CN107305199B - Method for separating and measuring two components and related substances in compound nasal spray of azelastine hydrochloride and fluticasone propionate - Google Patents
Method for separating and measuring two components and related substances in compound nasal spray of azelastine hydrochloride and fluticasone propionate Download PDFInfo
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- CN107305199B CN107305199B CN201610242312.2A CN201610242312A CN107305199B CN 107305199 B CN107305199 B CN 107305199B CN 201610242312 A CN201610242312 A CN 201610242312A CN 107305199 B CN107305199 B CN 107305199B
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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
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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
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring two components and related substances in a compound nasal spray of azelastine hydrochloride and fluticasone propionate. The method comprises the steps of taking octadecylsilane chemically bonded silica as a fixed phase, taking a mobile phase A and a mobile phase B as mobile phases, carrying out gradient elution, and carrying out solid-liquid separation, wherein the mobile phase A is a potassium hexafluorophosphate solution, and the mobile phase B is an organic solvent; the high performance liquid chromatography is used for separating and measuring two components and related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate, so that the separation and detection of the two components and 11 related substances of the azelastine hydrochloride and the fluticasone propionate can be realized simultaneously, and the method makes up the vacancy of the prior art, and has the advantages of good separation degree, strong specificity and high sensitivity; the method has the advantages of simple operation, simplicity, convenience and rapidness, and has important significance for controlling the quality of the compound nasal spray medicine of the azelastine hydrochloride and fluticasone propionate.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring two components and related substances in a compound nasal spray of azelastine hydrochloride and fluticasone propionate.
Background
Azelastine hydrochloride, chemical name (±) -4- (4-chlorobenzyl) -2- (hexahydro-1-methyl-1H-azepin-4-yl) -1- (2H) -phthalazine hydrochloride. The chemical structural formula is as follows:
fluticasone propionate, chemically 6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17- (1-oxopropoxy) -androsta-1, 4-diene-17-carbothioic acid (6a, 11b, 16a, 17a) -S- (fluoromethyl) ester. The chemical structural formula is as follows:
azelastine hydrochloride is an antihistamine medicine, fluticasone propionate is a glucocorticoid medicine, and can be used for treating seasonal allergic rhinitis and perennial allergic rhinitis. In recent years, the FDA approved a compound nasal spray of fluticasone propionate hydrochloride developed by MEDA corporation, with trade name: dymista, containing an H1 receptor antagonist and a corticoid, was administered by spraying 1 drop into each nostril at each time and 2 times daily. The effectiveness and safety of Dymista has been evaluated in several studies for the treatment of seasonal allergic rhinitis in people over 12 years of age, which is twice as effective as the spray currently on the market, and which can systematically improve the ocular and nasal symptoms of patients within six days.
The difficulty of checking related substances of the compound nasal spray is that the impurities possibly generated by azelastine hydrochloride and fluticasone propionate are more, the impurities comprise impurity A, impurity B, impurity C, impurity D and impurity E of the azelastine hydrochloride, and impurity B, impurity C, impurity D and impurity E of the fluticasone propionate, and the fluticasone propionate in the compound nasal spray is in a suspension state and is not easy to degrade; the azelastine hydrochloride is in a solution state, is possibly oxidized and degraded to generate 2 oxidation impurities which are isomers, and is not easy to separate from the azelastine, and auxiliary materials of phenethyl alcohol and benzalkonium chloride in the preparation can generate peaks in a chromatographic system, and the impurities are not easy to completely separate.
At present, the analysis and detection methods EP, JP and ChP for related substances of azelastine hydrochloride have load, and the analysis and detection methods EP, USP and EP for related substances of fluticasone propionate have load; however, no related substance related literature reports of the azelastine hydrochloride and fluticasone propionate compound preparation exist so far. All impurities and auxiliary materials in the compound preparation cannot be completely separated and detected by adopting the methods in the pharmacopoeias. Therefore, the prior art lacks a related substance detection method of the compound nasal spray of the azelastine hydrochloride and fluticasone propionate.
Therefore, the method for separating and measuring the two components and related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate is developed, and has important significance for the quality control of the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate.
