CN112051346A - HPLC method for simultaneously determining content of indacaterol and glycopyrronium bromide - Google Patents
HPLC method for simultaneously determining content of indacaterol and glycopyrronium bromide Download PDFInfo
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- 229940020900 indacaterol and glycopyrronium bromide Drugs 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 33
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
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- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 239000000945 filler Substances 0.000 claims abstract description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000004007 reversed phase HPLC Methods 0.000 claims abstract description 3
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- 238000000691 measurement method Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229960002462 glycopyrronium bromide Drugs 0.000 abstract description 14
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 abstract description 13
- 229960004078 indacaterol Drugs 0.000 abstract description 11
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 abstract description 11
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- 150000001875 compounds Chemical class 0.000 description 4
- 229960004735 indacaterol maleate Drugs 0.000 description 4
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
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- IREJFXIHXRZFER-PCBAQXHCSA-N indacaterol maleate Chemical compound OC(=O)\C=C/C(O)=O.N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 IREJFXIHXRZFER-PCBAQXHCSA-N 0.000 description 3
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- PZSMUPGANZGPBF-UHFFFAOYSA-N 4-[5-(dithiolan-3-yl)pentanoylamino]butanoic acid Chemical compound OC(=O)CCCNC(=O)CCCCC1CCSS1 PZSMUPGANZGPBF-UHFFFAOYSA-N 0.000 description 1
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
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- 229940015042 glycopyrrolate Drugs 0.000 description 1
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- -1 indacaterol maleate glycopyrronium bromide compound Chemical class 0.000 description 1
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- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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Abstract
The invention discloses an HPLC method for simultaneously determining the contents of indacaterol and glycopyrronium bromide, belonging to the technical field of pharmaceutical analysis. The chromatographic column adopted by the method adopts octadecylsilane chemically bonded silica as a filler, and adopts a mobile phase A and a mobile phase B to carry out reversed-phase high performance liquid chromatography gradient elution; wherein the mobile phase A is phosphate buffer solution with the salt concentration of 10-30 mmol/L and the pH adjusted to 2.5-4.0 by a pH adjusting agent, and the mobile phase B is methanol or acetonitrile. The method disclosed by the invention is simple, efficient, easy to operate, strong in universality and high in sensitivity, has lower quantitative limit on the determination of the indacaterol and the glycopyrronium bromide, is rapid and efficient, and can well meet the requirements of research and development and production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical analysis, in particular to an HPLC (high performance liquid chromatography) method for simultaneously determining the contents of indacaterol and glycopyrronium bromide.
Background
Indacaterol maleate is a long-acting β 2-adrenoceptor agonist (LABA) that activates a portion of the intracellular adenosine cyclase, which catalyzes the conversion of Adenosine Triphosphate (ATP) to cyclic-3 ', 5' -adenosine monophosphate (cyclic adenosine monophosphate). The increase of cyclic adenosine monophosphate (cAMP) level causes the relaxation of bronchial smooth muscle, can relax air passages, reduce the release of degranulation and medium of mast cells and basophils, reduce the permeability of capillaries, increase the swinging of airway epithelial cilia, locally play the role of a bronchodilator in the lung and relieve the symptoms of chronic obstructive pulmonary disease. Glycopyrrolate is an anticholinergic drug, is a long-acting acetylcholine receptor antagonist (LAMA), has 4-fold higher selectivity for human acetylcholine M3 receptor than for M2 receptor, and can specifically bind to and inhibit M3 type acetylcholine receptor distributed in bronchial smooth muscle to dilate airway.
The indacaterol maleate glycopyrronium bromide compound medicine is developed by Nowa and has the trade name of
The Chinese medicine is named as Jiehun, and is marketed in China 4 month and 11 day 2019, and the dosage form is capsule type inhalation powder cloud agent, and each capsule contains indacaterol maleate 110 μ g (as C)24H28N2O3Calculated) and glycopyrronium bromide 50. mu.g (in terms of C)19H28NO3Meter). Can be used for treating adult Chronic Obstructive Pulmonary Disease (COPD) patients with chronic bronchitis and emphysema to relieve symptoms.
