CN114924020B - Quality control method for diastereoisomer in arformoterol tartrate inhalation solution - Google Patents
Quality control method for diastereoisomer in arformoterol tartrate inhalation solution Download PDFInfo
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- CN114924020B CN114924020B CN202210599391.8A CN202210599391A CN114924020B CN 114924020 B CN114924020 B CN 114924020B CN 202210599391 A CN202210599391 A CN 202210599391A CN 114924020 B CN114924020 B CN 114924020B
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- arformoterol tartrate
- arformoterol
- phosphate
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- FCSXYHUNDAXDRH-OKMNHOJOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 FCSXYHUNDAXDRH-OKMNHOJOSA-N 0.000 title claims abstract description 214
- 229960000612 arformoterol tartrate Drugs 0.000 title claims abstract description 214
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
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- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 1
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- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a method for controlling the quality of an arformoterol tartrate inhalation solution or the production process of the arformoterol tartrate inhalation solution by high performance liquid chromatography detection using a chromatographic column based on octadecyl bonded ethylene bridge hybrid particles. The method of the present invention can achieve excellent resolution, high sensitivity and low detection limit. The method has important significance for improving the quality of the arformoterol tartrate inhalation solution product.
Description
Technical Field
The invention relates to a quality control method of a medicament, in particular to a method for performing quality control on an arformoterol tartrate inhalation solution or a production process of the arformoterol tartrate inhalation solution, and more particularly to a method for performing quality control on the arformoterol tartrate inhalation solution or the production process of the arformoterol tartrate inhalation solution by using high performance liquid chromatography detection of a chromatographic column based on octadecyl bonded ethylene bridge hybrid particles.
Background
Arformoterol tartrate is a drug against bronchial diseases, which produces a strong and lasting antiasthmatic effect mainly by acting on β 2 receptors.
The arformoterol tartrate inhalation solution is mainly used for clinically treating bronchospasm of patients with Chronic Obstructive Pulmonary Disease (COPD), the active ingredient of the arformoterol inhalation solution is arformoterol, and the main advantages of the formulation of the arformoterol inhalation solution include simple formula composition, quick response, small administration dosage, low side effect and the like. In the production of arformoterol tartrate solution formulations, there is a need for a method of quality control of arformoterol tartrate diastereoisomeric impurities that may be present in the arformoterol tartrate solution formulations produced.
Disclosure of Invention
The method for quality control of an arformoterol tartrate inhalation solution or a process for producing an arformoterol tartrate inhalation solution according to the present invention is embodied by the following aspects or embodiments.
In one aspect, the present invention provides a method for quality control of an arformoterol tartrate inhalation solution or a process for the production of an arformoterol tartrate inhalation solution, wherein the method comprises the step of determining the content of diastereomers in the arformoterol tartrate inhalation solution by high performance liquid chromatography, wherein the detection conditions of the high performance liquid chromatography comprise:
-a chromatographic column: waters Xbridge Peptide BEH 300A C18, with a specification of 4.6X 150mm,3.5 μm;
-a mobile phase: a mixed solution of a phosphate solution and acetonitrile, wherein the pH value of the phosphate solution is 11.0-12.0, and the volume ratio (V/V) of the phosphate solution to the acetonitrile is 88/12-80/20; preferably, the volume ratio (V/V) of the phosphate solution to the acetonitrile is 85/15;
-mobile phase flow rate: 0.5-1.5 ml/min;
column temperature of the column: 25-60 ℃;
-the detection wavelength: 220-230 nm; preferably, the detection wavelength is: 225nm; and
-sample size: 50-100 mul.
In some embodiments, the diastereomer of the arformoterol tartrate inhalation solution is selected from at least one of:
in some embodiments, the high performance liquid chromatography is performed in an isocratic elution mode.
In some embodiments, the phosphate solution is prepared from one or more of the following: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, and hydrates thereof; preferably, the phosphate solution is selected from the group consisting of one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, and hydrates thereof; more preferably, the phosphate solution is selected from the group consisting of potassium phosphate trihydrate.
In some embodiments, the high performance liquid chromatography is performed using a high performance liquid chromatograph of Agilent 1260 II or Waters e2695; and/or the detector adopted by the high performance liquid chromatography is a VWD detector.
In some embodiments, the method further comprises one or more of the following steps:
(a) Preparing a blank solution, a sensitivity solution, a resolution solution, a reference solution and an arformoterol tartrate inhalation solution, wherein:
-the blank solution is a mixed solution of citric acid and its salts;
-the control solution is prepared by dissolving arformoterol tartrate control in a mixed solution of phosphate solution and acetonitrile, and diluting to a certain concentration with the blank solution;
-the sensitivity solution is prepared by dilution of the control solution to a certain concentration; and
-the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereoisomer;
(b) Continuously and sequentially feeding the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution into a chromatograph, sequentially analyzing the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution by adopting a high performance liquid chromatography, and recording a chromatogram;
(c) And calculating the content of the diastereoisomer in the arformoterol tartrate solution according to the peak area of the chromatogram by an external standard method (a standard curve method or an external standard point method).
In some embodiments, the amount of diastereomer in the arformoterol tartrate solution is considered to be not meeting quality control standards if the amount of diastereomer in the arformoterol tartrate solution is greater than 1.0% (i.e., 0.075 μ g/ml or 0.075 ppm).
In some embodiments, the methods have a detection sensitivity (limit of quantitation) as low as 0.01% and a detection limit as low as 0.00333%, and a degree of separation of greater than 5.0.
The method of the invention can meet the quality control requirements of small-size arformoterol tartrate inhalation solution products, has high sensitivity (the sensitivity (quantification limit) can reach 0.01% (namely a signal-to-noise ratio of more than 10) and be as low as the detection limit of 0.00333%), excellent separation degree (the separation degree of arformoterol from the impurity I is far more than 3.0, which ensures that the accurate quantification of the impurity I cannot be interfered by unknown peaks even under accelerated stability condition test), and excellent accuracy, precision and durability (even if different detectors are used, the detection result is hardly influenced even under the error caused by small fluctuation of chromatographic conditions or human factors). In addition, the invention can also meet the requirement of realizing high detection sensitivity under the condition of lower sample injection amount. The method of the invention has important significance for improving the quality of the arformoterol tartrate inhalation solution product.
Drawings
FIG. 1: determining a chromatogram of the diastereoisomer in the arformoterol tartrate inhalation solution by adopting a detection method of Chinese pharmacopoeia analogues;
FIG. 2: determining a chromatogram of the diastereoisomer in the arformoterol tartrate inhalation solution by adopting a detection method of the United states pharmacopoeia and European pharmacopoeia analogues;
FIG. 3: the method is adopted to detect the chromatogram of the diastereoisomer of the solution to be detected (arformoterol tartrate inhalation solution);
FIG. 4: the chromatogram of the diastereomer in the aspirant solution of arformoterol tartrate (100 μ l loading) was determined using a Waters Xbridge C18.6 x 250mm 5 μm column;
FIG. 5: chromatograms of the diastereomers in the arformoterol tartrate inhalation solution (100 μ l loading) were determined using a SUPELCO apHera C18.6 x 150mm 5 μm column;
FIG. 6: detecting a typical chromatogram obtained by the blank solution/blank auxiliary material by adopting the method;
FIG. 7 is a schematic view of: detecting a typical chromatogram obtained by the resolution solution by adopting the method;
FIG. 8: detecting the quantitative limiting solution by adopting the method to obtain a chromatogram;
FIG. 9: detecting the chromatogram obtained by detecting the detection limiting solution by adopting the method;
FIG. 10: detecting a linear relation graph of arformoterol by using the method disclosed by the invention; and
FIG. 11: the linear relationship of diastereomer (impurity I) was detected using the method of the invention.
Detailed Description
The invention aims to realize the quality control of the arformoterol tartrate inhalation solution or the production process of the arformoterol tartrate inhalation solution by measuring the diastereoisomer in the arformoterol tartrate inhalation solution. To achieve stringent quality control requirements, the quality control method of the present invention needs to solve several problems.
Firstly, the invention needs to solve the problem of the separation degree between arformoterol and diastereoisomers in the detection of arformoterol tartrate inhalation solutions. The present inventors have found that arformoterol tartrate inhalation solutions generate impurity I during storage, and that as impurity I grows, a new unknown peak (as shown in fig. 3) appears between the arformoterol and the impurity I chromatographic peak, so that whether it is possible to provide a method with excellent resolution is one of the keys to accurately and quantitatively determine the content of impurity I.
Further, the present invention also needs to solve the problem of sensitivity for diastereomer detection in small-format arformoterol tartrate inhalation solution detection. It has been found in the present invention that for small format product formulations such as arformoterol tartrate inhalation solution (2ml 15 pg), it is desirable to provide a detection method which has a sensitivity of at least 0.1% minimum (i.e. 0.0075 pg/ml or 0.0075ppm, with a reported limit of impurities in quality control of at least 0.1% for product doses up to a maximum of less than 1g per day). If the chromatographic method used for detecting the arformoterol impurity, including the existing method, is used, the sample amount cannot meet the requirement even if the sample amount is adjusted to be 100 mu l at most.
In addition, the problems of short service life, poor reproducibility, low precision, poor tolerance and the like of a chromatographic column in the detection of the arformoterol tartrate inhalation solution also need to be solved. The present invention finds that if a chromatographic column (for example, a octadecyl bonded polyvinyl alcohol type chromatographic column) commonly used in the current methods including the pharmacopoeia analogue detection method is used, the service life of the chromatographic column is short, the tolerance is poor, and the reproducibility and the precision of the result are difficult to meet the requirements.
