CN114924020A - Quality control method for diastereoisomer in arformoterol tartrate inhalation solution - Google Patents
Quality control method for diastereoisomer in arformoterol tartrate inhalation solution Download PDFInfo
- Publication number
- CN114924020A CN114924020A CN202210599391.8A CN202210599391A CN114924020A CN 114924020 A CN114924020 A CN 114924020A CN 202210599391 A CN202210599391 A CN 202210599391A CN 114924020 A CN114924020 A CN 114924020A
- Authority
- CN
- China
- Prior art keywords
- solution
- arformoterol tartrate
- arformoterol
- phosphate
- detection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000612 arformoterol tartrate Drugs 0.000 title claims abstract description 217
- 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 216
- 229940041682 inhalant solution Drugs 0.000 title claims abstract description 125
- 238000003908 quality control method Methods 0.000 title claims description 33
- 238000000034 method Methods 0.000 claims abstract description 137
- 238000001514 detection method Methods 0.000 claims abstract description 127
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 82
- 230000035945 sensitivity Effects 0.000 claims abstract description 59
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 296
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 133
- 229910019142 PO4 Inorganic materials 0.000 claims description 68
- 239000010452 phosphate Substances 0.000 claims description 68
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 68
- BPZSYCZIITTYBL-YJYMSZOUSA-N R-Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 claims description 47
- 229960001692 arformoterol Drugs 0.000 claims description 47
- 239000012490 blank solution Substances 0.000 claims description 41
- 239000003643 water by type Substances 0.000 claims description 34
- 239000011259 mixed solution Substances 0.000 claims description 32
- 238000000926 separation method Methods 0.000 claims description 31
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 26
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000012088 reference solution Substances 0.000 claims description 21
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 20
- 238000007865 diluting Methods 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 11
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 10
- 238000010812 external standard method Methods 0.000 claims description 10
- 150000004677 hydrates Chemical class 0.000 claims description 10
- 238000010829 isocratic elution Methods 0.000 claims description 10
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 10
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 10
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 10
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 10
- 235000011009 potassium phosphates Nutrition 0.000 claims description 10
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 claims description 8
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 5
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 5
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 5
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 5
- 239000002245 particle Substances 0.000 abstract description 41
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 40
- 239000005977 Ethylene Substances 0.000 abstract description 39
- 239000012535 impurity Substances 0.000 description 101
- 239000000523 sample Substances 0.000 description 50
- 230000005526 G1 to G0 transition Effects 0.000 description 32
- 239000011550 stock solution Substances 0.000 description 31
- 238000004587 chromatography analysis Methods 0.000 description 25
- 238000012360 testing method Methods 0.000 description 23
- 238000005070 sampling Methods 0.000 description 20
- 238000002474 experimental method Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 239000000945 filler Substances 0.000 description 16
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- 239000012488 sample solution Substances 0.000 description 14
- 239000012085 test solution Substances 0.000 description 14
- 238000012856 packing Methods 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 239000004372 Polyvinyl alcohol Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 229920002451 polyvinyl alcohol Polymers 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 8
- 238000005259 measurement Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- 238000011835 investigation Methods 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000014181 Bronchial disease Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000012733 comparative method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- -1 octadecylsilyl Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 241001164604 Aphera Species 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 206010044302 Tracheitis Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000014974 beta2-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006828 beta2-adrenergic receptor activity proteins Proteins 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 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
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 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
- 229960002848 formoterol Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000011256 inorganic filler Substances 0.000 description 1
- 229910003475 inorganic filler Inorganic materials 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
Images
Classifications
-
- 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
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
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 carrying out quality control on an arformoterol tartrate inhalation solution or on a production process of the arformoterol tartrate inhalation solution, and more particularly to a method for carrying out quality control on the arformoterol tartrate inhalation solution or on 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 dosage forms, there is a need for a method of quality control of the arformoterol tartrate diastereoisomeric impurities that may be present in the arformoterol tartrate solution dosage forms produced.
Disclosure of Invention
The method for quality control of an arformoterol tartrate inhalation solution or a process for the production of an arformoterol tartrate inhalation solution according to the present invention is embodied by the following aspects and embodiments.