In the process of research and development of medicines, accurate determination and analysis of the content of effective substances and impurities are important conditions for ensuring the quality of medicines. In the compound medicine, the effective components of indacaterol and glycopyrronium are in the microgram grade, in the research of the powder inhalation, the important research on the distribution of fine particles is needed, and when the powder inhalation is analyzed in vitro by equipment, the deposition amount of each part is less and less, so that in the content analysis, the analysis method is required to have enough sensitivity and accuracy. The prior art reports about the content determination of indacaterol and glycopyrronium bromide (Rapid lateral calibration of indacaterol and glycopyrronium bromide in halogenated capsules using a validated stability-indicating monomeric LC method, Zayed and Bell Chemistry Central Journal, 2017, 11:36), and an ultra-high performance liquid chromatograph is required to be used for quantification by using an internal standard tenoxicam, and the sensitivities are respectively 0.16 μ g/mL and 0.34 μ g/mL, the operation is complicated, the requirement on operators is high, and the quantification limit cannot meet the research and development requirements. Further, it is reported that the limits of quantitation measured in the literature (RP-HPLC-DAD method for the quantitative determination of individual and physiological in the Pharmaceutical formulation, World Journal of Pharmaceutical and Pharmaceutical Sciences, 2018, Volume 7, Issue 3,166-176) are 0.5. mu.g/mL and 0.1. mu.g/mL, respectively, and thus the requirement of the fine particle distribution test cannot be satisfied. There are also references (HPLC Determination of Industrial hydroxide in Pharmaceutical Preparations and Fluorescence Determination, International Journal of Pharmaceutical Sciences and Research 2015, Volume 6, No 11) which use two detectors-UV detector and Fluorescence detector for measurement, and the operation is complicated, the equipment requirement is high, and the Detection cost is high.
Therefore, it is urgently needed to develop a high performance liquid chromatography analysis method with simple operation, strong versatility and high sensitivity to simultaneously determine the content of indacaterol maleate and glycopyrronium bromide in the compound preparation.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the HPLC method for simultaneously determining the contents of indacaterol and glycopyrronium bromide, the method is simple, efficient, easy to operate, strong in universality and high in sensitivity, has lower quantitative limit on the determination of indacaterol and glycopyrronium bromide, is rapid and efficient, and can well meet the requirements of research and development and production.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
an HPLC method for simultaneously determining the contents of indacaterol and glycopyrronium bromide is characterized in that a chromatographic column adopted in the method uses octadecylsilane chemically bonded silica as a filling agent, and a mobile phase A and a mobile phase B are adopted to carry out reversed-phase high performance liquid chromatography gradient elution;
the mobile phase A is a phosphate buffer solution with the salt concentration of 10-30 mmol/L and the pH adjusted to 2.5-4.0 by a pH adjusting agent, and the preferable salt concentration is 20mmol/L, pH to be 3.0; the mobile phase B is methanol or acetonitrile, preferably acetonitrile.
In a preferred embodiment of the present invention, the phosphate buffer is one selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, and disodium hydrogen phosphate.
In a preferred embodiment of the present invention, the pH adjuster is one of dilute phosphoric acid, glacial acetic acid, trifluoroacetic acid and formic acid, and preferably dilute phosphoric acid.
In a preferred embodiment of the present invention, the volume ratio of the mobile phase a to the mobile phase B is 50:50 to 85:15, preferably 70:30 to 80: 20.
In a preferred embodiment of the present invention, the flow rate of the mobile phase for elution is 0.8 to 1.2mL/min, preferably 1.0 mL/min.
As a preferred embodiment of the present invention, the chromatographic conditions are as follows: the length of the chromatographic column is 50-150 mm, preferably 100 mm; the column temperature is 20-40 ℃, preferably 25-35 ℃, and most preferably 30 ℃; the detection wavelength is 200 to 230nm, preferably 205 to 220nm, and most preferably 210 nm.
As a preferred embodiment of the present invention, the HPLC method of the present invention specifically comprises the steps of:
s1, preparation of a test solution:
accurately weighing a proper amount of sample, adding a diluent to dissolve and dilute the sample to be used as a test solution;
s2, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s3, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring the test solution and the reference solution, injecting the test solution and the reference solution into a chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
As a preferred embodiment of the present invention, the diluent in step S1 is mobile phase a and mobile phase B according to the ratio of mobile phase a: the mobile phase B is a mixture of 5:1 to 1:5 in volume ratio, and the volume ratio of the two is preferably 2:1 to 1: 1. Small amounts of additives or solvents may be added, including glacial acetic acid, triethylamine, water, ethanol, methanol, acetonitrile, and the like.
Compared with the prior art, the invention has the beneficial effects that:
the HPLC method provided by the invention can accurately and simultaneously determine the content of indacaterol and glycopyrronium bromide in a compound preparation, the quantitative limits of the indacaterol and the glycopyrronium bromide can be respectively as low as 0.005 mu g/mL and 0.015 mu g/mL, the quantitative limit required by a micro-particle distribution test can be well met, the method has low configuration requirement on an instrument and quick and efficient analysis, and solves the problems of high requirement on the instrument, large system pressure, insufficient quantitative limit, complex solution preparation operation and the like of the existing analysis method.
In conclusion, the HPLC method is simple and efficient, easy to operate, strong in universality, high in sensitivity and low in quantitative limit, can widely meet the research and development requirements, and can effectively control the contents of indacaterol and glycopyrronium bromide in a single or compound preparation.
Drawings
FIG. 1 is a HPLC chart of example 1 of the present invention;
FIG. 2 is a HPLC chart of example 2 of the present invention;
FIG. 3 is a HPLC chart of example 3 of the present invention;
FIG. 4 is a HPLC chart of example 4 of the present invention;
FIG. 5 is a HPLC chart of example 5 of the present invention;
FIG. 6 is a HPLC chart of example 6 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
The apparatus used in the following examples was: the purposes of the invention can be achieved by using an Agilent 1260 high performance liquid chromatograph, a DAD, a Waters C18 chromatographic column as a chromatographic column and other types of instruments and chromatographic column models.
Example 1
An HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: waters xbridge C18,50mm, column temperature: 35 ℃, wavelength: 210 nm;
mobile phase A: 30mM phosphate buffer adjusted to pH3.5 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.5ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of the sample was precisely weighed, dissolved and diluted with a diluent (glacial acetic acid: water: ethanol ═ 1:70:30) to obtain a test solution containing glycopyrronium bromide at a concentration of 6 μ g/ml and indacaterol at a concentration of 20 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 25 mu l of test solution and control solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
The chromatogram is shown in FIG. 1, and the chromatographic peak parameters are shown in Table 1.
TABLE 130 mM phosphate buffer (pH3.5) -acetonitrile equi-proportional elution chromatogram peaks parameters
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 1.804min | 195 | 84 | 9295 | 1.2 |
| 2.251min | 2118 | 581 | 7035 | 1.2 |
Example 2:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 35 ℃, wavelength: 210 nm;
mobile phase A: 30mM phosphate buffer adjusted to pH3.5 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.0ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of sample was precisely weighed, and dissolved and diluted with a diluent (mobile phase a: mobile phase B ═ 1:1) to obtain a test solution containing glycopyrronium bromide at a concentration of 3 μ g/ml and indacaterol at a concentration of 100 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 5 mul of the test solution and the reference solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
The chromatogram is shown in FIG. 2, and the chromatographic peak parameters are shown in Table 2.
TABLE 230 mM phosphate buffer (pH3.5) -chromatographic peak parameters at gradient elution in acetonitrile
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 5.598min | 58 | 8 | 14695 | 1.3 |
| 8.326min | 2007 | 367 | 5654 | 1.2 |
Example 3:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 35 ℃, wavelength: 210 nm;
mobile phase A: 20mM phosphate buffer adjusted to pH3.5 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 0.8ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of sample was precisely weighed, and dissolved and diluted with a diluent (mobile phase a: mobile phase B ═ 2:1) to obtain a test solution containing glycopyrronium bromide at a concentration of 6 μ g/ml and indacaterol at a concentration of 20 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 20 mul of the test solution and the control solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the content of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by using the peak area.