To this end, the present inventors have developed a method for quality control of arformoterol tartrate inhalation solutions or processes for producing arformoterol tartrate inhalation solutions by high performance liquid chromatography detection using a chromatographic column based on octadecyl-bonded ethylene bridge hybrid particles.
In one aspect, the present invention provides a method for quality control of an arformoterol tartrate inhalation solution or a process for the production of an arformoterol tartrate inhalation solution, the method comprising the step of determining the content of diastereomers of the arformoterol tartrate inhalation solution by high performance liquid chromatography.
In another aspect, the present invention provides a method for detecting the presence of impurities in an arformoterol tartrate inhalation solution, wherein the method comprises the step of determining the presence of impurities in the arformoterol tartrate inhalation solution by high performance liquid chromatography.
In another aspect, the present invention provides a method for detecting diastereoisomers in arformoterol tartrate solution, comprising the step of determining the content of diastereoisomers in arformoterol tartrate solution by high performance liquid chromatography.
In another aspect, the present invention provides a method for detecting the presence of impurities in an arformoterol tartrate inhalation solution, comprising the step of determining the presence of impurities in the arformoterol tartrate inhalation solution by high performance liquid chromatography.
As used herein, the term "Arformoterol Tartrate" is a long-acting β 2-adrenoceptor agonist, a compound useful for the treatment of dyspnea caused by airway obstructive diseases such as bronchial asthma, chronic tracheitis, asthmatic bronchitis, emphysema, etc., with CAS number 201815-49-2. The arformoterol tartrate has the following structural formula:
the term "diastereomer" as used herein refers to a diastereomer of arformoterol tartrate. Because the molecule has two chiral centers, 4 optical configurations are generated in total, wherein the arformoterol is in R, R configuration, and S, S isomer also exists in the arformoterol tartrate inhalation solution; the two formoterol optical isomers in the other two configurations, i.e. the R, S and S, R configurations, are referred to as diastereomers. The diastereoisomer of arformoterol tartrate is considered as an impurity. Herein, the terms "diastereomer of arformoterol tartrate", "diastereomer impurity", "impurity of arformoterol tartrate", and "impurity", "impurity I" have the same meaning and may be used interchangeably. The structural formula of the arformoterol tartrate diastereoisomer is as follows:
in some embodiments, the diastereomer or impurity in the arformoterol tartrate solution or inhalation solution is selected from at least one of:
in some embodiments, the diastereomer or impurity in the arformoterol tartrate solution or inhalation solution is a mixture of:
in this context, the term "arformoterol tartrate inhalation solution" refers to a solution which is passed through an atomizer to produce a continuous co-inhalation aerosol. For example, the arformoterol tartrate inhalation solution is a solution which is inhaled by directly pouring an arformoterol tartrate liquid medicine into an atomizing cup and atomizing by an atomizer.
The term "High Performance Liquid Chromatography" as used herein is known in the english name High Performance Liquid Chromatography (HPLC), also known as "High pressure Liquid Chromatography", "High Performance Liquid Chromatography", and the like. The principles, operating methods and process conditions of high performance liquid chromatography can be found, for example, in: zhang Danya, yangjixing, classification by high performance liquid chromatography and working principle [ J ] chemical engineering management, 2017 (20): 113; morning, zhang Ying, jue et al, laboratory HPLC safety usage and precautions [ J ] Guangzhou chemical engineering, 2022,50 (4): 115-117,120.DOI, 10.3969/J. Issn.1001-9677.2022.04.038; and yangyjuan, and the attention for maintenance and use of HPLC. Modern foods, 2015 (19), 66-68. Doi. The operation of high performance liquid chromatography and the conditions required to achieve chromatographic separation will be well within the skill of the art.
The stationary phase in a chromatography column is usually composed of solid packing, which achieves separation of components by the difference in the type of force and strength of action between the sample molecules. Depending on the packing, the column can be divided into: (1) silica gel column; (2) a chromatographic column chemically bonded to the stationary phase; (3) a polymer ball chromatographic column; (4) a polymer-coated chromatography column; and (5) chromatographic columns of the microparticle porous carbon filler, wherein the chromatographic columns of the chemically bonded stationary phase are further divided into non-polar bonded chromatographic columns (octadecylsilane bonded silica is the most commonly used non-polar reversed-phase chromatographic column) and polar bonded chromatographic columns (commonly used amino columns, cyano columns, glycol-based columns and the like). Alternatively, the column may be classified into silica gel column, polymer column and other inorganic column, wherein the silica gel column is mainly based on silica gel, the surface of the silica gel column can be bonded with various polar or weakly polar functional groups (such as C18 (ODS), C8, C4, C6H5 or n-ethane, chlorine, dichloromethane, etc.), and the polymer column is mostly polyethylene-divinylbenzene or polymethylpropionate; other inorganic fillers such as graphitized carbon fillers, alumina, zirconia, and the like.
The term "octadecyl bonded ethylene bridged hybrid particle" as used herein is a high purity silica gel filler synthesized from two high purity monomers using inorganic, organic hybrid particle technology, which is mainly applied to the analysis of peptides and proteins. The invention relates to a chromatographic column adopting octadecyl bonded ethylene bridge impurity particles, belonging to a silica gel chromatographic column.
In some embodiments, the high performance liquid chromatography detection conditions comprise the use of octadecyl bonded ethylene bridged hybrid particles as packing material for the stationary phase of the chromatography column. In some embodiments, the column using octadecyl bonded ethylene bridge hybrid particles as the stationary phase packing is Waters XBridge Peptide BEH 300A C18, specification 4.6X 150mm,3.5 μm.
In some embodiments, the high performance liquid chromatography detection conditions comprise the use of octadecyl bonded ethylene bridge hybrid particles as a packing material for the stationary phase of the chromatography column. In some embodiments, the chromatographic columns using octadecyl bonded ethylene bridge hybrid particles as stationary phase packing material are YMC Triart C18, YMC Triart ExRs C18 and Phenomenex Titank C18, with a specification of 4.6X 150mm,3.5 μm.
In some embodiments, the chromatographic column employing octadecyl bonded ethylene bridged hybrid particles as the stationary phase filler is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart ExRs C18, and Phenomenex titanium C18. In some embodiments, the chromatography column using octadecyl bonded ethylene bridge hybrid particles as stationary phase filler has a specification of 4.6 x 150mm,3.5 μm, and the chromatography column is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart ExRs C18, and Phenomenex titanium C18.
The inventor of the invention proves through experiments that no matter the current test method of analogs in Chinese, united states or European pharmacopoeia (HPLC using octadecyl bonded polyvinyl alcohol chromatographic column) or the test method of bulk pharmaceutical manufacturers (HPLC using octadecyl bonded polyvinyl alcohol chromatographic column) is adopted, when the arformoterol tartrate solution is tested, the obtained chromatogram shows that the main peak of the arformoterol tartrate and the diastereoisomer impurity peak thereof cannot be separated from each other by baseline, and the accurate quantitative detection of diastereoisomers in the arformoterol tartrate solution cannot be realized.
The present inventors speculate that the above methods are all detection methods for testing arformoterol tartrate bulk drugs and not for diastereomers in arformoterol tartrate inhalation solutions. For example, most of the above methods are methods for detecting diastereoisomers in arformoterol tartrate, the concentration of the sample of the drug substance is 100 μ g/ml in normal injection, and the difference between the concentration of the sample of the drug substance and the concentration of the sample of the inhalation solution of arformoterol tartrate is 13 times that of the test solution of arformoterol tartrate in normal injection. Furthermore, in the above method only 50ppm diastereomer in the arformoterol tartrate solution for inhalation was detected, but in contrast to the method of the present invention, 0.0075ppm diastereomer in the arformoterol tartrate solution for inhalation was detected by a factor of 6666.
The present inventors have unexpectedly found through experiments that the HPLC method can achieve detection of diastereoisomers in arformoterol solution when using octadecyl bonded ethylene bridge hybrid particles as a packing material for a column stationary phase, which is commonly used in the analysis of peptides and proteins, and the detection results show that the method can achieve excellent resolution, sensitivity and accuracy at the same time. The lowest detection sensitivity (limit of quantitation) of the method can reach 0.01 percent and the detection limit can be as low as 0.00333 percent; and in most cases a degree of separation of more than 5.0 can be achieved.
The term "limit of detection" as used herein refers to the lowest concentration or lowest amount of a component being detected by an assay under specified experimental conditions.
The term "limit of quantitation" as used herein means that the analytical method can quantitatively determine the lowest concentration or lowest amount of a component to be measured in a sample. The lower the limit of quantitation, the higher the sensitivity.
The high sensitivity and low detection limit of the method of the invention are critical for arformoterol tartrate inhalation solutions, especially small format arformoterol tartrate inhalation solutions. The term "small format formulation" or "small format arformoterol tartrate inhalation solution" as used herein refers to a formulation product containing an active pharmaceutical ingredient at a concentration of from 5 μ g/ml to 15 μ g/ml. For example, a 2ml specification for an arformoterol tartrate inhalation solution of 2ml. This specification can be administered twice daily, so that the maximum single daily intake is equivalent to 4ml, or 30 μ g.
Furthermore, in this context, the active pharmaceutical ingredient in the arformoterol tartrate inhalation solution is calculated as arformoterol. Thus, for example, when reference is made in the examples to a reference where 10.8mg of arformoterol tartrate (molecular weight of 494.5) is weighed, this is in fact equivalent to a reference where 7.5mg of arformoterol (molecular weight of 344.5) is weighed.
