment 1 is adjusted to n-hexane: isopropanol: trifluoroacetic acid is by volume
70:30:0.1 is used using the mobile phase of above-mentioned n-hexane, isopropanol and trifluoroacetic acid composition such as experimental solutions in embodiment 1
Blank solution, enantiomter positioning solution, contrast solution and test solution are prepared, then enantiomter positioning solution is dilute
100 times, then accurate measurement 2mL are released, 10mL is diluted, as system suitability solution.
(2) chromatographic condition and measuring method: high performance liquid chromatograph: Shimadzu LC-15C；Chromatographic column: 5 μm, 4.6 × 250
Mm, OD column；Chromatographic condition: flow velocity: 0.6mL/min；Column temperature: 30 DEG C；Sample volume: 10 μ l；Runing time: 30min；Detect wave
It is long: 222nm；Mobile phase: n-hexane: isopropanol: trifluoroacetic acid is 70:30:0.1 by volume.After system balancing, respectively into
Above-mentioned each solution records chromatogram, it is as shown in Figure 7 to obtain system suitability map.Do not gone out using above-mentioned system as can be seen from Figure 7
Peak, it is impossible to be used in the measurement of isomers in measurement Valsartan hydrocarbonylation object.
Comparative example 2
(1) solution is prepared: the mobile phase in embodiment 1 is adjusted to n-hexane: isopropanol: trifluoroacetic acid: diethylamine is pressed
Volume ratio is 70:30:0.1:0.1, is used using the mobile phase of above-mentioned n-hexane, isopropanol, trifluoroacetic acid and diethylamine composition
As experimental solutions preparation blank solution, enantiomter position solution, contrast solution and test solution, then incite somebody to action in embodiment 1
Enantiomter positions solution and dilutes 100 times, then accurate measurement 2mL, 10mL is diluted, as system suitability solution.
(2) chromatographic condition and measuring method: high performance liquid chromatograph: Shimadzu LC-15C；Chromatographic column: 5 μm, 4.6 × 250
Mm, AD column；Chromatographic condition: flow velocity: 0.6mL/min；Column temperature: 30 DEG C；Sample volume: 10 μ l；Runing time: 30min；Detect wave
It is long: 222nm；Mobile phase: hexane: isopropanol: trifluoroacetic acid: diethylamine is 70:30:0.1:0.1 by volume.To system balancing
Afterwards, chromatogram is recorded, it is as shown in Figure 8 to obtain system suitability map 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 measurement of isomers in Valsartan hydrocarbonylation object.
Table 7- system suitability result
Above embodiments are only the preferred embodiments of the invention, it is noted that for the ordinary skill of the art
For personnel, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (3)
1. the detection method of isomers in a kind of Valsartan hydrocarbonylation object, comprising the following steps:
(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) measuring method:
Using high performance liquid chromatograph, OD chromatographic column, chromatographic condition: flow velocity: 0.6 ± 0.2mL/min；Column temperature: 30 ± 2 DEG C；Into
Sample amount: 10 ± 2 μ l, runing 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 are as follows: flow velocity: 0.6mL/min；Column temperature: 30 DEG C；Sample volume: 10 μ l, runing time: 30min, Detection wavelength: 222nm.
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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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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 |
Non-Patent Citations (3)
| Title |
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| HPLC法测定氨氯地平缬沙坦片中D-缬沙坦的含量;管宜河 等;《中国药师》;20100831;第13卷(第8期);第1143-1144页 |
| 高光学纯度的缬沙坦的合成研究;许萌;《中国优秀硕士学位论文 工程科技I辑》;20120615;第2012年卷(第06期);第29-48页 |
| 高效液相色谱法测定缬沙坦氢氯噻嗪片中缬沙坦对映异构体;吕晴 等;《中国新药杂志》;20141015;第23卷(第19期);第2242-2245页 |
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