The chromatogram is shown in FIG. 3, and the chromatographic peak parameters are shown in Table 3.
TABLE 320 mM phosphate buffer (pH3.5) -chromatographic peak parameters at acetonitrile gradient elution
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 6.627min | 93 | 11 | 16405 | 1.2 |
| 9.721min | 2195 | 215 | 21697 | 1.4 |
Example 4:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 30 ℃, wavelength: 210 nm;
mobile phase A: 20mM phosphate buffer adjusted to pH3.0 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.0ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of sample was precisely weighed, and dissolved and diluted with a diluent (mobile phase a: mobile phase B ═ 2:1) to obtain a test solution containing glycopyrronium bromide at a concentration of 6 μ g/ml and indacaterol at a concentration of 20 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 20 mul of the test solution and the control solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the content of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by using the peak area.
The chromatogram is shown in FIG. 4, and the chromatographic peak parameters are shown in Table 4.
TABLE 420 mM phosphate buffer (pH3.0) -chromatographic peak parameters at gradient elution in acetonitrile
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 5.188min | 74 | 11 | 13504 | 1.3 |
| 7.847min | 1757 | 191 | 18206 | 1.4 |
Example 5:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 30 ℃, wavelength: 210 nm;
mobile phase A: 10mM phosphate buffer adjusted to pH4.0 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.0ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of sample was precisely weighed, and dissolved and diluted with a diluent (mobile phase a: mobile phase B ═ 3:1) to obtain a test solution containing glycopyrronium bromide at a concentration of 6 μ g/ml and indacaterol at a concentration of 5 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 100 mu l of test solution and reference solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
The chromatogram is shown in FIG. 5, and the chromatographic peak parameters are shown in Table 5.
TABLE 510 mM phosphate buffer (pH4.0) -chromatographic peak parameters at gradient elution in acetonitrile
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 5.670min | 323 | 38 | 12951 | 1.5 |
| 8.520min | 2748 | 240 | 23365 | 1.5 |
Example 6:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 30 ℃, wavelength: 210 nm;
mobile phase A: 20mM phosphate buffer adjusted to pH3.0 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.0ml/min according to the following gradient;
s2, preparation of a test solution:
an appropriate amount of sample was precisely weighed, and dissolved and diluted with a diluent (mobile phase a: mobile phase B ═ 1:1) to obtain a test solution containing glycopyrronium bromide at a concentration of 6 μ g/ml and indacaterol at a concentration of 5 μ g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 100 mu l of test solution and reference solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
The chromatogram is shown in FIG. 6, and the chromatographic peak parameters are shown in Table 6.
TABLE 620 mM phosphate buffer (pH3.0) -acetonitrile gradient elution time 20min chromatographic Peak parameters
| Retention time | Peak area | Peak height | Number of theoretical plate | Tailing factor |
| 5.168min | 324 | 42 | 10650 | 1.4 |
| 7.788min | 2747 | 269 | 14067 | 1.4 |
Example 7:
an HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide, which comprises the following steps:
s1, chromatographic conditions:
a chromatographic column: sunfire C18,100mm, column temperature: 30 ℃, wavelength: 210 nm;
mobile phase A: 20mM phosphate buffer adjusted to pH3.0 with dilute phosphoric acid;
mobile phase B: acetonitrile;
the mobile phase is subjected to gradient elution at the flow rate of 1.0ml/min according to the following gradient;
s2, preparation of a test solution:
a proper amount of sample is precisely weighed, and a diluent (mobile phase A: mobile phase B ═ 1:1) is added to dissolve and dilute the sample to obtain a test solution with glycopyrronium bromide concentration of 0.015 mu g/ml and indacaterol concentration of 0.005 mu g/ml.
S3, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s4, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring 100 mu l of test solution and reference solution, injecting into a high performance liquid chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
The chromatographic peak parameters are shown in Table 7.