Disclosure of Invention
In view of the above, the invention aims to provide a method for separating and measuring two components and related substances in a compound nasal spray of azelastine hydrochloride and fluticasone propionate.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for separating and measuring two components and related substances in a compound nasal spray of azelastine hydrochloride and fluticasone propionate comprises the steps of carrying out gradient elution by taking octadecylsilane chemically bonded silica as a fixed phase and taking a mobile phase A and a mobile phase B as mobile phases to carry out solid-liquid separation, wherein the mobile phase A is a potassium hexafluorophosphate solution, and the mobile phase B is an organic solvent; the two groups are azelastine hydrochloride and fluticasone propionate; the related substances are one or more of impurity A, impurity B, impurity C, impurity D and impurity E of azelastine hydrochloride, two oxidation impurities of azelastine hydrochloride, and impurity B, impurity C, impurity D and impurity E of fluticasone propionate.
The difficulty of checking related substances of the compound nasal spray is that the impurities possibly generated by azelastine hydrochloride and fluticasone propionate are more, the impurities comprise impurity A, impurity B, impurity C, impurity D and impurity E of the azelastine hydrochloride, and impurity B, impurity C, impurity D and impurity E of the fluticasone propionate, and the fluticasone propionate in the compound nasal spray is in a suspension state and is not easy to degrade; the azelastine hydrochloride is in a solution state, is possibly oxidized and degraded to generate 2 oxidation impurities which are isomers, and is not easy to separate from the azelastine, and auxiliary materials of phenethyl alcohol and benzalkonium chloride in the preparation can generate peaks in a chromatographic system, and the impurities are not easy to completely separate.
Further, the gradient elution was set as follows:
volume of mobile phase A and mobile phase B
As a preference, the gradient elution is set as follows:
further, the concentration of the potassium hexafluorophosphate solution is 0.01mol/l to 0.05 mol/l.
As a preference, the concentration of the potassium hexafluorophosphate solution is 0.02 mol/l.
Further, the pH value of the potassium hexafluorophosphate solution is 2.5-4.0.
Preferably, the pH of the potassium hexafluorophosphate solution is 3.0.
Further, the organic solvent is acetonitrile or/and methanol.
Preferably, the organic solvent is acetonitrile.
The invention also aims to provide a method for separating and measuring two components and related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate by utilizing a high performance liquid chromatography, wherein an adopted chromatographic column takes octadecylsilane chemically bonded silica as a filler, and a potassium hexafluorophosphate solution and an organic solvent as mobile phases for gradient elution, and the gradient elution enters a detector for detection; the related substances are impurity A, impurity B, impurity C, impurity D and impurity E of azelastine hydrochloride, two oxidation impurities of azelastine hydrochloride, and impurity B, impurity C, impurity D and impurity E of fluticasone propionate.
Further, before separation and measurement, a reference substance and/or a sample to be measured are dissolved firstly, a 0.1% phosphoric acid acetonitrile solution is adopted to dissolve the sample to be measured, and a 0.1% phosphoric acid water solution-acetonitrile is adopted to prepare a reference solution; the volume ratio of the 0.1% phosphoric acid aqueous solution to acetonitrile is 1: 1.
Further, the particle size of the octadecylsilane chemically bonded silica is 3-5 μm, and the length of the chromatographic column is 150-250 mm; the temperature of the chromatographic column box is 20-40 ℃.
Preferably, the particle size of the octadecylsilane chemically bonded silica is 5 μm, and the length of the chromatographic column is 250 mm; the column box temperature of the chromatographic column is 30 ℃.
Preferably, the size of the chromatographic column is 250mm × 4.6mm, 5 μm.
Further, the flow rate of the mobile phase is 0.8 ml/min-1.5 ml/min; the detector is an ultraviolet detector, and the detection wavelength of the detector is 239nm or/and 210 nm.
Preferably, the flow rate of the mobile phase is 1.0 ml/min; the detection wavelength of the detector is 239 nm.