In one aspect, the present invention provides a method for quality control of an arformoterol tartrate inhalation solution or a production process of the arformoterol tartrate inhalation solution, wherein the method comprises a step of determining the content of diastereoisomers 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, specification 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: 225 nm; 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 e 2695; 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 separation degree solution, a reference substance 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 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 is as low as the detection limit of 0.00333%), excellent separation degree (the separation degree of arformoterol from impurity I is far more than 3.0, which ensures that the accurate quantification of 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 map of diastereoisomers in the arformoterol tartrate inhalation solution by adopting a detection method of Chinese pharmacopoeia analogues;
FIG. 2 is a schematic diagram: 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: detecting the chromatogram map of the diastereoisomer of the solution to be detected (the arformoterol tartrate inhalation solution) by adopting the method;
FIG. 4 is a schematic view of: the chromatogram for the diastereomer in the arformoterol tartrate inhalation solution (100. mu.l aliquot) was determined using a Waters Xbridge C184.6X 250mm 5 μm column;
FIG. 5 is a schematic view of: chromatograms of the diastereomers in the arformoterol tartrate inhalation solution (100 μ l loading) were determined using a SUPELCO apHera C184.6 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: 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 detection limit solution by adopting the method to obtain a chromatogram;
FIG. 10: detecting a linear relation graph of arformoterol by using the method disclosed by the invention; and
FIG. 11: the method of the invention is used for detecting the linear relationship graph of diastereoisomers (impurity I).
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 present 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 that for small format product formulations such as arformoterol tartrate inhalation solutions (2 ml:15 μ g), it is desirable to provide a detection method which has a sensitivity of at least 0.1% minimum (i.e. 0.0075 μ g/ml or 0.0075ppm, with a reported limit of impurities in quality control of at least 0.1% for products having a maximum daily dose of less than 1 g). 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, octadecyl bonding polyvinyl alcohol chromatographic column) commonly used in the current methods including the pharmacopoeia analogue detection method is used, the chromatographic column has short service life and poor tolerance, and the repeatability and precision of the result are difficult to meet the requirement.
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 arformoterol tartrate inhalation solutions or of processes for the production of arformoterol tartrate inhalation solutions, said method comprising the step of determining the content of diastereomers in the arformoterol tartrate inhalation solutions 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 using high performance liquid chromatography.
In another aspect, the invention provides a method for detecting diastereoisomers in arformoterol tartrate solution, which comprises the step of determining the content of the diastereoisomers in the arformoterol tartrate solution by using high performance liquid chromatography.
In another aspect, the present invention provides a method for detecting whether impurities exist in an arformoterol tartrate inhalation solution, which includes the step of determining whether impurities exist in the arformoterol tartrate inhalation solution by using 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, high performance liquid chromatography classification and working principle [ J ] chemical engineering management, 2017(20): 113; in the morning, Zhang Ying, Juan Jue et al, laboratory HPLC safety and caution item [ J ] Guangzhou chemical 2022,50(4):115-117,120.DOI:10.3969/J. issn.1001-9677.2022.04.038; and Yangyuanjuan, and the maintenance and use cautions of the HPLC. Modern food, 2015(19), 66-68.DOI 10.3969/j. issn.1007-3582.2015.19.032. 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 the strength of action between the sample molecules. Depending on the packing, the column can be divided into: (1) a silica gel column; (2) a chromatographic column chemically bonded to a stationary phase; (3) a polymeric sphere 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, and various polar or weakly polar functional groups (such as C18(ODS), C8, C4, C6H5 or n-ethane, chlorine, dichloromethane, etc.) may be bonded on the surface of the silica gel column, and the polymer column is mostly poly-vinyl-divinylbenzene or poly-methyl propionate, etc.; 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 silica gel chromatographic columns.
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 chromatographic column using octadecyl bonded ethylene bridge hybrid particles as 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 bridged hybrid particles as 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 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 chromatography column using octadecyl bonded ethylene bridge hybrid particles as stationary phase packing material is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart C18, YMC Triart ExRs C18, and Phenomenex Titank C18. In some embodiments, the column using octadecyl bonded ethylene bridge hybrid particles as stationary phase packing material has a specification of 4.6 x 150mm,3.5 μm, and the column is selected from one of the following: waters XBidge Peptide BEH 300A C18, YMC Triart C18, YMC Triart ExRs C18, and Phenomenex Titank C18.