In some embodiments, the arformoterol tartrate solution is a small format arformoterol tartrate inhalation solution. In some embodiments, the arformoterol tartrate inhalation solution is a small format arformoterol tartrate inhalation solution. In some embodiments, the arformoterol tartrate inhalation solution is a solution having a volume ratio of 2ml: arformoterol tartrate inhalation solution at a format of 15 μ g. In some embodiments, the arformoterol tartrate solution has an arformoterol concentration of from 5 μ g/ml to 15 μ g/ml. In some embodiments, the arformoterol tartrate inhalation solution has an arformoterol concentration of from 5 μ g/ml to 15 μ g/ml. In some embodiments, the arformoterol tartrate solution has an arformoterol concentration of 7.5 μ g/ml. In some embodiments, the arformoterol tartrate inhalation solution has an arformoterol concentration of 7.5 μ g/ml.
In some embodiments, the high performance liquid chromatography detection conditions comprise the use of isocratic elution.
In some embodiments, the high performance liquid chromatography detection conditions comprise high performance liquid chromatography. In some embodiments, the hplc is selected from one of: agilent 1260 II, waters e2695, dalanimate 3000, shimadzu LC-2050C/2060C or any other chromatography instrument of the same type.
In some embodiments, the high performance liquid chromatography detection conditions include using a mixed solution of a phosphate solution and acetonitrile as a mobile phase. In some embodiments, the phosphate solution has a pH of 10.0 to 12.5. In some embodiments, the pH of the phosphate solution is selected from the following values: 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, and 12.5. In some embodiments, the phosphate solution has a pH selected from the range consisting of any two of the following values: 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4 and 12.5. For example, the phosphate solution has a pH selected from the range consisting of a value of 11.0 and a value of 12.0, i.e., the phosphate solution has a pH of 11.0 to 12.0. The inventors have shown through experiments that the higher the pH of the mobile phase, the more beneficial the arformoterol separation from impurity I. Thus, in some embodiments, the phosphate solution has a pH selected from 12.0.
In some embodiments, the volume ratio (V/V) of the phosphate solution to the acetonitrile is 90/10 to 75/25. In some embodiments, the volume ratio (V/V) of the phosphate solution to the acetonitrile is selected from the following values: 90/10, 89/11, 88/12, 87/13, 86/14, 85/15, 84/16, 83/17, 82/18, 81/19, 80/20, 79/21, 78/22, 77/23, 76/24, and 75/25. In some embodiments, the volume ratio (V/V) of the phosphate solution to the acetonitrile is selected from the range consisting of any two of the following values: 90/10, 89/11, 88/12, 87/13, 86/14, 85/15, 84/16, 83/17, 82/18, 81/19, 80/20, 79/21, 78/22, 77/23, 76/24, and 75/25. For example, the volume ratio (V/V) of the phosphate solution to the acetonitrile is selected from the range consisting of a value of 88/12 and a value of 80/20, i.e., the volume ratio (V/V) of the phosphate solution to the acetonitrile is from 88/12 to 80/20. In some embodiments, the volume ratio (V/V) of the phosphate solution to the acetonitrile is 85/15.
In some embodiments, the phosphate solution is prepared from one or more of the following: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, and hydrates thereof. In some embodiments, the phosphate solution is prepared from one or more of the following: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, and hydrates thereof. In some embodiments, the phosphate solution is selected from the group consisting of potassium phosphate trihydrate.
In some embodiments, the phosphate solution is prepared by: taking 5.3g of potassium phosphate trihydrate, adding 1000ml of water, ultrasonically dissolving, uniformly mixing, and adjusting the pH value to 12.0 +/-0.1 by using potassium hydroxide solution or phosphoric acid. In some embodiments, a mixed solution of a phosphate solution and acetonitrile is used as a mobile phase, which is prepared by the following method: taking 5.3g of potassium phosphate trihydrate, adding 1000ml of water, ultrasonically dissolving and uniformly mixing, adjusting the pH value to 12.0 +/-0.1 by using a potassium hydroxide solution or phosphoric acid, and then uniformly mixing according to the volume ratio (V/V) of a phosphate solution to acetonitrile of 85:15 to prepare a mobile phase.
In some embodiments, the high performance liquid chromatography detection conditions comprise using a mobile phase flow rate of 0.5ml/min to 1.5ml/min. In some embodiments, the mobile phase flow rate is selected from the following values: 0.5ml/min, 0.6ml/min, 0.7ml/min, 0.8ml/min, 0.9ml/min, 1ml/min, 1.1ml/min, 1.2ml/min, 1.3ml/min, 1.4ml/min and 1.5ml/min. In some embodiments, the mobile phase flow rate is selected from a range consisting of any two of the following values: 0.5ml/min, 0.6ml/min, 0.7ml/min, 0.8ml/min, 0.9ml/min, 1ml/min, 1.1ml/min, 1.2ml/min, 1.3ml/min, 1.4ml/min and 1.5ml/min. For example, the mobile phase flow rate is selected from the range consisting of a value of 0.9ml/min and a value of 1.1ml/min, i.e., the mobile phase flow rate is 0.9ml/min to 1.1ml/min. In some embodiments, the mobile phase flow rate is 1.0ml/min.
In some embodiments, the high performance liquid chromatography detection conditions comprise using a column temperature of 25 ℃ to 60 ℃. In some embodiments, the column temperature of the chromatography column is a value selected from the group consisting of: 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃,50 ℃, 55 ℃ and 60 ℃. In some embodiments, the column temperature of the chromatography column is in a range selected from any two of the following values: 25 deg.C, 30 deg.C, 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C and 60 deg.C. For example, the column temperature is selected from the range consisting of a value of 25 ℃ and a value of 35 ℃, i.e. the column temperature is 25 ℃ to 35 ℃. In some embodiments, the column temperature of the chromatography column is between 25 ℃ and 35 ℃. In some embodiments, the column temperature of the chromatography column is between 28 ℃ and 33 ℃. In some embodiments, the column temperature of the chromatography column is 30 ℃.
In some embodiments, the high performance liquid chromatography detection conditions comprise measuring wavelength using a UV detector. In some embodiments, the detector is selected from one of the following: a VWD detector, DAD detector, PDA detector or any other detector of the same type. In some embodiments, the detector is a VWD detector.
In some embodiments, the high performance liquid chromatography detection conditions comprise using a detection wavelength of 214nm to 230nm. In some embodiments, the detection wavelength is a value selected from the group consisting of: 214nm, 215nm, 216nm, 217nm, 218nm, 219nm, 220nm, 221nm, 222nm, 223nm, 224nm, 225nm, 226nm, 227nm, 228nm, 229nm, and 230nm. In some embodiments, the detection wavelength is a range selected from any two of the following values: 214nm, 215nm, 216nm, 217nm, 218nm, 219nm, 220nm, 221nm, 222nm, 223nm, 224nm, 225nm, 226nm, 227nm, 228nm, 229nm, and 230nm. For example, the detection wavelength is selected from the range consisting of a value of 220nm and a value of 230nm, i.e., the detection wavelength is 220nm to 230nm. In some embodiments, the detection wavelength is 220nm to 230nm. In some embodiments, the detection wavelength is 225nm.
In some embodiments, the high performance liquid chromatography detection conditions comprise using an aqueous solution of methanol as the needle wash. In some embodiments, the needle wash water uses a water-methanol formulated solution with a volume ratio (V/V) of 50.
In some embodiments, the HPLC detection conditions comprise the use of a sample size of 10-100. Mu.l. In some embodiments, the sample size is a value selected from the group consisting of: 10. Mu.l, 15. Mu.l, 20. Mu.l, 25. Mu.l, 30. Mu.l, 35. Mu.l, 40. Mu.l, 45. Mu.l, 50. Mu.l, 55. Mu.l, 60. Mu.l, 65. Mu.l, 70. Mu.l, 75. Mu.l, 80. Mu.l, 85. Mu.l, 90. Mu.l, 95. Mu.l, and 100. Mu.l. In some embodiments, the sample size is in a range selected from any two of the following values: 10. Mu.l, 15. Mu.l, 20. Mu.l, 25. Mu.l, 30. Mu.l, 35. Mu.l, 40. Mu.l, 45. Mu.l, 50. Mu.l, 55. Mu.l, 60. Mu.l, 65. Mu.l, 70. Mu.l, 75. Mu.l, 80. Mu.l, 85. Mu.l, 90. Mu.l, 95. Mu.l, and 100. Mu.l. For example, the amount of sample is selected from the range consisting of a value of 50. Mu.l and a value of 100. Mu.l, i.e., a sample amount of 50. Mu.l to 100. Mu.l. In some embodiments, the sample size is 50 μ l to 100 μ l. In some embodiments, the sample size is 100 μ l.
Experiments prove that compared with an HPLC method adopting an octadecylsilane bonded phase chromatographic column and an octadecylsilane bonded polyvinyl alcohol as a filler, the method can use lower sample injection amount under the same conditions. This suggests that the octadecyl bonding ethylene bridge hybrid particle chromatographic column adopted in the invention has higher peak response, so that the signal-to-noise ratio is higher and the sensitivity is higher under the condition of the same sample volume.
In some embodiments, the high performance liquid chromatography detection conditions comprise the use of one or more of the following conditions, or a combination thereof:
-a chromatography system: agilent 1260 II or Waters e2695 or the same type of instrument
-a chromatography column: peptide separation column with octadecyl group bonded as filler (Waters Xbridge Peptide BEH 300A C18.6mm. Times.150mm, 3.5 μm)
-a mobile phase: mixed solution of phosphate solution and acetonitrile in the volume ratio of 85 to 15, isocratic elution
-a detector: UV light
-the detection wavelength: 225nm
-flow rate: 1.0ml/min
Column temperature: 30 deg.C
-sample size: 100 μ L
-run time: 20min
-needle wash water: water-methanol (50.