As a preferable method, the method for separating and measuring two components and related substances in the compound nasal spray of azelastine hydrochloride and fluticasone propionate by using the high performance liquid chromatography specifically comprises the following steps:
1) taking appropriate amounts of azelastine hydrochloride and related impurities A, B, C, D, E and 2 oxidized impurities as reference substances, dissolving with 0.1% phosphoric acid solution-acetonitrile (50:50), and preparing into mixed solution containing 0.5mg of azelastine hydrochloride and 5ug of impurities per ml as system applicability solution 1;
2) dissolving a fluticasone propionate USP system applicability mixed standard product (which comprises fluticasone propionate and related impurities B, C, D and E) in 0.1% phosphoric acid solution-acetonitrile (50:50) to prepare a solution containing 0.2mg in each 1ml as a system applicability solution 2;
3) control solution: weighing appropriate amount of azelastine hydrochloride and fluticasone propionate reference substances, adding 0.1% phosphoric acid solution-acetonitrile (50:50) to dissolve and dilute to a mixed solution containing about 2.5ug of azelastine hydrochloride and 0.9ug of fluticasone propionate per 1 ml;
4) taking a proper amount of phenethyl alcohol reference substance and benzalkonium chloride reference substance, adding 0.1% phosphoric acid solution-acetonitrile (50:50) to dissolve, and preparing into a solution containing about 1.25mg of phenethyl alcohol and 0.05mg of benzalkonium chloride per 1ml as blank adjuvant solution;
5) taking a proper amount of a sample to be tested (a compound composition containing azelastine hydrochloride and fluticasone propionate), dissolving the sample with 0.1% of phosphoric acid acetonitrile solution, and preparing a test solution containing 0.5mg of azelastine hydrochloride or 0.18mg of fluticasone propionate per 1 ml;
6) respectively taking the system applicability solutions 1 and 2, the reference solution, the sample solution and the blank auxiliary material solution, injecting into a liquid chromatograph, performing gradient elution according to the chromatographic conditions of the invention (the chromatographic column filler is octadecylsilane chemically bonded silica, the column length is 250mm, the detection wavelength is 239nm, 0.02mol/l potassium hexafluorophosphate solution (the pH value is adjusted to 3.0 by dilute phosphoric acid) is taken as a mobile phase A and acetonitrile is taken as a mobile phase B, the gradient elution proportion is shown in table 1, the flow rate of the mobile phase is 1.0ml/min, the temperature of a column incubator is 30 ℃, and the sample injection volume is 20 mu l), calculating the content of each known impurity in the sample according to the reference external standard method with a correction factor, and calculating the content of other single impurities and the content of other impurities and other impurities according to the reference external standard method.
TABLE 1 volume of gradient elution mobile phase A and mobile phase B
The invention also aims to provide a reagent composition for solid-liquid separation and determination of two components and related substances in the compound nasal spray of azelastine hydrochloride and fluticasone propionate, which consists of the following reagents:
reagent A: potassium hexafluorophosphate solution;
and (3) reagent B: an organic solvent;
the concentration of the potassium hexafluorophosphate solution is 0.01-0.05 mol/l; the pH value of the potassium hexafluorophosphate solution is 2.5-4.0; the organic solvent is acetonitrile or/and methanol.
The application of a stationary phase and a mobile phase in separation and/or determination of two components and related substance chromatography in a compound nasal spray of azelastine hydrochloride and fluticasone propionate is characterized in that the stationary phase is octadecylsilane chemically bonded silica, the mobile phase is a potassium hexafluorophosphate solution and an organic solvent, and the concentration of the potassium hexafluorophosphate solution is 0.01-0.05 mol/l; the pH value of the potassium hexafluorophosphate solution is 2.5-4.0; the organic solvent is acetonitrile or/and methanol.
The invention has the beneficial effects that: the method for separating and measuring the two components and the related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate overcomes the defects of the prior art, the two components and the related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate are separated and measured by using the high performance liquid chromatography, the separation and the detection of the two components and 11 related substances of the azelastine hydrochloride and the fluticasone propionate can be realized at the same time, and auxiliary materials possibly appearing in a preparation can be effectively separated. The method has the advantages of good separation degree, strong specificity and high sensitivity; the method has the advantages of simple operation, simplicity, convenience and rapidness, and has important significance for controlling the quality of the compound nasal spray medicine of the azelastine hydrochloride and fluticasone propionate.
Drawings
FIG. 1 is an HPLC chart of a system suitability solution 1 in examples 1 and 2.