TABLE 720 mM phosphate buffer (pH3.0) -acetonitrile gradient elution time 20min chromatogram peaks parameters
| Retention time | Peak area | Peak height | Number of theoretical plate | Signal to noise ratio |
| 5.164min | 1.9 | 0.26 | 12372 | 13.7 |
| 7.786min | 2.8 | 0.28 | 16343 | 16.7 |
From the above experimental data, it can be seen that the quantitation limits of the present invention are respectively as low as: 0.015 mu g/ml of glycopyrronium bromide and 0.005 mu g/ml of indacaterol, and completely meets the requirements of quantitative limit and rapid detection in research and development and production.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (8)
1. An HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide is characterized in that: the chromatographic column adopted by the method is characterized in that octadecylsilane chemically bonded silica is used as a filler, and a mobile phase A and a mobile phase B are adopted for carrying out reversed-phase high performance liquid chromatography gradient elution;
the mobile phase A is a phosphate buffer solution with the salt concentration of 10-30 mmol/L and the pH adjusted to 2.5-4.0 by a pH regulator; the mobile phase B is methanol or acetonitrile.
2. An HPLC method for simultaneous determination of indacaterol and glycopyrronium bromide content according to claim 1, characterized in that: the phosphate in the phosphate buffer solution is selected from one of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate.
3. An HPLC method for simultaneous determination of indacaterol and glycopyrronium bromide content according to claim 1, characterized in that: the pH regulator is one of dilute phosphoric acid, glacial acetic acid, trifluoroacetic acid and formic acid.
4. An HPLC method for simultaneous determination of indacaterol and glycopyrronium bromide content according to claim 1, characterized in that: the volume ratio of the mobile phase A to the mobile phase B is 50: 50-85: 15.
5. An HPLC method for simultaneous determination of indacaterol and glycopyrronium bromide content according to claim 1, characterized in that: the flow rate of the mobile phase for elution is 0.8-1.2 mL/min.
6. An HPLC method for simultaneous determination of indacaterol and glycopyrronium bromide content according to claim 1, characterized in that: the chromatographic conditions were as follows: the length of the chromatographic column is 50-150 mm, the temperature of the chromatographic column is 20-40 ℃, and the detection wavelength is 200-230 nm.
7. An HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide according to any one of claims 1 to 6, characterized in that: the method specifically comprises the following steps:
s1, preparation of a test solution:
accurately weighing a proper amount of sample, adding a diluent to dissolve and dilute the sample to be used as a test solution;
s2, preparation of control solution:
precisely measuring a proper amount of a test solution, and diluting the test solution with a mobile phase to be used as a reference solution;
s3, measurement method:
injecting the reference solution into a liquid chromatograph, and adjusting the detection sensitivity to make the peak height of the main component chromatographic peak be 20% of the full-scale range; and precisely measuring the test solution and the reference solution, injecting the test solution and the reference solution into a chromatograph, recording a chromatogram, and calculating the contents of indacaterol and glycopyrronium bromide in the test solution according to an external standard method by peak area.
8. An HPLC method for simultaneously determining the content of indacaterol and glycopyrronium bromide according to claim 7, characterized in that: the diluent in step S1 is mobile phase a and mobile phase B as mobile phase a: and the mobile phase B is a mixture with the volume ratio of 5: 1-1: 5.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102665680A (en) * | 2009-12-23 | 2012-09-12 | 奇斯药制品公司 | Aerosol formulation for copd |
| CN104955449A (en) * | 2013-01-31 | 2015-09-30 | 普罗索尼克斯有限公司 | Multi-component crystalline particles for inhalation therapy |
| US20150182450A1 (en) * | 2013-12-30 | 2015-07-02 | Chiesi Farmaceutici S.P.A. | Stable pressurised aerosol solution composition of glycopyrronium bromide and formoterol combination |
| GB201615910D0 (en) * | 2016-09-19 | 2016-11-02 | Mexichem Fluor Sa De Cv | Pharmaceutical composition |
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