The inventor of the invention proves through experiments that no matter the current test method of the analogs in Chinese, United states or European pharmacopoeia (HPLC using octadecyl bonded polyvinyl alcohol chromatographic column) or the test method of raw material 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 arformoterol tartrate and the diastereoisomer impurity peak thereof cannot be separated from each other at the baseline, and the accurate quantitative detection of the diastereoisomer 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 is 100 μ g/ml in normal injection, and the concentration of the sample of the drug is 7.5 μ g/ml in the case of arformoterol tartrate inhalation solution, which is different by 13 times. Furthermore, only 50ppm of diastereomer in the arformoterol tartrate inhalation solution was detected in the above method, but compared to the method of the present invention, 0.0075ppm of diastereomer in the arformoterol tartrate inhalation solution was detected by 6666 times.
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 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.
For the arformoterol tartrate inhalation solutions, especially small-format arformoterol tartrate inhalation solutions, the high sensitivity and low detection limit of the method of the invention are critical. 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 2 ml/15 μ g format for an arformoterol tartrate inhalation solution is an exemplary small format formulation, which means that each sample is 2ml in a single dose package containing 15 μ g of arformoterol at a concentration of 7.5 μ g/ml. 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 in the examples it is mentioned that a 10.8mg reference arformoterol tartrate (molecular weight 494.5) is weighed, this is in fact equivalent to a 7.5mg reference arformoterol tartrate (molecular weight 344.5)).
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 15 μ g format. 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 inventor has experimentally shown that the higher the pH of the mobile phase, the more beneficial the arformoterol can be separated 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 90/10-75/25. 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 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: 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 1.5 ml/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 1.5 ml/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 1.5 ml/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 1.1 ml/min. In some embodiments, the mobile phase flow rate is 1.0 ml/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 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃,50 ℃, 55 ℃ and 60 ℃. 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 230 nm. 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 230 nm. 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 230 nm. 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 230 nm. In some embodiments, the detection wavelength is between 220nm and 230 nm. In some embodiments, the detection wavelength is 225 nm.
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 50:50 volume ratio (V/V) water-methanol solution.
In some embodiments, the HPLC detection conditions comprise using a sample size of 10 μ l to 100 μ 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 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 Ι.
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 chromatographic column: peptide separation column with octadecyl group bonded as filler (Waters Xbridge Peptide BEH 300A C184.6mm. times.150 mm,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 (ultraviolet) 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: 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 skilled person according to the requirements of the HPLC assay.
In some embodiments, diluent-1, a mixed solution of phosphate buffer and acetonitrile is formulated, wherein the volume ratio (V/V) of phosphate buffer to acetonitrile is 84: 16.
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 arformoterol tartrate, about 10.8mg (equivalent to about 7.5mg arformoterol), accurately weighed, in a 100mL volumetric flask, and adding 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 a diluent-2 to a constant volume, and shaking up.
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, a stock solution of impurity I (37.5 μ g/mL) is prepared by taking about 3.8mg of impurity I control, dissolving and diluting to the mark with a diluent (water: acetonitrile 90:10) in a 100mL volumetric flask.
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 100mL volumetric flasks, diluting with diluent-2 to a constant volume, and shaking.
In some embodiments, the additional step comprises the step of introducing into the high performance liquid chromatograph 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 further step comprises the step of sequentially feeding 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: (1) blank solution (the sampling times are more than or equal to 1 needle), (2) sensitivity solution (the sampling times are more than or equal to 1 needle), (3) resolution solution (the sampling times are more than or equal to 1 needle), (4) reference solution (the sampling times are more than or equal to 6 needles), (5) test solution (namely arformoterol tartrate solution to be tested; the sampling times are more than or equal to 1 needle; one accompanying reference solution is needed for the test solution to enter the 6 needles), and (6) accompanying reference solution (the sampling times are 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: the peak area of the 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 amounts of arformoterol tartrate inhalation solution products.