FIG. 2 is a HPLC chart of the system suitability solution 2 in example 1.
FIG. 3 is an HPLC chart of a solution of the hollow white excipient of example 1.
FIG. 4 is a HPLC chart of related substances of the compound nasal spray of fluticasone propionate hydrochloride determined in example 1.
FIG. 5 is an HPLC chart of 0.1% phosphoric acid solution-acetonitrile (50:50) solution in examples 1 and 2.
Figure 6 is an HPLC profile of azelastine hydrochloride in example 2.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
In the following examples, the apparatus and chromatographic conditions used are as follows:
(1) high performance liquid chromatograph: LC2010A (SHIMADZU);
a detector: UV;
a chromatographic workstation: and (6) LC Solution.
(2) A chromatographic column: octadecylsilane chemically bonded silica is used as a filler, the particle size of silica particles is 5 μm, the length of a chromatographic column is 250mm, and the diameter is 4.6 mm.
(3) Mobile phase
Solution A: 0.02mol/l potassium hexafluorophosphate solution (pH adjusted to 3.0 with dilute phosphoric acid);
an organic solvent B: and (3) acetonitrile.
(5) Detection conditions
Mobile phase: mixing the solution A and the organic solvent B according to the volume ratio shown in the following table to be used as a mobile phase for gradient elution;
flow rate: 1.0 ml/min;
temperature of the column oven: 30 ℃;
detector detection wavelength after elution: 239 nm;
sample introduction amount: 20 μ l.
Example 1 detection of two components and related substances in Compound nasal spray of Fluticasone propionate hydrochloride
1) Appropriate amounts of azelastine hydrochloride and related impurities A, B, C, D, E and 2 oxidized impurities as reference substances are dissolved in 0.1% phosphoric acid solution-acetonitrile (50:50) to prepare a mixed solution containing 0.5mg of azelastine hydrochloride and 5ug of impurities per ml as a system applicability solution 1.
2) Taking a fluticasone propionate USP system applicability mixed standard product (comprising fluticasone propionate and related impurities B, C, D and E), adding 0.1% phosphoric acid solution-acetonitrile (50:50) for dissolving, and preparing solution containing 0.2mg in each 1ml as system applicability solution 2.
3) Taking a proper amount of phenethyl alcohol reference substance and benzalkonium chloride reference substance, adding 0.1% phosphoric acid solution-acetonitrile (50:50) for dissolving, and preparing into a solution containing about 1.25mg of phenethyl alcohol and 0.05mg of benzalkonium chloride per 1ml as blank adjuvant solution.
4) Control solution: appropriate amounts of azelastine hydrochloride and fluticasone propionate controls were weighed, dissolved in 0.1% phosphoric acid solution-acetonitrile (50:50) and diluted to a solution containing about 2.5ug azelastine hydrochloride and 0.9ug fluticasone propionate per 1 ml.
5) Shaking 1 bottle, collecting 10.0g of the product, weighing precisely, adding 0.1% phosphoric acid acetonitrile solution 10ml, ultrasonically treating for 10min to dissolve the main drug, centrifuging at 4000 rpm for 10min, collecting supernatant, filtering with 0.45 μm filter membrane, and collecting filtrate as sample solution.
6) Injecting the sample solution into a high performance liquid chromatograph, and recording a chromatogram according to the chromatographic conditions of the invention. And calculating the content of each known impurity, unknown impurity and other impurities in the test sample according to a reference substance method with a correction factor.
The calculation formula is as follows:
known impurity calculation formula of azelastine hydrochloride: 100 (FAt1/As1) 0.5;
the calculation formula of the known impurities of the fluticasone propionate is as follows: 100 (FAt2/As2) 0.5;
unknown impurities and other impurities and a calculation formula: 100 (FAt3/As3) 0.5;
in the formula:
at1 is the peak area of each known impurity peak of azelastine hydrochloride in the test solution;
at2 is the peak area of each known impurity peak of fluticasone propionate in the test solution;
at3 is the peak area of each other impurity peak in the test solution;
as1 is the peak area of azelastine in the control solution;
as2 is the peak area of fluticasone propionate in the control solution;
as3 is the sum of the peak areas of azelastine and fluticasone propionate in the control solution;
f is a correction factor for each impurity.