In some embodiments, the method for quality control of an arformoterol tartrate inhalation solution of the present invention, the method for quality control of a process for producing an arformoterol tartrate inhalation solution of the present invention, the method for detecting diastereomers in an arformoterol tartrate solution of the present invention, or the method for detecting the presence of impurities in an arformoterol tartrate inhalation solution of the present invention further comprises additional steps.
In some embodiments, the additional steps include the step of preparing a blank solution, a sensitivity solution, a resolution solution, a control solution, and/or an arformoterol tartrate solution. In some embodiments, the blank solution is a mixed solution of citric acid and its salt. In some embodiments, the control solution is prepared by dissolving an arformoterol tartrate control in a mixed solution of a phosphate solution and acetonitrile, and diluting the solution to a certain concentration with a blank solution. In some embodiments, the sensitivity solution is prepared by diluting the control solution to a concentration. In some embodiments, the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereomer.
In some embodiments, the additional step further comprises the step of preparing diluent-1, diluent-2, a test solution, a control stock solution, a control solution, a sensitivity solution, an impurity I stock solution, and/or a resolution solution. Methods for formulating such solutions are known in the art. The solution required for formulation can be selected by the person skilled in the art according to the requirements of the HPLC assay.
In some embodiments, a diluent-1, i.e., a mixed solution of phosphate buffer and acetonitrile is prepared, wherein the volume ratio (V/V) of phosphate buffer to acetonitrile is 84.
In some embodiments, diluent-2 (i.e., a blank solution), a mixed solution of citric acid and its salts, is formulated.
In some embodiments, a stock control (75 μ g/mL) is prepared by dissolving about 10.8mg of the arformoterol tartrate control (equivalent to about 7.5mg arformoterol), accurately weighed, in a 100mL volumetric flask with the appropriate amount of diluent-1.
In some embodiments, a control solution (0.075 μ g/mL) is prepared by precisely transferring 0.1mL of a control stock solution into a 100mL volumetric flask, diluting with diluent-2 to a constant volume, and shaking.
In some embodiments, a sensitivity solution (0.0075 μ g/mL) is prepared by placing 5.0mL of the working control solution in a 50mL volumetric flask, diluting with diluent-2 to a constant volume, and shaking up.
In some embodiments, an impurity I stock solution (37.5 μ g/mL) is prepared by taking about 3.8mg of impurity I control in a 100mL volumetric flask, and dissolving and diluting to the mark with a diluent (water: acetonitrile = 90).
In some embodiments, a separation solution (arformoterol: 7.5 μ g/mL; impurity I:0.075 μ g/mL) is prepared by placing 0.5mL of impurity I stock solution and 10mL of control stock solution in a 100mL volumetric flask, diluting with diluent-2 to a constant volume, and shaking.
In some embodiments, the additional step comprises the step of feeding one or more solutions selected from the group consisting of: a blank solution, a sensitivity solution, a resolution solution, a control solution, and/or the arformoterol tartrate solution to be tested.
In some embodiments, the additional step comprises the step of sequentially feeding the following solutions to the high performance liquid chromatograph: blank solution, sensitivity solution, resolution solution, control solution, arformoterol tartrate solution to be tested and control solution.
In some embodiments, the further step comprises the step of feeding a solution selected from the group consisting of: the kit comprises (1) a blank solution (the sampling frequency is more than or equal to 1 needle), (2) a sensitivity solution (the sampling frequency is more than or equal to 1 needle), (3) a separation degree solution (the sampling frequency is more than or equal to 1 needle), (4) a reference substance solution (the sampling frequency is more than or equal to 6 needles), (5) a test solution (namely the arformoterol tartrate solution to be tested; the sampling frequency is more than or equal to 1 needle; one needle of the reference substance solution is required to be added when the test solution enters 6 needles), and (6) a follow-up reference substance solution (the sampling frequency is more than or equal to 1 needle).
In some embodiments, the further step comprises the step of recording the chromatogram.
In some embodiments, the additional step comprises the step of determining whether there is a chromatographic peak for the diastereomer in the chromatogram of the arformoterol tartrate inhalation solution. In some embodiments, if there is a chromatographic peak of a diastereomer in the chromatogram of the arformoterol tartrate inhalation solution, it is determined that the arformoterol tartrate inhalation solution contains the diastereomer as an impurity.
In some embodiments, the further steps further comprise the step of determining the impurity level in the arformoterol tartrate inhalation solution: when determining that the chromatogram of the arformoterol tartrate inhalation solution has a chromatographic peak of a diastereoisomer, determining the content of the impurity I by an external standard method (external standard one-point method); or calculating the content of the impurity I by a standard curve method.
In some embodiments, the additional step further comprises calculating the amount of diastereomer in the arformoterol tartrate solution by the following method. In one embodiment, the amount of diastereomer in the arformoterol tartrate solution may be calculated using the following formula, for example, as disclosed in the pharmacopoeia.
Wherein, A Supplying: peak area of impurity I in the solution to be detected; a. The For the following steps: the average peak area of arformoterol in the control solution; c For the following steps: concentration of control solution; LC: labeled amount of arformoterol tartrate inhalation solution product.
In some embodiments, if the content of impurity I in the arformoterol tartrate inhalation solution is greater than 1.0% (i.e., 0.075 μ g/ml or 0.075 ppm), impurity I in the arformoterol tartrate inhalation solution is considered to be not in compliance with quality control standards. In some embodiments, if the chromatogram of the arformoterol tartrate inhalation solution has a chromatographic peak consistent with the retention time of known impurity I in the resolution solution, it should not be greater than 1.0% (i.e., 0.075 μ g/ml or 0.075 ppm) by external standard methods without the addition of a correction factor; otherwise it is believed that the impurity I content of the arformoterol tartrate inhalation solution exceeds the quality control requirements. The quality control criteria may be specified by those skilled in the art in accordance with various circumstances. The invented method can be used to implement high standards of quality control standards.
In some embodiments, the present invention provides a method for quality control of an arformoterol tartrate inhalation solution or a process for the production of an arformoterol tartrate inhalation solution, the method comprising the steps of:
(a) Preparing a blank solution, a sensitivity solution, a separation degree solution, a reference solution and an arformoterol tartrate solution, wherein:
-the blank solution is a mixed solution of citric acid and its salts;
-the control solution is prepared by dissolving arformoterol tartrate control in a mixed solution of phosphate solution and acetonitrile and diluting to a certain concentration with the blank solution;
-the sensitivity solution is prepared by dilution of the control solution to a certain concentration; and
-the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereoisomer;
(b) Continuously and sequentially feeding the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution into a chromatograph, sequentially analyzing the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution by adopting a high performance liquid chromatography, recording a chromatogram,
wherein the detection conditions of the high performance liquid chromatography comprise:
packing of the stationary phase of the chromatographic column: octadecyl bonded ethylene bridged hybrid particles;
-a mobile phase: a mixed solution of a phosphate solution and acetonitrile, wherein the pH value of the phosphate solution is 12.0, and the volume ratio (V/V) of the phosphate solution to the acetonitrile is 88/12-85/15;
-mobile phase flow rate: 0.9-1.1 ml/min;
column temperature of the column: 25-35 ℃;
-the detection wavelength: 25-35 ℃; and
-sample size: 50-100 mul;
(c) Calculating the content of the diastereoisomer in the arformoterol tartrate solution according to the peak area of a chromatogram by an external standard point method;
(d) If the diastereomer content of the arformoterol tartrate inhalation solution is greater than 1.0% (i.e. 0.075 μ g/ml or 0.075 ppm), the diastereomer I in the arformoterol tartrate inhalation solution is considered to be not meeting the quality control criteria;
wherein the diastereoisomers in the arformoterol tartrate solution are a mixture of:
in some embodiments, the detection sensitivity (limit of quantitation) of the methods of the invention is as low as 0.1% and the limit of detection is as low as 0.0333%. In some embodiments, the detection sensitivity (limit of quantitation) of the methods of the invention is as low as 0.01% and the limit of detection is as low as 0.00333%. In some embodiments, the degree of separation of the methods of the invention is greater than 3.0. In some embodiments, the degree of separation of the methods of the invention is greater than 4.0. In some embodiments, the method of the invention has a degree of separation of greater than 5.0.
The invention establishes a high performance liquid chromatography detection method capable of accurately and quantitatively detecting diastereoisomers in arformoterol tartrate inhalation solution by using an HPLC (high performance liquid chromatography) technology based on octadecyl bonded ethylene bridge hybrid particles. A series of experiments prove that the method has the advantages of good separation degree, high sensitivity, low detection limit, good specificity, high accuracy, high precision, strong durability and the like, and is suitable for detecting and controlling the quality of the diastereoisomer in the arformoterol tartrate inhalation solution. The method provides a basis for formulating a reasonable quality standard so as to better control and master the product quality and ensure the safety of clinical medication.
Examples
The following examples are intended only to further illustrate the invention and do not limit the scope of the invention to these examples.
Experimental materials and reagents:
examples
The following examples are intended only to further illustrate the invention and do not limit the scope of the invention to these examples.
Experimental materials and reagents:
the starting materials and reagents for use in the present invention may be obtained from commercial sources or formulated by the skilled artisan. In addition, unless otherwise specifically indicated or described, the same names of test materials and reagents mentioned in the examples of the present invention are specifically as follows:
phosphate buffer (mobile phase part): taking 5.3g of potassium phosphate trihydrate, adding 1000ml of water, ultrasonically dissolving and uniformly mixing, and adjusting the pH value to 12.0 +/-0.1 by using a potassium hydroxide solution or a phosphoric acid test solution).
-diluent-1: phosphate buffer (taking sodium dihydrogen phosphate monohydrate 6.10g and disodium hydrogen phosphate dihydrate 1.03g, adding water 1000ml dissolved, with phosphoric acid or sodium hydroxide test solution to adjust the pH value to 6.0 +/-0.1) -acetonitrile (84.
Diluent-2 (blank solution): a blank adjuvant solution of arformoterol tartrate inhalation solution (a mixed solution of citric acid and its salt, prepared by ultrasonic dissolving, mixing, and filtering).
-a sensitivity solution: precisely measuring 5.0ml of the reference substance solution in a 50ml volumetric flask, adding the diluent-2 to be diluted to a scale mark, and shaking up to obtain a sensitive solution of 0.0075 mu g/ml.
-resolution solution: appropriate amount of the arformoterol tartrate reference stock solution and appropriate amount of the impurity I stock solution are respectively put into the same volumetric flask and diluted by the diluent-2 to prepare mixed solution containing 7.5 mu g/ml arformoterol and 0.075 mu g/ml impurity I respectively.
-control solution: precisely measuring a proper amount of reference stock solution in a volumetric flask, and adding a diluent-2 to prepare about a reference stock solution containing 0.075 mu g/ml of arformoterol.
Impurity I localization solution: and (3) taking a proper amount of the impurity I stock solution to be put into a volumetric flask, adding a diluent-2 to a constant volume, and preparing into a positioning solution with the concentration of 0.075 mu g/ml.
The solution to be tested (arformoterol tartrate inhalation solution): arformoterol tartrate inhalation Solution (SUNOVION) was packaged commercially in 5 packs, and the contents were removed and mixed well to prepare the solution to be tested.
Control stock solution: an appropriate amount of arformoterol tartrate reference substance (standard dpharm Co., ltd.) is precisely weighed, and is dissolved by adding diluent-1 in a volumetric flask to prepare a stock solution with the arformoterol concentration of 75 mug/ml.
Impurity I stock solution: an appropriate amount of impurity I control (standardcharm co., ltd.) was weighed into a volumetric flask, and water was added: acetonitrile =90, 10 was dissolved and diluted to the scale to make a 37.5 μ g/ml stock solution of impurity I.
Example 1 detection of diastereoisomers in Arformoterol tartrate inhalation solutions by pharmacopoeia methods for the detection of similar drugs
During a stability study of a commercially packaged arformoterol tartrate inhalation solution product, it was found that the diastereomer (impurity I) in the product had a tendency to increase (zero point-no impurity detected; 1 month-0.21% impurity I; 0.39% for 2 months; 0.48% for 3 months) over a period of time (accelerated conditions-25 ℃/60% rh). In order to carry out quality detection on the production process of the arformoterol tartrate inhalation solution product, particularly the content of impurities in a final product, particularly the product with the specification of 2ml: the detection requirements for a 15 μ g arformoterol tartrate inhalation solution product (at least to achieve a sensitivity requirement of 0.1% concentration (0.0075 μ g/ml)) were first determined for the diastereomers in the arformoterol tartrate inhalation solution using the methods described in the pharmacopoeia for the detection of similar drugs. The detection method of the diastereoisomer (impurity I) disclosed by the arformoterol tartrate bulk drug Manufacturer (MSN) is basically consistent with the detection method recorded by the analogues in the United states and European pharmacopoeias, so that the detection method of the bulk drug manufacturer is not repeatedly tested.
The purpose of this experiment was therefore to test whether a similar drug detection method, which has been described in chinese, us and european pharmacopoeias, can be used for the detection of diastereoisomers (impurity I) in arformoterol tartrate inhalation solutions.
The test methods, conditions and reagents were as follows:
the detection method of the Chinese pharmacopoeia analogue comprises the following steps:
-HPLC method, octadecyl-bonded polyvinyl alcohol chromatography column (Shodex Asahipak ODP-50 e,4.6 x 250mm,5 μm);
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile =88 (v/v) isocratic elution;
-flow rate: 1.0ml/min; column temperature: 30 ℃; detection wavelength: 225nm; sample introduction amount: 100 mul; operating time: and (5) 35min.
Methods for detection of usp analogs:
-HPLC method, octadecyl-bonded polyvinyl alcohol chromatography column (Shodex Asahipak ODP-50 d,4.6 x 150mm,5 μm);
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile =88 (v/v) isocratic elution;
-flow rate: 0.5ml/min; column temperature: 30 ℃; detection wavelength: 225nm; sample introduction amount: 100 mul; operating time: and (5) 35min.
Detecting the solution:
a separation degree solution, namely a mixed solution with the concentration of the arformoterol being 7.5 mu g/ml and the concentration of the impurity I being 0.075 mu g/ml is taken for sample injection analysis.
The results are shown in Table 1 below
TABLE 1
Based on the above experiments, the current test methods for similar drugs in chinese and united states and european pharmacopeia show that the main peak of arformoterol cannot be separated from the peak of its diastereoisomer impurity at baseline, and the detection of diastereoisomers in arformoterol tartrate inhalation solution cannot be realized, and the detection requirement for small dose arformoterol tartrate inhalation solution (e.g. inhalation solution with maximum daily intake (30 μ g)) cannot be met.
Example 2 detection of diastereoisomers in Alformoterol tartrate inhalation solution by HPLC method based on octadecyl bonded ethylene bridge hybrid particles as stationary phase
In order to develop a detection method of arformoterol tartrate inhalation solution products with high sensitivity and high resolution and capable of meeting the maximum daily intake (30 mug), the experiment tests whether the HPLC method using octadecyl bonded ethylene bridge hybrid particles as chromatographic column stationary phase fillers can be used for detecting diastereoisomer (impurity I) in the arformoterol tartrate inhalation solution.
The test methods, conditions and reagents were as follows:
-HPLC method, octadecyl bonded ethylene bridged hybrid particle chromatography column (Waters XBridge Peptide BEH 300A c18,4.6 x 150mm,3.5 μm), agilent 1260 ii (VWD detector) high performance liquid chromatograph;
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile =85:15 (v/v) isocratic elution;
-flow rate: 1.0ml/min; column temperature: 30 ℃; detection wavelength: 225nm; sample injection amount: 100 mul; the running time was 20min.
Samples of the solution to be tested, arformoterol tartrate inhalation Solution (SUNOVION), in accelerated conditions for 3 months, in three batches (batch number: S20C005, S20G005 and S20G 008), the contents of which are taken out and mixed uniformly to prepare the solution to be tested.
And respectively taking a blank solution, a sensitivity solution, a separation degree solution, a reference substance solution and each solution to be detected, carrying out sample injection analysis, and recording a chromatogram. The sample injection process is as follows: the kit comprises (1) a blank solution (the sampling frequency is more than or equal to 1 needle), (2) a sensitivity solution (the sampling frequency is 1 needle), (3) a separation degree solution (the sampling frequency is 1 needle), (4) a reference substance solution (the sampling frequency is 6 needles), (5) a test solution (namely the arformoterol tartrate solution to be tested; the sampling frequency is more than or equal to 1 needle; one needle is required to be added into the test solution for 6 needles, and (6) a follow-up reference substance solution (the sampling frequency is more than or equal to 1 needle).
Subsequently, the content of the impurity I in the test solution was calculated by peak area according to an external standard method (external standard one-point method, see general rules of chinese pharmacopoeia 0512, 2020).
Figure 3 shows a chromatogram for detecting the diastereoisomers of a solution to be tested (arformoterol tartrate inhalation solution) using the method of the invention.
The results of detecting impurity I in the three test solutions are shown in Table 2.
TABLE 2 diastereomer content of arformoterol tartrate in inhalation solution
As can be seen from fig. 3, in the HPLC method using octadecyl bonded ethylene bridge hybrid particles as the chromatographic column stationary phase filler, even if a new unknown peak appears between arformoterol and impurity I, the quantitative detection of impurity I is not interfered because the separation degree of arformoterol and impurity I is excellent; as can be seen from the results in table 2, this method can be accurately used for the detection of the diastereomer (impurity I) in the arformoterol tartrate inhalation solution.
Example 3 detection of diastereoisomers in Arformoterol tartrate inhalation solution method System suitability test
One objective of this experiment was to determine the systematic applicability of the chromatography column using octadecyl bonded ethylene bridge hybrid particles as stationary phase (Waters XBridge Peptide BEH 300A c18,4.6 x 150mm,3.5 μm) for the diastereomer detection method in arformoterol tartrate inhalation solution.
Another objective of this experiment was to examine whether there was a difference in the resolution and sensitivity between the column using octadecyl bonded ethylene bridge hybrid particles as stationary phase (Waters XBridge Peptide BEH 300A C18, 4.6X 150mm,3.5 μm) and the other columns (i.e., octadecyl silane bonded phase column and octadecyl bonded polyvinyl alcohol column). In this experiment, a sensitivity solution and a resolution solution were used for the above three methods.
The determination conditions of the method of the invention are as follows:
-HPLC method, octadecyl bonded ethylene bridged hybrid particle chromatography column (Waters XBridge Peptide BEH 300A c18,4.6 x 150mm,3.5 μm), waters e2695 (PDA detector) high performance liquid chromatograph;
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile =85:15 (v/v) isocratic elution;
-flow rate: 1.0ml/min; column temperature: 30 ℃; detection wavelength: 225nm; sample injection amount: 100 mul; the running time was 20min.
Measurement conditions of comparative method 1:
-HPLC method, octadecylsilane bonded phase chromatography column (Waters Xbridge C18 (4.6 x 250mm,5 μm), waters e2695 (PDA detector) high performance liquid chromatograph;
-a mobile phase: solution a is tetrabutylammonium hydroxide aqueous solution (0.6%, v/v) adjusted to pH 8.5 with phosphoric acid, solution B is acetonitrile, solution a =80 (v/v) isocratic elution;
-flow rate: 1.0ml/min; column temperature: 35 ℃; detection wavelength: 225nm; sample introduction amount: 50 mu l; the running time was 30min.