In some embodiments, if the amount of impurity I in the arformoterol tartrate inhalation solution is greater than 1.0% (i.e., 0.075 μ g/ml or 0.075ppm), the impurity I in the arformoterol tartrate inhalation solution is considered to be not within 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 0.075ppm) by an external standard method without the addition of a correction factor; otherwise it is assumed that the content of impurity I in 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 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 0.075ppm), 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 degree of separation of the methods of the invention is 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 6.10g of sodium dihydrogen phosphate monohydrate and 1.03g of disodium hydrogen phosphate dihydrate, adding 1000ml of water for dissolving, and adjusting the pH value to 6.0 +/-0.1) -acetonitrile (84:16) by using phosphoric acid or sodium hydroxide test solution.
Diluent-2 (blank solution): the arformoterol tartrate inhalation solution is prepared from blank adjuvant solution (mixed solution of citric acid and its salt, by ultrasonic dissolving, mixing, and filtering).
-a sensitivity solution: precisely measuring 5.0ml of the reference solution in a 50ml volumetric flask, adding a diluent-2 to dilute to a scale, and shaking up to obtain a 0.0075 mu g/ml sensitivity solution.
-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 the reference substance stock solution into a volumetric flask, and adding a diluent-2 to prepare about a reference substance 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: a proper amount of arformoterol tartrate reference substances (standardcharm Co., Ltd.) is precisely weighed and dissolved in a volumetric flask by adding a diluent-1 to prepare a stock solution with the arformoterol concentration of 75 mu g/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 mark to make a stock solution of impurity I of 37.5 μ g/ml.
Example 1 detection of diastereoisomers in Alformoterol tartrate inhalation solutions by pharmacopoeia 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 similar drug detection methods, which have been documented 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-504E, 4.6 x 250mm, 5 μm);
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile 88:12(v/v) isocratic elution;
-flow rate: 1.0 ml/min; column temperature: 30 ℃; detection wavelength: 225 nm; sample introduction amount: 100 mul; operating time: and (5) 35 min.
Methods for detection of usp analogs:
-HPLC method, octadecyl bonded polyvinyl alcohol chromatography column (Shodex Asahipak ODP-504D, 4.6 x 150mm, 5 μm);
mobile phase ph12.0 ± 0.1 phosphate solution: acetonitrile 88:12(v/v) isocratic elution;
-flow rate: 0.5 ml/min; column temperature: 30 ℃; detection wavelength: 225 nm; sample introduction amount: 100 mul; operating time: and (5) 35 min.
Detection 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 diastereoisomers (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 × 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: 1.0 ml/min; column temperature: 30 ℃; detection wavelength: 225 nm; sample injection amount: 100 mul; the running time was 20 min.
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 S20G008), 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 injection process is as follows: (1) blank solution (the sampling times are more than or equal to 1 needle), (2) sensitivity solution (the sampling times are 1 needle), (3) resolution solution (the sampling times are 1 needle), (4) contrast solution (the sampling times are 6 needles), (5) test solution (namely arformoterol tartrate solution to be tested; the sampling times are more than or equal to 1 needle; one needle is needed to be added when the test solution enters 6 needles, and (6) follow-up contrast solution (the sampling times are 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 the 2020 edition of the general rules 0512 of chinese pharmacopoeia).
Fig. 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, the HPLC method using octadecyl bonded ethylene bridge hybrid particles as the chromatographic column stationary phase filler does not interfere with the quantitative detection of impurity I due to the excellent separation degree between arformoterol and impurity I even if a new unknown peak appears between arformoterol and impurity I; 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 columns using octadecyl bonded ethylene bridge hybrid particles as stationary phase (Waters XBidge Peptide BEH 300A C18, 4.6 x 150mm,3.5 μm) and other columns (i.e., using 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 of examination, respectively.
The measuring conditions of the method of the invention are as follows:
-HPLC method, octadecyl bonded ethylene bridge 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: 1.0 ml/min; column temperature: 30 ℃; detection wavelength: 225 nm; sample injection amount: 100 mul; the running time was 20 min.
