CN107966519A - The detection method of impurity in HPLC analytical method and Telmisartan medicine - Google Patents

The detection method of impurity in HPLC analytical method and Telmisartan medicine Download PDF

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Publication number
CN107966519A
CN107966519A CN201810081672.8A CN201810081672A CN107966519A CN 107966519 A CN107966519 A CN 107966519A CN 201810081672 A CN201810081672 A CN 201810081672A CN 107966519 A CN107966519 A CN 107966519A
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impurity
telmisartan
mobile phase
solution
analysis
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CN201810081672.8A
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CN107966519B (en
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何亮
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威特(湖南)药业有限公司
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/86Signal analysis

Abstract

The present invention relates to Telmisartan detection, specifically the invention discloses a kind of detection method of impurity in HPLC analytical method and Telmisartan medicine, the analysis method can be by 8 kinds of impurity As in Telmisartan and Telmisartan medicine, B, C, E, F, G, H, I all separately detections, Telmisartan medicine sample is detected using the HPLC analytical method, whether it can be quickly detected by a chromatography in the medicine containing the one or more in 8 kinds of impurity above, and the detection to impurity content is realized by efficient liquid phase chromatographic analysis, to achieve the purpose that drug quality control.The detection method substantially reduces analysis time, easy to operate, reliable, accurate, changes that conventional operating procedure is more, analysis time length, the factors such as disturbing factor is more, is the effective means of telmisartan drug research and production process quality management and control.

Description

The detection method of impurity in HPLC analytical method and Telmisartan medicine

Technical field

The present invention relates to Telmisartan detection, and in particular, to a kind of HPLC analytical method and Telmisartan The detection method of impurity in medicine.

Background technology

Telmisartan (Telmisartan) for 4'- [(1,4'- dimethyl -2'- propyl group [bis- -1H- benzimidazoles of 2,6'-] - 1'- yls) methyl]-[1,1'- dibiphenylyl] -2- carboxylic acids, molecular formula C33H30N4O2, Telmisartan Tablets are primary for adult Property hypertension treatment drop, low cardiovascular risk, this product be suitable for 55 years old age and more than, there are generation major cardiovascular events Excessive risk and the patient that cannot receive Angiotensin-Converting (ACE) inhibitor for treating, occur myocardial infarction, soldier to reduce it In or angiocardiopathy cause death risk.

The formulations such as existing Telmisartan Tablets, dispersible tablet, capsule list, and Telmisartan has plurality of impurities, including following 8 Kind:Impurity A:4- methyl -6- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-yl) -2- propyl group -1H- benzimidazoles (4-methyl-6- (1- methyl-1H-benzimidazol-2-yl)-2-propyl1H-benzimidazole);Impurity B:4'- [[7- methyl -5- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-yl) -2- propyl group -1H- benzimidazole -1- bases] methyl] diphenyl-2-carboxylic acid (4 '-[[7- methyl-5-(1-methyl-1H-benzimidazol-2-yl)2-propyl-1H-benzimidazol-1-yl]methyl] biphenyl-2carboxylicacid);Impurity C:4'- [[4- methyl -6- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-yl) -2- third Base -1H- benzimidazole -1- bases] methyl] diphenyl-2-carboxylic acid 1,1- dimethyl ethyls ester (1,1-dimethylethyl-4 ' - [[4-methyl-6-(1-methyl-1Hbenzimidazol-2-yl)-2-propyl-1H-benzimidazol-1yl] methyl]biphenyl-2-carboxylate);Impurity E:1- [(2'- carboxyl biphenyl -4- bases) methyl] -4- methyl -2- third Base -1H- benzimidazole -6- carboxylic acids (1- [(2 '-carboxybiphenyl-4-yl) methyl] -4-methyl-2- propyl1H-benzimidazol-6-carboxylicacid);Impurity F:4'- [[4- methyl -6- (1- methyl isophthalic acid H- benzo miaows Azoles -2- bases) -2- propyl group -1H- benzimidazole -1- bases] methyl] biphenyl -2- formamides (4 '-[[4-methyl-6- (1- methyl-1H-benzimidazol-2-yl)2-propyl-1H-benzimidazol-1-yl]methyl]biphenyl- 2carboxamide);Impurity G:4'- [[4- methyl -6- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-yl) -2- propyl group -1H- benzo miaows Azoles -1- bases] methyl] biphenyl -2- formonitrile HCNs (4 '-[[4-methyl-6- (1-methyl-1H-benzimidazol-2-yl) 2- propyl-1H-benzimidazol-1-yl]methyl]biphenyl-2carbonitrile);Impurity H:4'- [[4- methyl- 6- (1- methyl isophthalic acids H- benzimidazolyl-2 radicals-yl) -2- propyl group -1H- benzimidazole -1- bases] methyl] biphenyl -2- formonitrile HCNs (1,1- dimethylethyl4’-(bromomethyl)biphenyl-2carboxylate);Impurity I:4- bromomethyls-biphenyl -2- first Sour methyl esters, respectively such as A, B, C, E, F, G, H, I in formula.