Measurement conditions of comparative method 2:
-HPLC method, column packed with octadecyl bound polyvinyl alcohol (SUPELCO apHera C18 Polymer (4.6 × 150mm,5 μm), waters e2695 (PDA detector) high performance liquid chromatograph;
-mobile phase a: phosphate solution ph12.0 ± 0.1: acetonitrile =85 (v/v); mobile phase B: water: acetonitrile =15 (v/v) gradient elution
-flow rate: 1.0ml/min; column temperature: 40 ℃; detection wavelength: 225nm; sample introduction amount: 20 mu l of the mixture; the run time was 55.1min.
-gradient elution procedure:
| Time | 0min | 15min | 35min | 55.1min |
| mobile phase A% | 100 | 100 | 71 | 100 |
| Mobile |
0 | 0 | 29 | 0 |
And respectively sampling a blank solution, a sensitivity solution and a resolution solution, respectively, sampling one needle, sampling a reference substance solution in parallel, and sampling 6 needles to investigate the applicability of the system.
The results of comparing the sensitivity and the resolution effect of the above methods are shown in table 3:
the results are shown in Table 3 below
System applicability requirements: the blank solution should not interfere, and the signal-to-noise ratio of the arformoterol in the sensitivity solution should not be less than 10; the separation degree of arformoterol from impurity I in the separation degree solution should be not less than 3.0; the RSD of the arformoterol peak area in 6-needle reference substance solution after repeated sample injection is not more than 2.0%, and the repeated sample injection result by adopting the method of the invention is shown in the following table 4.
TABLE 4 comparative solution Peak area System suitability results
| |
1 | 2 | 3 | 4 | 5 | 6 | RSD |
| Peak area | 32187 | 32465 | 32372 | 32315 | 32282 | 32287 | 0.3％ |
According to the results, the chromatographic column using the octadecyl bonding ethylene bridge hybrid particles as the stationary phase can realize effective separation of the arformoterol and the impurity I within the sample amount range of 20-100 mul. In contrast, for the detection method using an octadecylsilane bonded phase chromatographic column and an octadecylsilane bonded polyvinyl alcohol chromatographic column, effective separation of arformoterol and impurity I cannot be realized in the same sample amount range of 20 μ l or 50 μ l; moreover, when the sample volume (100 μ l) is increased, the separation of arformoterol from impurity I still cannot be achieved, and the requirements of the detection on the degree of separation and sensitivity cannot be satisfied. This result shows that the method of the present invention (a chromatography column using octadecyl bonded ethylene bridge hybrid particles as a stationary phase (Waters XBridge Peptide BEH 300A c18,4.6 x 150mm,3.5 μm)) has the advantages of high sensitivity and good resolution under the same sample size. In contrast, for the detection method using an octadecylsilane bonded phase column and an octadecylsilyl polyvinyl alcohol column, detection of diastereoisomers in arformoterol tartrate inhalation solution (2ml.
Example 4 specificity test for HPLC method based on octadecyl bonded ethylene bridged hybrid particles as stationary phase
The purpose of this experiment was to investigate the ability of the HPLC method using octadecyl bonded ethylene bridge hybrid particles as column stationary phase (Waters XBidge Peptide BEH 300AC18, 4.6X 150mm,3.5 μm) to accurately measure the analyte (impurity I) in the possible presence of other components (e.g., blank diluent, excipients, impurities, etc.).
The chromatographic conditions for this experiment were the same as in example 2.
Taking blank solution/blank auxiliary material solution, reference substance solution, impurity I positioning solution, separation degree solution and sample solution, carrying out sample injection analysis according to the chromatographic conditions, and recording a chromatogram. Figure 6 shows a typical chromatogram resulting from the detection of a blank solution/blank excipient using the method of the invention. As shown in fig. 6, the blank solution/blank vehicle did not interfere at the position of the arformoterol or impurity I peak. FIG. 7 shows a typical chromatogram resulting from the detection of a resolution solution using the method of the present invention. As shown in fig. 7, the separation degree of arformoterol from impurity I in the separation degree solution was 5.3, and the result showed excellent specificity.
Example 5: limit of quantitation and limit of detection tests
The purpose of this experiment was to accurately determine the minimum amount (limit of quantitation) and the minimum amount (limit of detection) that impurity I in the test sample can be quantitatively determined by an HPLC analysis method using octadecyl bonded ethylene bridge hybrid particles as a stationary phase chromatographic column (Waters XBidge Peptide BEH 300A C18, 4.6X 150mm,3.5 μm).
The chromatographic conditions were the same as in example 2.
Impurity I stock solution: approximately 7.5mg of the impurity I control was taken, precisely weighed, dissolved and diluted to the scale with a diluent (water: acetonitrile = 90) in a 100ml volumetric flask, to prepare a stock solution of 75 μ g/ml.
Reference stock solution: about 10.8mg of arformoterol tartrate control (about equivalent to 7.5mg arformoterol) was dissolved in diluent-1 in a 100ml volumetric flask to prepare a stock solution of 75 μ g/ml.
LOQ (limit of quantitation) solution (equivalent to 0.1% of product concentration): precisely transferring 1.0mL of impurity I stock solution and 1.0mL of arformoterol reference stock solution into a 100mL volumetric flask, diluting to a constant volume with a diluent-2, shaking up, precisely transferring 1.0mL of the above solution into a 100mL volumetric flask, diluting to a constant volume with the diluent-2, and shaking up.
LOD (limit of detection) solution (equivalent to 0.0333% of product concentration): diluting the quantitative limiting solution by 3 times to obtain a detection limiting solution
Respectively sampling the above solutions, wherein the signal-to-noise ratio (S/N) of 6 needles of the quantitative limit solution in parallel sampling is more than 10, and the RSD of the peak area is not more than 5.0%; the signal-to-noise ratio (S/N) of the detection limiting solution should be no less than 3. FIGS. 8 and 9 show chromatograms obtained by detecting a quantitative limiting solution using the method of the present invention and a detection limiting solution using the method of the present invention, respectively. The results are given in the following table:
TABLE 5 quantitative Limit test results
TABLE 6 examination of limits
The results show that: the signal-to-noise ratio is far greater than 10 at quantitative limit concentration levels of the test article concentration of 0.1% (report limit of arformoterol tartrate inhalation solution 2ml; the signal-to-noise ratios are all larger than 3 under the detection limit of 0.0333% of the concentration of the test sample, which indicates that the method can accurately and quantitatively detect the content of the impurity I in the arformoterol tartrate inhalation solution. This result is quite satisfactory if, on the basis of an acceptable signal-to-noise ratio of 10, a minimum limit of quantitation of up to 0.01% can be deduced, and correspondingly a minimum limit of detection of up to 0.00333% can be deduced.
Example 6: linear and Range testing
The purpose of this experiment was to investigate the ability of HPLC method using octadecyl bonded ethylene bridge hybrid particles as stationary phase chromatography column (Waters XBridge Peptide BEH 300A C18, 4.6X 150mm,3.5 μm) to have a proportional relationship between the peak area and concentration of the measured substance within the designed range (LOQ-3.0%), and the accuracy of calculating the content of impurity I by external standard method.
The chromatographic conditions were the same as in example 2.
Linear stock solutions: precisely transferring 1.0mL of impurity I stock solution (75 μ g/mL) and 1.0mL of reference stock solution (75 μ g/mL) into a 100mL volumetric flask, diluting with diluent-2 to a constant volume, and shaking to obtain a mixed solution of 0.75 μ g/mL.
Linear solution: the linear stock solutions with appropriate volumes were transferred into 10ml volumetric flasks, diluted with diluent-2 to a constant volume, and shaken up.
TABLE 7 preparation of Linear solutions
Respectively feeding the solutions, recording a chromatogram, and performing linear recovery by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate, wherein the correlation coefficient is required to be not less than 0.990; the y-axis intercept is within 25% of the target concentration; the residual should not be greater than 10%. The results are given in the following table:
TABLE 8 results of linear investigation of arformoterol tartrate inhalation solutions
Fig. 10 shows a linear relationship of arformoterol tartrate in the inhaled solution by the method of the present invention, and the results show that arformoterol has a good linear relationship in the concentration range of 0.0075 μ g/ml (LOQ) to 0.225 μ g/ml.
Fig. 11 shows a linear plot of the diastereomer of arformoterol tartrate in the inhaled solution (impurity I) using the method of the present invention, showing that the impurity I is present in concentrations ranging from 0.0075 μ g/ml (LOQ) to 0.225 μ g/ml with good linearity.
Example 7: accuracy test
The purpose of this experiment was to investigate the HPLC method using octadecyl bonded ethylene bridge hybrid particles as columns (Waters XBidge Peptide BEH 300A C18,4.6 x 150mm,3.5 μm) by adding solutions of impurity I of various known concentrations to the sample solution containing the assay adjuvant, to investigate whether the added impurity I could be extracted completely and to investigate how close the assay results were to the true values, generally expressed as recovery rates.
The chromatographic conditions were the same as in example 2.
Impurity I stock solution: precisely transferring 1.0mL of impurity I stock solution (75 mug/mL) into a 100mL volumetric flask, diluting with a diluent-2 to a constant volume, and shaking up to obtain 0.75 mug/mL stock solution.
R0 test solution: and (3) taking a sufficient amount of sample content solution and uniformly mixing in the same reagent bottle to obtain the reagent.
R1 accuracy solution (LOQ-0.1%): precisely transferring 0.1mL of the impurity I stock solution into a 10mL volumetric flask, performing constant volume by using the R0 sample solution, shaking up, and preparing three parts in parallel.