Measurement conditions of comparative method 1:
-HPLC method, octadecylsilane bonded phase chromatography column (Waters Xbridge C18(4.6 × 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) with pH adjusted to 8.5 by phosphoric acid, solution B is acetonitrile, and solution A and solution B are eluted at equal intervals of 80:20 (v/v);
-flow rate: 1.0 ml/min; column temperature: 35 ℃; detection wavelength: 225 nm; sample introduction amount: 50 μ l; the running time was 30 min.
Measurement conditions of comparative method 2:
-HPLC method, column packed with octadecyl bound polyvinyl alcohol (SUPELCO aphara C18 Polymer (4.6 x 150mm, 5 μm), Waters e2695(PDA detector) high performance liquid chromatograph;
-mobile phase a: phosphate solution ph12.0 ± 0.1: acetonitrile 85:15 (v/v); mobile phase B: water: gradient elution with acetonitrile 15:85(v/v)
-flow rate: 1.0 ml/min; column temperature: 40 ℃; detection wavelength: 225 nm; sample introduction amount: 20 mu l of the mixture; the run time was 55.1 min.
-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 the arformoterol and the impurity I in the separation degree solution is 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 chromatographic column using octadecyl bonded ethylene bridge hybrid particles as the stationary phase (Waters XBridge Peptide BEH 300A C18, 4.6 × 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 diastereomer in arformoterol tartrate inhalation solution (2 ml: 15. mu.g) could not be achieved under substantially the same measurement conditions.
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 the stationary phase (Waters XBidge Peptide BEH 300AC18, 4.6X 150mm,3.5 μm) of a chromatographic column to accurately measure the analyte (impurity I) in the possible presence of other components (e.g. blank diluents, 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: quantitative limit and detection limit test
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 XBridge Peptide BEH 300A C18, 4.6 × 150mm,3.5 μm).
The chromatographic conditions were the same as in example 2.
Impurity I stock solution: about 7.5mg of the impurity I control sample was weighed precisely, and dissolved and diluted to the scale with a diluent (water: acetonitrile: 90:10) in a 100ml volumetric flask to prepare a stock solution of 75 μ g/ml.
Control stock solution: about 10.8mg of arformoterol tartrate control (about equivalent to 7.5mg arformoterol), was dissolved in a 100ml volumetric flask with diluent-1 to make a 75 μ g/ml stock solution.
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 the 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 under the quantitative limit concentration level of the test article concentration of 0.1 percent (the report limit of the arformoterol tartrate inhalation solution is 0.1 percent in 2ml:15 mu g of the product); 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, it can be deduced that the minimum limit of quantitation can be reached at 0.01% and, correspondingly, the minimum limit of detection can be reached at 0.00333%.
Example 6: linear and Range testing
The purpose of this experiment was to investigate the ability of the HPLC method using octadecyl bonded ethylene bridge hybrid particles as stationary phase chromatography column (Waters XBidge Peptide BEH 300A C18, 4.6X 150mm,3.5 μm) to give a proportional relationship between the peak area and concentration of the measured substance within the designed range (LOQ-3.0%), and the accuracy of the calculation of the impurity I content 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
Sampling the solutions respectively, 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 for the detection of arformoterol tartrate inhalation solutions using the method of the present invention, showing that arformoterol is well linear over a concentration range of 0.0075 μ g/ml (loq) to 0.225 μ g/ml.
Figure 11 shows a linear plot of the diastereomer of arformoterol tartrate in the inhaled solution (impurity I) using the method of the invention, showing that impurity I is present in a concentration range of 0.0075 μ g/ml (loq) to 0.225 μ g/ml with good linearity.
Example 7: accuracy test
The objective of this experiment was to investigate the HPLC method using octadecyl bonded ethylene bridge hybrid particles as a column (Waters XBidge Peptide BEH 300A C18, 4.6X 150mm,3.5 μm) by adding solutions of impurity I of various known concentrations to the sample solution containing the assay adjuvant, to examine whether the added impurity I could be extracted completely, and to examine how close the assay results were to the true values, generally expressed as recovery.