Wherein impurity A, impurity B, impurity C, impurity E, impurity F, impurity G and impurity H are European Pharmacopoeia Telmisartan matter Listed impurity in amount standard, impurity I are impurity listed in Chinese Pharmacopoeia Telmisartan quality standard, this 8 kinds of impurity There may be being produced in the synthesis technique of raw material or by degradation pathway, research control need to be carried out to it, to ensure this product The safety and effectiveness of quality.

It is next difficult to subsequent detection process bands due to the similitude of above impurity structure, for component in Telmisartan Tablets Detection, it is of the prior art to use high performance liquid chromatography, use gradient elution in European Pharmacopoeia, but can not will replace rice 8 kinds of impurity of Sha Tan and the above detect, and baseline is poor, and interference is more.Method in Chinese Pharmacopoeia uses isocratic elution, also without Method 8 kinds of impurity will be gathered all above, and the impurity behind principal component need to extend acquisition time and can measure, this assay method is not Reagent dosage that is only time-consuming and using is larger, and testing cost is higher.

For this reason, it may be necessary to provide a kind of efficiently by the whole separated high performance liquid chromatography of 8 kinds of impurity of Telmisartan and the above Analysis method, is current urgent problem to be solved.

The content of the invention

The object of the present invention is to provide a kind of detection side of impurity in HPLC analytical method and Telmisartan medicine Method, the analysis method can be by Telmisartans and as shown in I:It is impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, miscellaneous Matter H and impurity I all separately detections, it is possible to achieve qualitative, the quantitative purpose of impurity in Telmisartan.Using the efficient liquid phase Chromatogram analysis method is detected Telmisartan medicine sample, can be quickly detected by a chromatography in the medicine whether One or more containing more than in 8 kinds of impurity, and the detection to impurity content is realized by efficient liquid phase chromatographic analysis, with up to To the purpose of drug quality control.The detection method substantially reduces analysis time, easy to operate, reliable, accurate, change with Past operating procedure is more, analysis time length, and the factors such as disturbing factor is more, are telmisartan drug research and production process quality The effective means of management and control.

To achieve these goals, the present invention provides a kind of HPLC analytical method, the analysis method bag Include:To containing Telmisartan and as shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I Solution carry out constituent analysis with high performance liquid chromatography;Wherein, the high performance liquid chromatography uses gradient elution, wherein ladder The mobile phase of degree elution includes the first mobile phase and the second mobile phase;First mobile phase is to contain phosphate and pentane sulfonate Aqueous solution, wherein, phosphatic concentration is 10-20 μm of ol/L, and the concentration of pentane sulfonate is 15-25 μm of ol/L, water-soluble The pH of liquid is 3.0-3.6;Second mobile phase is the mixed solution of methanol and acetonitrile, and the volume ratio of methanol and acetonitrile is 1:0.9- 1.1。