Example 2 detection of azelastine hydrochloride-related substances
A chromatographic column: octadecylsilane chemically bonded silica as filler (SHIMADZU VP-ODS, 250 mm. times.4.6 mm, 5 μm);
detection wavelength: 239 nm;
sample introduction amount: 20 mu l of the mixture;
mobile phase: solution A: 0.02mol/l potassium hexafluorophosphate solution (pH adjusted to 3.0 with dilute phosphoric acid); an organic solvent B: acetonitrile, gradient elution according to the following table:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 8 | 60 | 40 |
| 30 | 60 | 40 |
| 50 | 20 | 80 |
| 60 | 20 | 80 |
| 61 | 75 | 25 |
| 70 | 75 | 25 |
1) Appropriate amounts of azelastine hydrochloride and related impurities A, B, C, D, E and 2 oxidized impurities as reference substances are dissolved in 0.1% phosphoric acid solution-acetonitrile (50:50) to prepare a mixed solution containing 0.5mg of azelastine hydrochloride and 5ug of impurities per ml as a system applicability solution 1.
2) Taking a proper amount of azelastine hydrochloride raw material medicine, dissolving with 0.1% phosphoric acid solution-acetonitrile (50:50), and preparing into a test solution containing 0.5mg of azelastine hydrochloride per 1 ml.
3) 1ml of the test solution was precisely measured, placed in a 200ml measuring flask, and diluted to the mark with 0.1% phosphoric acid solution-acetonitrile (50:50) as a control solution.
4) And (3) respectively taking the system applicability solution, the control solution and the test solution, injecting the solutions into a liquid chromatograph, measuring according to the chromatographic conditions, and recording a chromatogram. And calculating the content of each known impurity, unknown impurities and other impurities in the test sample according to a self-dilution comparison method with a correction factor.
The calculation formula is as follows:
100*(FAt/As)*0.5；
in the formula:
at is the peak area of each impurity peak in the test solution;
as is the peak area of azelastine in the control solution;
f is a correction factor for each impurity.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (5)
1. The method for separating and measuring two components and related substances in the compound nasal spray of the azelastine hydrochloride and the fluticasone propionate is characterized in that a chromatographic column taking octadecylsilane chemically bonded silica as a fixed phase is adopted, gradient elution is carried out by taking a mobile phase A and a mobile phase B as mobile phases, high performance liquid chromatography separation is carried out, and then the mixture enters a detector for detection; the mobile phase A is potassium hexafluorophosphate solution, and the mobile phase B is organic solvent; the detector is an ultraviolet detector, and the detection wavelength of the detector is 239 nm;
the two groups are azelastine hydrochloride and fluticasone propionate; the related substances are impurity A, impurity B, impurity C, impurity D and impurity E of azelastine hydrochloride, two oxidation impurities of azelastine hydrochloride, and impurity B, impurity C, impurity D and impurity E of fluticasone propionate; the concentration of the potassium hexafluorophosphate solution is 0.01-0.05 mol/l; the organic solvent is acetonitrile or/and methanol;
the gradient elution was set as follows:
2. the method according to claim 1, wherein the pH of the potassium hexafluorophosphate solution is 2.5 to 4.0.
3. The method of claim 1, wherein before the separation determination, the reference substance and the sample to be tested are dissolved, the sample to be tested is dissolved by using acetonitrile solution with 0.1% phosphoric acid by mass fraction, and the reference solution is prepared by using 0.1% phosphoric acid water solution-acetonitrile by mass fraction; the volume ratio of the phosphoric acid aqueous solution with the mass fraction of 0.1% to the acetonitrile is 1: 1.
4. The method of claim 1, wherein the octadecylsilane chemically bonded silica has a particle size of 3 to 5 μm, and the column length of the chromatographic column is 150 to 250 mm; the temperature of the chromatographic column box is 20-40 ℃.
5. The method of claim 1, wherein the mobile phase flow rate is 0.8ml/min to 1.5 ml/min.
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| CN103134864A (en) * | 2011-11-30 | 2013-06-05 | 天津金耀集团有限公司 | Detection method for salmeterol fluticasone compound inhalant related substances |
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