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, fixing the 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, fixing the 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 assays performed under certain conditions using 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 to obtain a sample solution, and preparing 6 parts in parallel; respectively and precisely measuring 100 mu l of each of the reference solution and the 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 table below.
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 impurity I content% detected in 12 sample solutions with intermediate precision and repeatability is less than 15%, 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: stability test 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 test 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 the chromatographic columns of different brands but all belong to octadecyl bonding ethylene bridge hybrid particles as the filler of the stationary phase of the chromatographic column have similar detection effects. In addition, chromatographic columns of different brands with the same packing have better durability.
Example 11: chromatographic condition reference screening assay
The purpose of this experiment is to find the tolerance of the optimum chromatographic parameters to sensitivity and separation without being affected by the pH of the mobile phase and the proportion of the mobile phase by examining the key chromatographic parameters. 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 under the conditions of pH11-12 and mobile phase ratio 80/20-88/12, the method of the invention can meet the requirements of sensitivity and separation degree.
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 bonding ethylene bridge hybrid particles as a chromatographic column of a stationary phase filler; preferably, the high performance liquid chromatography adopts a chromatographic column of Waters Xbridge Peptide BEH 300A C18 with the specification of 4.6X 150mm and 3.5 μm; and is provided with
Suitable detection conditions for high performance liquid chromatography are selected such that the high performance liquid chromatography has a detection sensitivity as low as 0.01% (minimum limit of quantitation) and a minimum limit of detection 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 column: 25-60 ℃;
-the detection wavelength: 214-230 nm; and
-sample size: 10 to 100 mul.
3. The detection method according to the technical scheme 1 or 2, characterized in that the pH value of the phosphate solution is 11.0-12.0; preferably, the pH value of the phosphate solution is 11.0-12.0; 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: 1.0 ml/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: 225 nm; 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 C18, YMC Triart ExRs C18, and Phenomenex titanium C18;
preferably, the chromatographic column using octadecyl bonded ethylene bridge hybrid particles as 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 C18, YMC Triart ExRs C18, and Phenomenex Titank 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, a DAD detector, a 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 resolution 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 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) 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 method for detecting impurities in the arformoterol tartrate inhalation solution, according to any one of claims 1 to 7, further comprising the steps of determining the content of impurities in the arformoterol tartrate inhalation solution, comprising the steps of determining a chromatographic peak of a diastereomer in a chromatogram of the arformoterol tartrate inhalation solution, and calculating the content of the diastereomer 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 the chromatogram by an external standard method (standard curve method or external standard point method) when the chromatogram of the arformoterol tartrate inhalation solution is determined to have a chromatographic peak of the diastereoisomer.
Technical solution group B:
1. a method for detecting diastereoisomers in arformoterol tartrate solution, which comprises the steps of analyzing the arformoterol tartrate solution by 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 the technical scheme 1, characterized in that the pH value of the phosphate solution is 11.0-12.0; preferably, the pH value of the phosphate solution is 11.0-12.0; 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: 1.0 ml/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: 225 nm; 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 C18, YMC Triart ExRs C18, and Phenomenex titanium C18;
preferably, the chromatographic column using the octadecyl bonded ethylene bridge hybrid particle as the 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 Titank 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.
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, Dalanimate 3000, Shimadzu LC-2050C/2060C or any other chromatography device of the same type; and/or
The detector adopted by the high performance liquid chromatography is a UV detector; preferably, the detector used for 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, 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) 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 drug comprises arformoterol tartrate inhalation solution, arformoterol tartrate solution prepared from arformoterol tartrate bulk drug, arformoterol tartrate solution prepared from arformoterol tartrate aerosol, arformoterol tartrate solution prepared from arformoterol tartrate tablets, arformoterol tartrate solution prepared from arformoterol tartrate dry syrup, arformoterol tartrate solution prepared from arformoterol tartrate inhalation aerosol powder, and arformoterol-containing solution prepared from arformoterol tartrate 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 (9)
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 chromatographic column: waters Xbridge Peptide BEH 300A C18, specification 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: 225 nm; and
-sample size: 50-100 mul.