The present invention also provides a kind of detection method of impurity in Telmisartan medicine, the detection method comprises the following steps: A, Telmisartan is taken and as shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I, are prepared System suitability solution, is detected with previously described efficient liquid-phase chromatography method, obtains system suitability curve;Wherein, In system suitability curve occur 9 absworption peaks, correspond to respectively Telmisartan, impurity A, impurity B, impurity C, impurity E, impurity F, Impurity G, impurity H and impurity I;B, Telmisartan medicine sample to be measured is taken, prepares test solution, with the height identical with step a Effect liquid phase chromatogram method is detected, and obtains test sample sample curves;C, by test sample sample curves and system suitability curve Compareed, if occurring absorption corresponding with corresponding one or more in system suitability curve in test sample sample curves Peak, then judge in Telmisartan medicine to be measured containing the Telmisartan corresponding to absworption peak, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I.

Through the above technical solutions, the present invention can be by Telmisartan and as shown in I with high performance liquid chromatography:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I all separately detections, in order to realize in Telmisartan Qualitative, the quantitative purpose of impurity.Telmisartan medicine sample is detected using the HPLC analytical method, can be with Quickly detected by a chromatography whether containing the one or more in 8 kinds of impurity above in the medicine, and by efficient Liquid-phase chromatographic analysis realizes the detection to impurity content, to achieve the purpose that drug quality control.The detection method greatly shortens It is analysis time, easy to operate, reliable, accurate, change that conventional operating procedure is more, analysis time length, disturbing factor is more It is the effective means of telmisartan drug research and production process quality management and control etc. factor.

Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.

Brief description of the drawings

Attached drawing is for providing a further understanding of the present invention, and a part for constitution instruction, with following tool Body embodiment is used to explain the present invention together, but is not construed as limiting the invention.In the accompanying drawings:

Fig. 1 is high-efficient liquid phase chromatogram in embodiment 1;

Fig. 2 is high-efficient liquid phase chromatogram in embodiment 2;

Fig. 3 is high-efficient liquid phase chromatogram in comparative example 1;

Fig. 4 is high-efficient liquid phase chromatogram in comparative example 2;

Fig. 5 is high-efficient liquid phase chromatogram in comparative example 3.

Embodiment

The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific Embodiment is merely to illustrate and explain the present invention, and is not intended to limit the invention.

The endpoint of disclosed scope and any value are not limited to the accurate scope or value herein, these scopes or Value should be understood to comprising the value close to these scopes or value.For number range, between the endpoint value of each scope, respectively It can be combined with each other between the endpoint value of a scope and single point value, and individually between point value and obtain one or more New number range, these number ranges should be considered as specific open herein.

The present invention provides a kind of HPLC analytical method, it is characterised in that the analysis method includes:To containing There is Telmisartan and as shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, the solution of impurity H and impurity I Constituent analysis is carried out with high performance liquid chromatography;Wherein, the high performance liquid chromatography uses gradient elution, wherein gradient elution Mobile phase include the first mobile phase and the second mobile phase;First mobile phase is water-soluble containing phosphate and pentane sulfonate Liquid, wherein, phosphatic concentration is 10-20 μm of ol/L, and the concentration of pentane sulfonate is 15-25 μm of ol/L, the pH of aqueous solution For 3.0-3.6;Second mobile phase is the mixed solution of methanol and acetonitrile, and the volume ratio of methanol and acetonitrile is 1:0.9-1.1.