R2 accuracy solution (1.0%): precisely transferring 1.0mL of the impurity I stock solution into a 10mL volumetric flask, performing constant volume by using the R0 sample solution, shaking up, and preparing three parts in parallel.
R3 accuracy solution (2.0%): precisely transferring 2.0mL of the impurity I stock solution into a 10mL volumetric flask, fixing the volume by using the R0 sample solution, shaking up, and preparing three parts in parallel.
And (3) respectively taking the solutions, carrying out sample injection analysis, recording a chromatogram, and calculating the recovery rate of the impurity I according to the peak area by an external standard method, wherein the results are as follows:
TABLE 9 accuracy results for impurity I in arformoterol tartrate inhalation solutions
The results show that: the recovery rate and the average recovery rate of each sample of the impurity I under each concentration level are both between 90% and 110%, and the RSD of 9 recovery rates is less than 10%, which shows that the method has good accuracy, and the impurity I in the sample solution can be completely extracted and accurately quantified.
Example 8: precision test
The purpose of this experiment was to test the closeness between the results of multiple sampling measurements performed under certain conditions on a column (Waters XBridge Peptide BEH 300A c18,4.6 x 150mm,3.5 μm) using octadecyl bonded ethylene bridge hybrid particles as the stationary phase.
1.1 repeatability test
The chromatographic conditions were the same as in example 2.
Precisely transferring 1.0mL of impurity I stock solution (0.75 mu g/mL) into a 10mL volumetric flask by the same analyst, carrying out constant volume by using a sample solution (arformoterol tartrate inhalation solution), shaking up, and preparing 6 parts in parallel as a test solution; respectively and precisely measuring 100 mu l of reference solution and test solution, carrying out sample injection analysis, recording a chromatogram, and calculating the content of the impurity I by peak area according to an external standard method, wherein the result is shown in the following table.
TABLE 10 repeatability results
The results show that: the RSD of the impurity I content percent detected in 6 sample solutions prepared in parallel by the same analyst is less than 10 percent, which shows that the method has good repeatability.
1.2 intermediate precision test
The chromatographic conditions were the same as in example 2 except for HPLC.
Another analyst independently establishes a system, takes a sample solution with the same batch number as a repetitive sample, prepares 6 test sample solutions with the same concentration by the same method, and uses different instruments to perform measurement on different days, wherein the results are shown in the table below.
Table 11 arformoterol tartrate inhalation solution precision results
The results show that: RSD of the content percent of the impurity I detected in 12 sample solutions with intermediate precision and repeatability is less than 15 percent, which shows that different personnel and different instruments have small influence on the measurement result of the method, and the method has good precision.
Example 9: test for stability of test and reference solutions
The purpose of the experiment is to investigate the stability of the solution to be tested and the reference solution at room temperature and 2-8 ℃ after the preparation is completed, so as to support the accurate reliability of data in the testing process.
The chromatographic conditions were the same as in example 2.
Taking the arformoterol tartrate inhalation solution sample solution, placing the arformoterol tartrate inhalation solution sample solution at room temperature and 2-8 ℃, respectively testing samples in zero days, 1 day and 2 days, and inspecting the stability of the test solution; the stability of the control solution was examined under the same conditions and time points using 0.075 μ g/ml arformoterol control solution, the results of which are given in the table below.
TABLE 12 Arformoterol tartrate inhalation solution investigation of solution stability results
The results show that: the reference solution and the sample solution are stable within 2 days at 2-8 deg.C or room temperature.
Example 10: durability test
The purpose of the experiment is to find out the optimal chromatographic parameters and determine the degree of bearing the results unaffected after slight changes of the target parameters by investigating the changes of conditions such as flow rate of chromatographic conditions, pH of a mobile phase, proportion of the mobile phase, chromatographic columns with the same brand and different batch numbers, chromatographic columns with the same filler and different brands and the like. The specific items under investigation are shown in the following table.
TABLE 13 durability examination item
Other chromatographic conditions were the same as in example 2. The results of the measurements are given in the following table
TABLE 14 durability examination results
The results show that: when the flow rate, the mobile phase pH and the mobile phase ratio varied within the above test ranges, the results of the measurement of impurity I were substantially consistent, indicating that the method was excellent in durability. Meanwhile, the chromatographic column of the octadecyl bonding ethylene bridge hybrid particles is the key for whether the method can realize the expected detection requirement, and chromatographic columns of different brands but all belong to the octadecyl bonding ethylene bridge hybrid particles as the filler of the chromatographic column stationary phase have similar detection effects. In addition, chromatographic columns with the same packing and different brands also have better durability.
Example 11: reference screening test for chromatographic conditions
The purpose of this experiment is to find the tolerance of the optimum chromatographic parameters to sensitivity and resolution unaffected by the study of key chromatographic parameters, such as pH of the mobile phase and the proportion of the mobile phase. The specific items under investigation are shown in the following table.
TABLE 15 optimal parameter screening results
The results show that: the process of the invention can be adapted to different chromatographic conditions. The results prove that the method can meet the requirements of sensitivity and separation degree under the conditions of pH11-12 and mobile phase ratio of 80/20-88/12.
Set of technical solutions
Technical solution group a:
1. a method for detecting whether impurities exist in an arformoterol tartrate inhalation solution, which is characterized by comprising the step of determining whether impurities exist in the arformoterol tartrate inhalation solution by using high performance liquid chromatography,
wherein the impurities comprise diastereomers of the arformoterol tartrate inhalation solution selected from at least one of:
wherein the high performance liquid chromatography adopts octadecyl bonded ethylene bridge hybrid particles as a chromatographic column of a fixed phase filler; preferably, the high performance liquid chromatography adopts a chromatographic column of Waters XBidge Peptide BEH 300A C18 with the specification of 4.6X 150mm and 3.5 μm; and is
Suitable detection conditions for high performance liquid chromatography are selected such that the high performance liquid chromatography has a detection sensitivity (lowest limit of quantitation) as low as 0.01% and a lowest detection limit as low as 0.00333%, and a degree of separation of greater than 5.0.
2. The method according to claim 1, wherein the detection conditions of high performance liquid chromatography comprise:
-a mobile phase: a mixed solution of a phosphate solution and acetonitrile, wherein the pH value of the phosphate solution is 10.0-12.5, and the volume ratio (V/V) of the phosphate solution to the acetonitrile is 90/10-75/25;
-mobile phase flow rate: 0.5-1.5 ml/min;
column temperature of the chromatography column: 25-60 ℃;
-the detection wavelength: 214-230 nm; and
-sample size: 10 to 100 mul.
3. The detection method according to claim 1 or 2, characterized in that the pH value of the phosphate solution is 11.0 to 12.0; preferably, the phosphate solution has a pH value of 11.0 to 12.0; and/or
The phosphate solution is selected from the group consisting of one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, and hydrates thereof; preferably, the phosphate solution is selected from the group consisting of one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, and hydrates thereof; more preferably, the phosphate solution is selected from the group consisting of potassium phosphate trihydrate; and/or
The volume ratio (V/V) of the phosphate solution to the acetonitrile is 88/12-80/20; preferably, the volume ratio (V/V) of the phosphate solution to the acetonitrile is 85/15; and/or
The flow rate of the mobile phase: 0.8-1.2 ml/min; preferably, the mobile phase flow rate: 0.9-1.1 ml/min; more preferably, the mobile phase flow rate: 1.0ml/min; and/or
Column temperature of the chromatographic column: 25-40 ℃; preferably, the column temperature of the chromatographic column is: 25-35 ℃; more preferably, the column temperature of the chromatography column is: 30 ℃; and/or
The detection wavelength is as follows: 220-230 nm; preferably, the detection wavelength is: 225nm; and/or
The sample injection amount is as follows: 20-110 mul; preferably, the sample size: 50-100 mul; more preferably, the sample size: 100 μ l.
4. The detection method according to any one of claims 1 to 3, wherein the chromatographic column using the octadecyl bonded ethylene bridge hybrid particle as a stationary phase filler is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart ExRs C18, and Phenomenex titan C18;
preferably, the chromatographic column using the octadecyl bonded ethylene bridge hybrid particle as a stationary phase filler has a specification of 4.6 × 150mm,3.5 μm, and the chromatographic column is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart ExRs C18, and Phenomenex titanium C18;
more preferably, the chromatographic column using octadecyl bonded ethylene bridge hybrid particles as stationary phase filler is Waters XBidge Peptide BEH 300A C18 with specification of 4.6X 150mm,3.5 μm.
5. The detection method according to any one of claims 1 to 4, wherein the elution manner of the high performance liquid chromatography is isocratic elution.
6. The detection method according to any one of claims 1 to 5, characterized in that,
the high performance liquid chromatography adopts a high performance liquid chromatograph selected from one of the following: agilent 1260 II, waters e2695, dalanimate 3000, shimadzu LC-2050C/2060C or any other chromatography device of the same type; and/or
The high performance liquid chromatography uses a detector selected from one of the following: a VWD detector, DAD detector, PDA detector or any other detector of the same type.
7. The detection method according to any one of claims 1 to 6, characterized in that the method further comprises one or more of the following steps:
(a) Preparing a blank solution, a sensitivity solution, a separation degree solution, a reference substance solution and an arformoterol tartrate solution, wherein:
-the blank solution is a mixed solution of citric acid and its salts;
-the control solution is prepared by dissolving arformoterol tartrate control in a mixed solution of phosphate solution and acetonitrile and diluting to a certain concentration with the blank solution;
-the sensitivity solution is prepared by dilution of the control solution to a concentration; and
-the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereoisomer;
(b) Continuously and sequentially feeding the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution into a chromatograph, sequentially analyzing the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution by adopting a high performance liquid chromatography, and recording a chromatogram;
(c) If the chromatogram of the arformoterol tartrate inhalation solution has a chromatographic peak of a diastereomer, it is determined that the arformoterol tartrate inhalation solution contains the diastereomer as an impurity.