2. The method of claim 1, wherein the elution manner of the HPLC is isocratic elution.
3. 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; 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.
4. The method of quality control according to any one of claims 1-3, wherein the high performance liquid chromatography is performed by using a high performance liquid chromatograph of Agilent 1260 II or Waters e 2695; and/or
The detector adopted by the high performance liquid chromatography is a VWD detector.
5. A method of quality control according to any one of claims 1 to 4, 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) 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 (a standard curve method or an external standard one-point method).
6. The method of quality control according to any one of claims 1 to 5, 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% (i.e. 0.075 μ g/ml or 0.075 ppm).
7. The method of quality control according to any one of claims 1 to 6, wherein the diastereoisomers of the arformoterol tartrate inhalation solution are selected from at least one of:
8. the method of quality control according to any one of claims 1 to 7, wherein the arformoterol tartrate inhalation solution is a small-format arformoterol tartrate inhalation solution; preferably, the arformoterol tartrate inhalation solution has a concentration of arformoterol tartrate of from 5 μ g/ml to 15 μ g/ml; more preferably, the arformoterol tartrate inhalation solution has an arformoterol tartrate concentration of 7.5 μ g/ml.
9. The method of quality control according to any one of claims 1-8, wherein the method has 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 greater than 5.0.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310273793.3A CN116298046B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomers in arformoterol tartrate inhalation solution |
| CN202210599391.8A CN114924020B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210599391.8A CN114924020B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310273793.3A Division CN116298046B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomers in arformoterol tartrate inhalation solution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114924020A true CN114924020A (en) | 2022-08-19 |
| CN114924020B CN114924020B (en) | 2023-04-14 |
Family
ID=82812690
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310273793.3A Active CN116298046B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomers in arformoterol tartrate inhalation solution |
| CN202210599391.8A Active CN114924020B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310273793.3A Active CN116298046B (en) | 2022-05-30 | 2022-05-30 | Quality control method for diastereoisomers in arformoterol tartrate inhalation solution |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN116298046B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5684199A (en) * | 1993-12-28 | 1997-11-04 | Novartis Corporation | Process for the preparation of an optically pure enantiomer of formoterol |
| CN101393186A (en) * | 2007-09-21 | 2009-03-25 | 北京德众万全药物技术开发有限公司 | Method for separating and analyzing tartaric acid formoterol chiral isomer by HPLC method |
| CN107233311A (en) * | 2017-06-27 | 2017-10-10 | 长风药业股份有限公司 | It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof |
| CN111398441A (en) * | 2020-03-09 | 2020-07-10 | 南京华盖制药有限公司 | Method for detecting diastereoisomers in arformoterol tartrate solution for inhalation |
| CN114544809A (en) * | 2022-02-16 | 2022-05-27 | 汉瑞药业(荆门)有限公司 | HPLC detection method for arformoterol intermediate and enantiomer chiral purity thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120053246A1 (en) * | 2010-08-26 | 2012-03-01 | Actavis Group Ptc Ehf | Purification process for preparing highly pure arformoterol tartrate substantially free of desformyl impurity |
| CN110376313B (en) * | 2019-08-20 | 2022-06-07 | 广州健康元呼吸药物工程技术有限公司 | Method for detecting impurities in formoterol fumarate or related preparation thereof |
-
2022
- 2022-05-30 CN CN202310273793.3A patent/CN116298046B/en active Active
- 2022-05-30 CN CN202210599391.8A patent/CN114924020B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5684199A (en) * | 1993-12-28 | 1997-11-04 | Novartis Corporation | Process for the preparation of an optically pure enantiomer of formoterol |
| CN101393186A (en) * | 2007-09-21 | 2009-03-25 | 北京德众万全药物技术开发有限公司 | Method for separating and analyzing tartaric acid formoterol chiral isomer by HPLC method |