Through the above technical solutions, the present invention can be by Telmisartan and as shown in I with high performance liquid chromatography:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I all separately detections, in order to realize in Telmisartan Qualitative, the quantitative purpose of impurity.Telmisartan medicine sample is detected using the HPLC analytical method, can be with Quickly detected by a chromatography whether containing the one or more in 8 kinds of impurity above in the medicine, and by efficient Liquid-phase chromatographic analysis realizes the detection to impurity content, to achieve the purpose that drug quality control.The detection method greatly shortens It is analysis time, easy to operate, reliable, accurate, change that conventional operating procedure is more, analysis time length, disturbing factor is more It is the effective means of telmisartan drug research and production process quality management and control etc. factor.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that using the cumulative volume of mobile phase as 100% Meter, temporally setting stepwise is the condition of the gradient elution:0 to 10 minute, the first mobile phase was 45-55% parts by volume, the Two mobile phases are 45-55% parts by volume;More than 10 minutes to 30 minutes, the first mobile phase was 50-30% parts by volume, and second flows It is mutually 50-70% parts by volume;More than 30 minutes to 60 minutes, the first mobile phase was 0-30% parts by volume, and the second mobile phase is 70- 100% parts by volume.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that using the cumulative volume of mobile phase as 100% Meter, temporally setting stepwise is the condition of the gradient elution:0 to 10 minute, the first mobile phase was 50% parts by volume, second Dynamic is mutually 50% parts by volume;More than 10 minutes to 30 minutes, the first mobile phase was 50-30% parts by volume, and the second mobile phase is 50- 70% parts by volume;More than 30 minutes to 60 minutes, the first mobile phase was 0-30% parts by volume, and the second mobile phase is 70-100% bodies Product part.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that what the high performance liquid chromatography used Detection wavelength is 230nm.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that what the high performance liquid chromatography used Chromatographic column is:Agilent, 150mm × 4.6 μm, 5 μm, C18.

For sampling volume, those skilled in the art can be adjusted flexibly, the size of how many influence spectral peaks of sample introduction and elution Efficiency.In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and as shown in I 's:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all detected in high performance liquid chromatography, Also, baseline is smooth, interference is reduced, makes testing result accurate, efficient, it is preferable that sampling volume:5-15μL.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that flow velocity 0.8-1.2mL/min.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that flow velocity 1.0mL/min.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that phosphate is sodium phosphate, potassium phosphate, phosphorus One or more in sour hydrogen sodium, potassium hydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that pentane sulfonate is pentane sulfonic acid Sodium or pentane potassium sulfonate.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduce interference, make testing result accurate, efficiently, it is preferable that the reagent of the first mobile phase pH of adjustment is Phosphoric acid.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H

All detected in high performance liquid chromatography with impurity I, also, baseline is smooth, reduces interference, makes testing result accurate Really, efficiently, it is preferable that phosphate is potassium dihydrogen phosphate, and pentane sulfonate is pentane sodium sulfonate.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that the concentration of potassium dihydrogen phosphate is 14.7 μ Mol/L, the concentration of sodium pentanesulfonate is 21.8 μm of ol/L, and the pH of aqueous solution is 3.5;Second mobile phase is the mixed of methanol and acetonitrile Solution is closed, wherein, the volume ratio of methanol and acetonitrile is 1:1.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that the mass concentration of Telmisartan in solution For 0.1-0.8mg/mL.Increase the mass concentration of Telmisartan in solution, although not influencing to detect, may increase and wash The de- time;And the mass concentration of Telmisartan in solution is reduced, and although nor affecting on detection, it is likely to result in main peak not It is fairly obvious, it is unfavorable for positioning analysis.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduce interference, make testing result accurate, efficiently, it is preferable that impurity A in solution, impurity B, impurity C, Impurity E, impurity F, impurity G, impurity H and the respective mass concentrations of impurity I are respectively 3-10 μ g/mL.Increase solution in impurity A, Impurity B, impurity C, impurity E, impurity F, impurity G, the mass concentration of impurity H and impurity I, although not influencing to detect, may Elution time can be increased;And reduce impurity A in solution, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I Mass concentration, although nor affecting on detection, it is not fairly obvious to be likely to result in impurity peaks in curve, is unfavorable for positioning point Analysis.

In a kind of more preferred embodiment of the present invention, in order to ensure the Telmisartan that contains in solution and such as I institute Show:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I are all examined in high performance liquid chromatography Go out, also, baseline is smooth, reduces interference, makes testing result accurate, efficient, it is preferable that the solvent in solution is to contain 0.003- The methanol solution of 0.008mol/L sodium hydroxides.

The present invention also provides a kind of detection method of impurity in Telmisartan medicine, the detection method comprises the following steps: A, Telmisartan is taken and as shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I, are prepared System suitability solution, is detected with previously described efficient liquid-phase chromatography method, obtains system suitability curve;Wherein, In system suitability curve occur 9 absworption peaks, correspond to respectively Telmisartan, impurity A, impurity B, impurity C, impurity E, impurity F, Impurity G, impurity H and impurity I;B, Telmisartan medicine sample to be measured is taken, prepares test solution, with the height identical with step a Effect liquid phase chromatogram method is detected, and obtains test sample sample curves;C, by test sample sample curves and system suitability curve Compareed, if occurring absorption corresponding with corresponding one or more in system suitability curve in test sample sample curves Peak, then judge in Telmisartan medicine to be measured containing the Telmisartan corresponding to absworption peak, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I.

Through the above technical solutions, the present invention can be by Telmisartan and as shown in I with high performance liquid chromatography:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I all separately detections, in order to realize in Telmisartan Qualitative, the quantitative purpose of impurity.Telmisartan medicine sample is detected using the HPLC analytical method, can be with Quickly detected by a chromatography whether containing the one or more in 8 kinds of impurity above in the medicine, and by efficient Liquid-phase chromatographic analysis realizes the detection to impurity content, to achieve the purpose that drug quality control.The detection method greatly shortens It is analysis time, easy to operate, reliable, accurate, change that conventional operating procedure is more, analysis time length, disturbing factor is more It is the effective means of telmisartan drug research and production process quality management and control etc. factor.

For the ease of being quantified to the content of impurity in Telmisartan medicine sample, it is preferable that the detection method is also wrapped Include to Telmisartan in the Telmisartan medicine sample, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and The content of impurity I is measured, and the measure includes:D, the Telmisartan of various concentrations, impurity A, impurity B, miscellaneous is prepared respectively Matter C, impurity E, impurity F, impurity G, the standard solution of impurity H and impurity I, institute is measured using the high performance liquid chromatography respectively The peak area of each standard solution is stated, and for Telmisartan, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H Peak area-concentration standard curve is drawn respectively with impurity I;E, by Telmisartan medicine sample preparation into sample solution, using described The area at each peak of sample solution described in high effective liquid chromatography for measuring;F, the sample solution is calculated by the standard curve In each component concentration, and thus calculate the content of each component in the Telmisartan medicine sample.

The drafting of preparation, each peak area-concentration standard curve for standard solution and according to standard curve to impurity The conversion of content, those skilled in the art can rule of thumb carry out, and belong to routine operation, here, the present invention repeats no more.

The present invention will be described in detail by way of examples below.In the examples below, chromatograph is Shimadzu 2010 Type high performance liquid chromatograph.

Preparation example 1

Accurately weighed Telmisartan and impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I, add In the methanol solution for entering 0.005mol/L sodium hydroxides, solution is configured to, wherein, the mass concentration of Telmisartan is 0.5mg/ mL;Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and the respective mass concentrations of impurity I are respectively in solution 5μg/mL。

Embodiment 1

With the solution in efficient liquid phase chromatographic analysis preparation example 1, chromatogram, the chromatostrip of the high performance liquid chromatography are recorded Part is as follows:

Chromatographic column:5 μm of 150mm × 4.6 μm C18,35 DEG C of column temperature

Wavelength:230nm

Sample size:10μL

Flow velocity:1.0mL/min

First mobile phase:2.0g potassium dihydrogen phosphates and mono- water pentane sodium sulfonates of 3.8g are into 1L water, with phosphorus acid for adjusting pH It is worth to 3.5;

Second mobile phase:The volume ratio of methanol and acetonitrile is 50:50;

Counted in gradient elution using the cumulative volume of mobile phase as 100%, the condition of the gradient elution temporally setting stepwise As shown in table 1:

Table 1

Time (min) First mobile phase (%) Second mobile phase (%) 0-10 50 50 10-30 50-30 50-70 30-60 30-0 70-100

Obtained chromatogram is as shown in Figure 1, it is seen then that 9 absworption peaks is obtained in Fig. 1, by the Telmisartan in solution and miscellaneous Matter A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I are totally separated and come, also, miscellaneous peak in chromatogram Few, baseline is smooth.On this condition, the detection of 9 kinds of components of the above can be completed within when the used time 1 is small, analysis time is short.

Solution after to elution carries out quantitative analysis, the amount of more theoretical recycling, finds Telmisartan and impurity A, miscellaneous Between 99%-101%, the rate of recovery is high for matter B, impurity C, impurity E, impurity F, impurity G, impurity H, the rate of recovery of impurity I, point Analysis is accurately and reliably.

Through the spectrogram shown in Fig. 1 is further analyzed, result as shown in Table 2 is obtained, it is seen then that on this condition, Each peak can efficiently separate, and theoretical cam curve and tailing factor meet the requirements.

Table 2

Peak sequence number Retention time Theoretical cam curve Separating degree 1 9.514 31256 / 2 19.353 33568 30.855 3 20.192 75981 2.346 4 26.151 119855 20.024 5 28.88 92175 7.996 6 33.768 154506 13.5 7 40.154 233738 18.896 8 44.835 182939 12.458 9 50.714 322641 15.144

Embodiment 2

With the solution in efficient liquid phase chromatographic analysis preparation example 1, chromatogram, the chromatostrip of the high performance liquid chromatography are recorded Part is as follows:

Chromatographic column:5 μm of 150mm × 4.6 μm C18,35 DEG C of column temperature

Wavelength:230nm

Sample size:10μL

Flow velocity:1.0mL/min

First mobile phase:2.0g potassium dihydrogen phosphates and mono- water pentane sodium sulfonates of 3.8g are into 1L water, with phosphorus acid for adjusting pH It is worth to 3.0;

Second mobile phase:The volume ratio of methanol and acetonitrile is 50:50;

Counted in gradient elution using the cumulative volume of mobile phase as 100%, the condition of the gradient elution temporally setting stepwise As shown in table 3.

Table 3

Obtained chromatogram is as shown in Figure 2, it is seen then that 9 absworption peaks is obtained in Fig. 2, by the Telmisartan in solution and miscellaneous Matter A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H, impurity I are totally separated and come, also, miscellaneous peak in chromatogram Few, baseline is also calculated smoothly.On this condition, the detection of 9 kinds of components of the above can be completed within when the used time 1 is small, analysis time is short.

Through the spectrogram shown in Fig. 2 is further analyzed, result as shown in table 4 is obtained, it is seen then that on this condition, Although each peak can efficiently separate, second impurity peak shape is poorer than in embodiment 1, and theoretical cam curve is relatively low.

Table 4

Peak sequence number Retention time Theoretical cam curve Separating degree 1 9.735 33098 / 2 19.639 15006 23.16 3 20.556 75835 1.951 4 26.525 119609 19.72 5 29.37 98907 8.363 6 34.264 152747 13.516 7 40.35 228535 17.682 8 45.452 178230 13.283 9 50.943 311815 13.803

Comparative example 1

With the solution in efficient liquid phase chromatographic analysis preparation example 1, chromatogram, the chromatostrip of the high performance liquid chromatography are recorded Part is as follows:

Chromatographic column:5 μm of 150mm × 4.6 μm C18,35 DEG C of column temperature

Wavelength:230nm

Sample size:10μL

Flow velocity:1.0mL/min

First mobile phase:2.0g potassium dihydrogen phosphates and mono- water pentane sodium sulfonates of 3.8g are into 1L water, with phosphorus acid for adjusting pH It is worth to 3.0;

Second mobile phase:The volume ratio of methanol and acetonitrile is 1:4;

Counted in gradient elution using the cumulative volume of mobile phase as 100%, the condition of the gradient elution temporally setting stepwise As shown in table 5.

Table 5

Time (min) First mobile phase (%) Second mobile phase (%) 0-3 70 30 3-28 70-20 30-80

Obtained chromatogram is as shown in Figure 3, it is seen then that 7 absworption peaks are obtained in Fig. 3, can not all detect impurity.

Comparative example 2

With the solution in efficient liquid phase chromatographic analysis preparation example 1, chromatogram, the chromatostrip of the high performance liquid chromatography are recorded Part is as follows:

Chromatographic column:5 μm of 150mm × 4.6 μm C18,35 DEG C of column temperature

Wavelength:230nm

Sample size:10μL

Flow velocity:1.0mL/min

First mobile phase:2.0g potassium dihydrogen phosphates and mono- water pentane sodium sulfonates of 3.8g are into 1L water, with phosphorus acid for adjusting pH It is worth to 3.0;

Second mobile phase:The volume ratio of methanol and acetonitrile is 1:4;

Counted in gradient elution using the cumulative volume of mobile phase as 100%, the condition of the gradient elution temporally setting stepwise As shown in table 6.

Table 6

Time (min) First mobile phase (%) Second mobile phase (%) 0-3 70 30 3-15 70-55 30-45 15-28 55-10 45-90

Obtained chromatogram is as shown in Figure 4, it is seen then that 8 absworption peaks are obtained in Fig. 4, can not all detect impurity.

Comparative example 3

With the solution in efficient liquid phase chromatographic analysis preparation example 1, chromatogram, the chromatostrip of the high performance liquid chromatography are recorded Part is as follows:

Chromatographic column:5 μm of 150mm × 4.6 μm C18,35 DEG C of column temperature

Wavelength:230nm

Sample size:10μL

Flow velocity:1.0mL/min

First mobile phase:2.0g potassium dihydrogen phosphates and mono- water pentane sodium sulfonates of 3.8g are into 1L water, with phosphorus acid for adjusting pH It is worth to 3.0;

Second mobile phase:The volume ratio of methanol and acetonitrile is 25:75;

Counted in gradient elution using the cumulative volume of mobile phase as 100%, the condition of the gradient elution temporally setting stepwise As shown in table 7:

Table 7

Obtained chromatogram is as shown in Figure 5, it is seen then that although obtaining 9 absworption peaks in Fig. 5, baseline is reported to the leadship after accomplishing a task, and it is fixed to be unfavorable for Amount analysis.

The preferred embodiment of the present invention described in detail above, still, during present invention is not limited to the embodiments described above Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this A little simple variants belong to protection scope of the present invention.

It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can The combination of energy no longer separately illustrates.

In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally The thought of invention, it should equally be considered as content disclosed in this invention.

Claims (10)

1. a kind of HPLC analytical method, it is characterised in that the analysis method includes:To containing Telmisartan and such as Shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, the solution high performance liquid chromatography of impurity H and impurity I Method carries out constituent analysis;Wherein, the high performance liquid chromatography uses gradient elution, and wherein the mobile phase of gradient elution includes the One mobile phase and the second mobile phase;
First mobile phase is the aqueous solution containing phosphate and pentane sulfonate, wherein, phosphatic concentration is 10-20 μ Mol/L, the concentration of pentane sulfonate is 15-25 μm of ol/L, and the pH of aqueous solution is 3.0-3.6;
Second mobile phase is the mixed solution of methanol and acetonitrile, and the volume ratio of methanol and acetonitrile is 1:0.9-1.1.
2. analysis method according to claim 1, wherein, counted using the cumulative volume of mobile phase as 100%, the gradient elution Condition temporally setting stepwise is:
0 to 10 minute, the first mobile phase was 45-55% parts by volume, and the second mobile phase is 45-55% parts by volume;
More than 10 minutes to 30 minutes, the first mobile phase was 50-30% parts by volume, and the second mobile phase is 50-70% parts by volume;
More than 30 minutes to 60 minutes, the first mobile phase was 0-30% parts by volume, and the second mobile phase is 70-100% parts by volume;It is excellent Selection of land,
0 to 10 minute, the first mobile phase was 50% parts by volume, and the second mobile phase is 50% parts by volume.
3. analysis method according to claim 2, wherein, the Detection wavelength that the high performance liquid chromatography uses for 230nm;And/or
The chromatographic column that the high performance liquid chromatography uses for:Agilent, 150mm × 4.6 μm, 5 μm, C18.
4. analysis method according to claim 2, wherein, sampling volume:5-15μL;And/or
Flow velocity is 0.8-1.2mL/min, it is preferable that flow velocity 1.0mL/min.
5. according to the analysis method any one of claim 1-4, wherein, phosphate is sodium phosphate, potassium phosphate, phosphoric acid hydrogen One or more in sodium, potassium hydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate;And/or
Pentane sulfonate is pentane sodium sulfonate or pentane potassium sulfonate;And/or the reagent of the first mobile phase pH of adjustment is phosphorus Acid.
6. analysis method according to claim 5, wherein, phosphate is potassium dihydrogen phosphate, and pentane sulfonate is positive penta Alkyl sulfonic acid sodium.
7. analysis method according to claim 6, wherein, the concentration of potassium dihydrogen phosphate is 14.7 μm of ol/L, pentanesulfonic acid The concentration of sodium is 21.8 μm of ol/L, and the pH of aqueous solution is 3.5;
Second mobile phase is the mixed solution of methanol and acetonitrile, wherein, the volume ratio of methanol and acetonitrile is 1:1.
8. analysis method according to claim 5, wherein, the mass concentration of Telmisartan is 0.1-0.8mg/ in solution mL;And/or
Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and the respective mass concentration difference of impurity I in solution For 3-10 μ g/mL;And/or
Solvent in solution is the methanol solution containing 0.003-0.008mol/L sodium hydroxides.
9. the detection method of impurity in a kind of Telmisartan medicine, it is characterised in that the detection method comprises the following steps:
A, Telmisartan is taken and as shown in I:Impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I, Compounding system adaptability solution, is detected with claim 1-8 any one of them efficient liquid-phase chromatography methods, obtains system Adapt to linearity curve;
Wherein, occur 9 absworption peaks in system suitability curve, correspond to Telmisartan, impurity A, impurity B, impurity C, miscellaneous respectively Matter E, impurity F, impurity G, impurity H and impurity I;
B, take Telmisartan medicine sample to be measured, prepare test solution, with the efficient liquid-phase chromatography method identical with step a into Row detection, obtains test sample sample curves;
C, test sample sample curves are compareed with system suitability curve, if occurring fitting with system in test sample sample curves Corresponding one or more corresponding adsorption peaks in linearity curve are answered, then it is right containing absworption peak institute in Telmisartan medicine to be measured to judge Telmisartan, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and the impurity I answered.
10. detection method according to claim 9, wherein, the detection method is further included to the Telmisartan medicine sample Telmisartan in product, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, the content of impurity H and impurity I are measured, The measure includes:
D, prepare respectively the Telmisartans of various concentrations, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and The standard solution of impurity I, the peak area of each standard solution is measured using the high performance liquid chromatography respectively, and is directed to and is replaced Meter Sha Tan, impurity A, impurity B, impurity C, impurity E, impurity F, impurity G, impurity H and impurity I draw peak area-concentration mark respectively Directrix curve;
E, by Telmisartan medicine sample preparation into sample solution, using sample solution described in the high effective liquid chromatography for measuring The area at each peak;
F, the concentration of each component in the sample solution is calculated by the standard curve, and thus calculates the Telmisartan The content of each component in medicine sample.
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