8. The detection method according to any one of claims 1 to 7, characterized in that the method further comprises a step of determining the content of impurities in the arformoterol tartrate inhalation solution, comprising a step of determining that a chromatogram of the arformoterol tartrate inhalation solution contains a chromatographic peak of a diastereoisomer, and calculating the content of the diastereoisomer in the arformoterol tartrate solution according to the peak area of the chromatogram; preferably, the method comprises the step of calculating the content of the diastereoisomer in the arformoterol tartrate inhalation solution according to the peak area of a chromatogram by an external standard method (a standard curve method or an external standard point method) when the chromatogram of the arformoterol tartrate inhalation solution is determined to have a chromatographic peak of the diastereoisomer.
Technical scheme group B:
1. a method for detecting diastereoisomers in arformoterol tartrate solution is characterized by comprising the steps of analyzing the arformoterol tartrate solution by using a high performance liquid chromatography, and calculating the content of the diastereoisomers in the arformoterol tartrate solution according to peak areas of chromatograms, wherein the detection conditions of the high performance liquid chromatography comprise:
packing of the stationary phase of the chromatographic column: octadecyl bonded ethylene bridged hybrid particles;
-a mobile phase: a mixed solution of a phosphate solution and acetonitrile, wherein the pH value of the phosphate solution is 10.0-12.5, and the volume ratio (V/V) of the phosphate solution to the acetonitrile is 90/10-75/25;
-mobile phase flow rate: 0.5-1.5 ml/min;
column temperature of the column: 25-60 ℃;
-the detection wavelength: 214-230 nm; and
-sample size: 10 to 100 mul.
2. The detection method according to claim 1, wherein the pH value of the phosphate solution is 11.0 to 12.0; preferably, the phosphate solution has a pH value of 11.0 to 12.0; and/or
The phosphate solution is selected from the group consisting of one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, and hydrates thereof; preferably, the phosphate solution is selected from the group consisting of one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, and hydrates thereof; more preferably, the phosphate solution is selected from the group consisting of potassium phosphate trihydrate; and/or
The volume ratio (V/V) of the phosphate solution to the acetonitrile is 88/12-80/20; preferably, the volume ratio (V/V) of the phosphate solution to the acetonitrile is 85/15; and/or
The flow rate of the mobile phase: 0.8-1.2 ml/min; preferably, the mobile phase flow rate: 0.9-1.1 ml/min; more preferably, the mobile phase flow rate: 1.0ml/min; and/or
Column temperature of the chromatographic column: 25-40 ℃; preferably, the column temperature of the chromatographic column is: 25-35 ℃; more preferably, the column temperature of the chromatography column is: 30 ℃; and/or
The detection wavelength is as follows: 220-230 nm; preferably, the detection wavelength is: 225nm; and/or
The sample injection amount is as follows: 20-110 mul; preferably, the sample size: 50-100 mul; more preferably, the sample size: 100 μ l.
3. The detection method according to claim 1 or 2, wherein the chromatographic column using octadecyl bonded ethylene bridge hybrid particles as the stationary phase filler is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart ExRs C18, and Phenomenex titan C18;
preferably, the chromatographic column using the octadecyl bonded ethylene bridge hybrid particle as a stationary phase filler has a specification of 4.6 × 150mm,3.5 μm, and the chromatographic column is selected from one of the following: waters XBidge Peptide BEH 300AC18, YMC Triart C18, YMC Triart ExRs C18, and Phenomenex titan C18;
more preferably, the chromatographic column using octadecyl bonded ethylene bridge hybrid particles as stationary phase packing material is Waters XBridge Peptide BEH 300A C18 with specification of 4.6X 150mm,3.5 μm.
4. The detection method according to any one of claims 1 to 3, wherein the elution manner of the high performance liquid chromatography is isocratic elution.
5. The detection method according to any one of claims 1 to 4, characterized in that,
the high performance liquid chromatography adopts a high performance liquid chromatograph selected from one of the following: agilent 1260 II, waters e2695, daliminate 3000, shimadzu LC-2050C/2060C or any other chromatograph of the same type; and/or
The detector adopted by the high performance liquid chromatography is a UV detector; preferably, the detector used in the high performance liquid chromatography is one selected from the group consisting of: a VWD detector, a DAD detector, a PDA detector or any other detector of the same type.
6. The detection method according to any one of claims 1 to 5, wherein the method further comprises one or more of the following steps:
(a) Preparing a blank solution, a sensitivity solution, a separation degree solution, a reference substance solution and an arformoterol tartrate solution, wherein:
-the blank solution is a mixed solution of citric acid and its salts;
-the control solution is prepared by dissolving arformoterol tartrate control in a mixed solution of phosphate solution and acetonitrile and diluting to a certain concentration with the blank solution;
-the sensitivity solution is prepared by dilution of the control solution to a certain concentration; and
-the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereoisomer;
(b) Continuously and sequentially feeding the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution into a chromatograph, sequentially analyzing the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate solution by using high performance liquid chromatography, and recording a chromatogram;
(c) And calculating the content of the diastereoisomer in the arformoterol tartrate solution according to the peak area of the chromatogram by an external standard method (a standard curve method or an external standard point method).
7. The assay according to any one of claims 1 to 6, wherein the arformoterol tartrate solution is selected from at least one of the following: the drug comprises arformoterol tartrate inhalation solution, arformoterol tartrate solution prepared from arformoterol tartrate raw material drug, arformoterol tartrate solution prepared from arformoterol tartrate aerosol, arformoterol tartrate solution prepared from arformoterol tartrate tablet, arformoterol tartrate solution prepared from arformoterol tartrate dry syrup, arformoterol tartrate solution prepared from arformoterol tartrate inhalation powder inhalation aerosol, and arformoterol-containing solution prepared from compound preparation products prepared from arformoterol and other drugs; preferably, the arformoterol tartrate solution is an arformoterol tartrate inhalation solution.
8. The assay according to any one of claims 1 to 7, wherein the diastereomer of the arformoterol tartrate solution is selected from at least one of the following:
Claims (12)
1. a method for quality control of arformoterol tartrate inhalation solution or a process for the production of arformoterol tartrate inhalation solution, comprising the step of measuring the content of diastereomers in the arformoterol tartrate inhalation solution by high performance liquid chromatography, wherein the detection conditions of the high performance liquid chromatography comprise:
-a chromatography column: waters Xbridge Peptide BEH 300A C18, with a specification of 4.6X 150mm,3.5 μm;
-a mobile phase: the mixed solution of phosphate solution and acetonitrile, wherein the pH value of the phosphate solution is 11.0-12.0, and the volume ratio of the phosphate solution to the acetonitrile is 88/12-80/20;
-mobile phase flow rate: 0.5-1.5 ml/min;
column temperature of the column: 25-60 ℃;
-the detection wavelength: 220-230 nm; and
-sample size: 50-100 mul;
the diastereoisomers of the arformoterol tartrate inhalation solution are selected from at least one of the following:
2. the method of quality control according to claim 1, wherein the volume ratio of the phosphate solution to the acetonitrile is 85/15.
3. The method of quality control according to claim 1, wherein the detection wavelength is: 225nm.
4. The method of claim 1, wherein the elution manner of the high performance liquid chromatography is isocratic elution.
5. The method of quality control according to claim 1, wherein the phosphate solution is prepared from one or more of the following: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, and hydrates thereof.
6. The method of quality control according to claim 1, wherein the phosphate solution is prepared from one or more of: sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, and hydrates thereof.
7. The method of quality control according to claim 1, wherein the phosphate solution is selected from the group consisting of potassium phosphate trihydrate.
8. The method for quality control according to any one of claims 1 to 7, wherein the high performance liquid chromatography uses a high performance liquid chromatograph of Agilent 1260 II or Waters e2695; and/or
The detector adopted by the high performance liquid chromatography is a VWD detector.
9. A method of quality control according to any one of claims 1 to 7, wherein the method further comprises one or more of the following steps:
(a) Preparing a blank solution, a sensitivity solution, a resolution solution, a reference solution and an arformoterol tartrate inhalation solution, wherein:
-the blank solution is a mixed solution of citric acid and its salts;
-the control solution is prepared by dissolving arformoterol tartrate control in a mixed solution of phosphate solution and acetonitrile and diluting to a certain concentration with the blank solution;
-the sensitivity solution is prepared by dilution of the control solution to a concentration; and
-the resolution solution is prepared from a mixed solution of a concentration of arformoterol and a diastereoisomer;
(b) Continuously and sequentially feeding the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate inhalation solution into a chromatograph, sequentially analyzing the blank solution, the sensitivity solution, the resolution solution, the reference solution and the arformoterol tartrate inhalation solution by adopting a high performance liquid chromatography, and recording a chromatogram;
(c) And calculating the content of the diastereoisomer in the arformoterol tartrate inhalation solution according to the peak area of the chromatogram by an external standard method.
10. The method of quality control according to any one of claims 1 to 7, wherein the amount of diastereomer in the arformoterol tartrate inhalation solution is considered to be out of quality control standards if the amount of diastereomer in the arformoterol tartrate inhalation solution is greater than 1.0%.
11. The method of quality control according to any one of claims 1 to 7, wherein the arformoterol tartrate inhalation solution has a concentration of arformoterol tartrate of from 5 μ g/ml to 15 μ g/ml.
12. The method of quality control according to any one of claims 1 to 7, wherein the arformoterol tartrate inhalation solution has a concentration of arformoterol tartrate of 7.5 μ g/ml.
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