| CN107233311A (en) * | 2017-06-27 | 2017-10-10 | 长风药业股份有限公司 | It is a kind of by the Alevaire of active component of Afromoterol and glycopyrronium bromide and preparation method thereof |
| CN111398441A (en) * | 2020-03-09 | 2020-07-10 | 南京华盖制药有限公司 | Method for detecting diastereoisomers in arformoterol tartrate solution for inhalation |
| CN114544809A (en) * | 2022-02-16 | 2022-05-27 | 汉瑞药业(荆门)有限公司 | HPLC detection method for arformoterol intermediate and enantiomer chiral purity thereof |
Non-Patent Citations (5)
| Title |
|---|
| SAMUEL AKAPO 等: "Chiral HPLC analysis of formoterol stereoisomers and thermodynamic study of their interconversion in aqueous pharmaceutical formulations" * |
| YAN GOU 等: "A new strategy for quality evaluation and control of Chinese patent medicine based on chiral isomer ratio analysis: With Yuanhuzhitong tablet as an example" * |
| 刘延奎 等: "富马酸福莫特罗有关物质的LC-MS/MS测定" * |
| 孙悦 等: "醋酸曲普瑞林缓释注射剂中杂质的检测分析" * |
| 韩睿 等: "LC-PDA-MS/MS法分析酒石酸阿福特罗中的有关物质" * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116298046A (en) | 2023-06-23 |
| CN116298046B (en) | 2023-11-17 |
| CN114924020B (en) | 2023-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115015459B (en) | Method for detecting diastereoisomers in formoterol fumarate inhalation solution | |
| CN109870521B (en) | Method for separating oseltamivir phosphate enantiomers by normal phase chromatography | |
| CN112630365B (en) | Method for determining content of dimyristoyl phosphatidylcholine by high performance liquid chromatography | |
| CN111487348B (en) | Pramipexole dihydrochloride solution prepared by pramipexole dihydrochloride solid preparation and determination method thereof | |
| CN113484430A (en) | Method for determining L-alanine isopropyl ester hydrochloride related substances by adopting high performance liquid chromatography | |
| CN114924020B (en) | Quality control method for diastereoisomer in arformoterol tartrate inhalation solution | |
| CN114354789B (en) | Method for simultaneously measuring cabozantinib analogue and related substances thereof | |
| CN113514589B (en) | High performance liquid chromatography analysis method of stannous glucoheptonate relative substance for injection | |
| CN113514588B (en) | High performance liquid chromatography analysis method of relevant substances of cysteamine for injection | |
| CN113156009A (en) | Method for analyzing lamotrigine by high performance liquid chromatography | |
| CN111579688A (en) | Method for determining content of enantiomer in dapoxetine hydrochloride | |
| CN113933413B (en) | Method for detecting impurity K in ganciclovir and method for separating impurity | |
| CN114280169B (en) | Method for determining isomer in monabivir | |
| CN114113402B (en) | Method for measuring pinanediol content in bortezomib by adopting high performance liquid chromatography | |
| CN112611822B (en) | Detection method and application of cefoperazone sodium and sulbactam sodium related substances | |
| CN114518423B (en) | Method for detecting impurities in dopamine hydrochloride injection | |
| CN114487192B (en) | Method for measuring content of edetate disodium in desloratadine oral solution | |
| CN113092656B (en) | Method for detecting related substances in vecuronium bromide medicine for injection | |
| CN113640446B (en) | Method for detecting 6-chloro-1, 3-indoline-2-ketone related substances | |
| Foppa et al. | Development, validation and stability study of pediatric atenolol syrup | |
| CN113777180B (en) | Method for simultaneously detecting sitafloxacin and various isomer impurities thereof | |
| CN113777185A (en) | Detection method of Propofovir in Propofovir fumarate preparation | |
| CN114354788A (en) | Method for determining Molnbupiravir raw material and related substances in preparation thereof | |
| CN114252538A (en) | Tenofovir alafenamide fumarate and separation and determination method of isomer thereof | |
| CN117890496A (en) | Method for detecting related substances of compound preparation of novel oral solution of guaifenesin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: No.10, Lane 100, Banxia Road, Pudong New Area, Shanghai, 201318 Applicant after: Shanghai Aokeda Pharmaceutical Technology Co.,Ltd. Address before: No.10, Lane 100, Banxia Road, Pudong New Area, Shanghai, 201318 Applicant before: SHANGHAI AUCTA PHARMACEUTICALS Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |