CN110308222A - A kind of related substance detecting method of carbetocin bulk pharmaceutical chemicals - Google Patents
A kind of related substance detecting method of carbetocin bulk pharmaceutical chemicals Download PDFInfo
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- CN110308222A CN110308222A CN201910643080.5A CN201910643080A CN110308222A CN 110308222 A CN110308222 A CN 110308222A CN 201910643080 A CN201910643080 A CN 201910643080A CN 110308222 A CN110308222 A CN 110308222A
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- NSTRIRCPWQHTIA-DTRKZRJBSA-N carbetocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSCCCC(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(OC)C=C1 NSTRIRCPWQHTIA-DTRKZRJBSA-N 0.000 title claims abstract description 37
- 108700021293 carbetocin Proteins 0.000 title claims abstract description 36
- 229960001118 carbetocin Drugs 0.000 title claims abstract description 36
- 239000000126 substance Substances 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title abstract description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 93
- 239000000243 solution Substances 0.000 claims abstract description 52
- 239000012535 impurity Substances 0.000 claims abstract description 51
- 238000001514 detection method Methods 0.000 claims abstract description 26
- 239000012085 test solution Substances 0.000 claims abstract description 19
- 239000013558 reference substance Substances 0.000 claims abstract description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000872 buffer Substances 0.000 claims abstract description 12
- 238000010828 elution Methods 0.000 claims abstract description 8
- 238000005070 sampling Methods 0.000 claims abstract description 7
- 239000000945 filler Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000007791 liquid phase Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 4
- 239000012490 blank solution Substances 0.000 claims description 3
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- -1 Phenyl-Hexyl Chemical group 0.000 claims description 2
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 claims description 2
- 239000003643 water by type Substances 0.000 claims description 2
- 230000003139 buffering effect Effects 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 238000010790 dilution Methods 0.000 abstract description 4
- 239000012895 dilution Substances 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 11
- 239000011550 stock solution Substances 0.000 description 10
- 239000003085 diluting agent Substances 0.000 description 9
- 210000004291 uterus Anatomy 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000010200 validation analysis Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101800000989 Oxytocin Proteins 0.000 description 3
- 102400000050 Oxytocin Human genes 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 2
- 208000018525 Postpartum Hemorrhage Diseases 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 2
- 229960001723 oxytocin Drugs 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000015170 shellfish Nutrition 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 238000010671 solid-state reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention belongs to pharmaceutical technology fields, are related to a kind of carbetocin bulk pharmaceutical chemicals Related substance method.Carbetocin bulk pharmaceutical chemicals Related substance method of the present invention, comprising the following steps: step 1: taking carbetocin bulk pharmaceutical chemicals and impurity reference substance each appropriate, and system suitability solution and test solution is made with the dilution of 20% acetonitrile solution；Step 2: using phenyl bonded silica as chromatographic column filler, using UV detector, selecting acetonitrile and buffer is mobile phase, gradient elution；Detection wavelength is 220nm；Flow velocity is 1.0ml/min；Sampling volume is 20 μ l；Column temperature is 35 ~ 40 DEG C.This method efficiently solves the problems, such as the related substance detection of carbetocin bulk pharmaceutical chemicals and separation, and specificity is strong, reproducible, accuracy is high, can guarantee the controllability in carbetocin bulk pharmaceutical chemicals in relation to substance, improves product quality.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of analyzing detecting method of active peptides raw material medicine, especially relate to
And the related substance detecting method of carbetocin bulk pharmaceutical chemicals.
Background technique
Carbetocin (Carbetocin), its chemical name is: deammoniation -2- oxygen-methyl-tyrosine -1- κ oxytocin, point
Minor: C45H69N11O12S, molecular weight 988.17.
Its structural formula:
Carbetocin is a kind of long-acting oxytocins nonapeptide analog with agonist characteristics of synthesis.Under Epidural cavity or lumbar anesthesia
It Single-dose intravenous can be administered immediately after caesarean section, to prevent uterus tension deficiency and postpartum haemorrhage.
The clinic and pharmacological property of carbetocin are with naturally-produced oxytocins similar, can urge with uterine smooth muscle
It produces plain receptor to combine, causes the Rythmic contractions characteristic in uterus, on the basis of original contraction, increase its frequency and increase uterus
Power.Under non pregnant state, the ocytocin receptor content in uterus is very low, during gestation increases, and peak is reached when childbirth.Therefore block
Shellfish oxytocin does not act on non-pregnant uterus, but uterus to gestation and the just uterus that produces are with effective uterus receipts
Contracting effect.
Studies have shown that give carbetocin 100 micro- for Single-dose intravenous immediately after caesarean section under Epidural cavity or lumbar anesthesia
Gram, in prevention uterus tension deficiency and in terms of reducing postpartum haemorrhage, carbetocin is substantially better than placebo.
Carbetocin can be mingled with plurality of impurities, the detailed feelings of impurity in bulk pharmaceutical chemicals using polypeptide solid-state reaction method
Condition is as follows:
Above-mentioned impurity influences whether the quality of carbetocin, it is therefore necessary to content control is carried out to impurity, currently, amino acid
Analysis mostly use high performance liquid chromatography (HPLC), but it is accurate to the analysis result of different aminoacids to be different method condition
Degree is affected.In Peptide systhesis, in order to preferably control product quality, impurity must accurately be analyzed, existing skill
In art, carbetocin impurity analysis is had not been reported.For this purpose, the present invention constructs a kind of dividing for related substance of carbetocin
Analysis method, this method specificity is strong, precision is good, and accuracy is high, can will likely degradation impurity and process impurity and principal component
It effectively separates, and high sensitivity, can be applied to the quality control of carbetocin bulk pharmaceutical chemicals, to raising carbetocin product matter
It measures significant.
Summary of the invention
The present invention provides a kind of carbetocin efficient liquid phase detection method, and chromatographic condition is as follows: with phenyl bonded silica
It selects acetonitrile using UV detector for chromatographic column filler and buffer is mobile phase, gradient elution；Wherein the gradient is washed
De-, mode is as follows: 0~35 minute, it was 20% that acetonitrile, which elutes ratio,；35~50 minutes, acetonitrile eluted ratio 20% ~ 50%；50
~55 minutes, it was 50% that acetonitrile, which elutes ratio,；Detection wavelength is 220nm；Flow velocity is 1.0ml/min；Sampling volume is 20 μ l；Column
Temperature is 35 ~ 40 DEG C.
In the above method, the buffer is selected from: sodium hexanesulfonate buffer, sodium heptanesulfonate buffer, preferably heptan
Alkyl sulfonic acid sodium buffer.
In the above method, the chromatographic column is selected from Waters XBridge BEH Phenyl 4.6*100mm 5 μ
m；Agilent ZORBAX SB-Phenyl 4.6*75mm 3.5μm；Phenomenex Luna Phenyl-Hexyl 4.6*
100mm 3μm。
In the above method, the gradient elution, mode is as follows: 0~35 minute, it was 20% that acetonitrile, which elutes ratio,；35~50
Minute, acetonitrile elutes ratio 20% ~ 50%；50~55 minutes, it was 50% that acetonitrile, which elutes ratio,；Detection wavelength is 220nm；Flow velocity
For 1.0ml/min；Sampling volume is 20 μ l；Column temperature is 35 ~ 40 DEG C.
The present invention also provides a kind of related substance detecting methods of carbetocin bulk pharmaceutical chemicals, the method comprises the following steps:
Step 1: the preparation of solution:
The preparation of blank solution: 20% acetonitrile solution (v/v)；
The preparation of impurity reference substance solution: it is appropriate to weigh carbetocin impurity, add blank solvent to make to dissolve and dilute be made it is miscellaneous
Matter reference substance solution；
The preparation of test solution: it is appropriate to weigh carbetocin, and blank solvent is added to make to dissolve and dilute that test solution is made；
Step 2: the setting of high-efficient liquid phase chromatogram condition:
Using phenyl bonded silica as chromatographic column filler, using UV detector, selecting acetonitrile and buffer is mobile phase, and gradient is washed
De-: wherein the gradient elution, mode are as follows:
0~35 minute, it was 20% that acetonitrile, which elutes ratio,；35~50 minutes, acetonitrile eluted ratio 20% ~ 50%；50~55 minutes,
It is 50% that acetonitrile, which elutes ratio,；Detection wavelength is 220nm；Flow velocity is 1.0ml/min；Sampling volume is 20 μ l；Column temperature is 35 ~ 40
℃。
Under above-mentioned chromatographic condition, accurate extraction system applicability solution and each 20 μ l of test solution, injecting chromatograph,
Record chromatogram.In the map of system suitability solution, each impurity peaks and carbetocin peak separating degree are all larger than 1.5.
Detection method of the carbetocin bulk pharmaceutical chemicals in relation to substance provided by the invention can effectively detect the contracting of card release shellfish
Gong Su and each impurity peaks, and separating degree is both greater than 1.5, good separating effect, method specificity is strong, precision is good, and accuracy is high, and
It is simple and easy, it is swift to operate, there is important researching value in terms of bulk pharmaceutical chemicals and quality of the pharmaceutical preparations research.
Detailed description of the invention
Fig. 1: methodology validation blank solvent map
Fig. 2: methodology validation system suitability solution map
Fig. 3: methodology validation detection line solution map
Fig. 4: methodology validation quantitative limit solution map
Fig. 5: 0.2% test sample own control solution map of methodology validation
Fig. 6: methodology validation test solution map
Fig. 7: methodology validation accuracy solution map
Form is again described in further details the contents of the present invention by the following examples, but not that should not be interpreted as the present invention with regard to this
Following embodiment is only limitted in above-mentioned subject area.Under the premise of not departing from above-mentioned technology of the invention, according to the common skill in this field
The corresponding modification replaced or change that art knowledge and customary means are made, is included in the present invention.
Embodiment one: the selection of chromatographic column
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, principal component and rear other impurities separating degree are 1.3, are unable to satisfy test requirements document.
Embodiment two: the selection of chromatographic column
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, principal component and rear other impurities separating degree are 1.1, are unable to satisfy test requirements document.
Embodiment three: the selection of chromatographic column
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, principal component and rear other impurities separating degree are 1.9, meet test requirements document.
Example IV: the selection of buffer salt
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, impurity IMP-03 and IMP-07 points be unable to do without, and principal component and rear other impurities separating degree are 1.4, are unable to satisfy test requirements document.
Embodiment five: the selection of buffer salt
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, each impurity can good separation, principal component and rear other impurities separating degree are 1.9, meet test requirements document.
Embodiment six: the selection of column temperature
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, each impurity can good separation, principal component and rear other impurities separating degree are 1.5, meet the requirements, but method durability compared with
Difference.
Embodiment seven: the selection of column temperature
Conclusion: it takes impurity reference substance solution and test solution that mixed solution injection high performance liquid chromatograph is made, obtains chromatography
Figure, each impurity can good separation, principal component and rear other impurities separating degree are 1.9, meet test requirements document.
Embodiment eight: system suitability and specificity are tested
Solution is prepared:
Diluent: 20% acetonitrile solution (v/v)
Impurity stock solution: IMP-01 10.36mg, IMP-02 10.18mg, IMP-03 10.55mg, IMP-04 are weighed respectively
10.49mg, IMP-05 10.82mg, IMP-06 10.29mg, IMP-07 10.17mg are set in 50ml measuring bottle, add 0.1% acetic acid
Scale is dissolved and be diluted to, each impurity stock solution is obtained.
Positioning solution: measuring each impurity stock solution 1ml respectively and set in 10ml measuring bottle respectively, diluent is added to be diluted to scale,
Solution is positioned as each impurity.
System suitability solution: weighing carbetocin 10.25mg in 10ml measuring bottle, add IMP-01, IMP-02,
Each 0.1ml of IMP-03, IMP-04, IMP-05, IMP-06, IMP-07 impurity stock solution adds diluent to dissolve and is diluted to scale,
It shakes up, as system suitability solution.
Each component retention time and separating degree:
Conclusion: blank solvent does not interfere the detection of main peak and impurity peaks, and the separating degree of main peak and preceding other impurities peak is all larger than
1.5, system suitability and specificity meet regulation.
Embodiment nine: quantitative limit and detection limit test
Solution is prepared
Diluent: 20% acetonitrile solution (v/v)
Quantitative limit solution: take IMP-01, IMP-02 under system suitability and specificity item, IMP-03, IMP-04, IMP-05,
IMP-06 and IMP-07 impurity stock solution adds diluent to be diluted to the solution of each about 0.5 μ g/ml.
Detection limit solution: it measures quantitative limit solution 3ml and sets in 10ml measuring bottle, add diluted to scale, shake up.
Quantitative limit repetitive test result
Conclusion: quantifying for each impurity is limited to 0.05%, and each continuous 6 needle quantitative limit solution peak area RSD of known impurities is respectively less than 10%.
Detection is limited to 0.015%, meets regulation.
Embodiment ten: accuracy test
Solution is prepared
Dilution (blank solvent): 20% acetonitrile solution (v/v)
Impurity stock solution: IMP-01 15.24mg, IMP-02 14.35mg, IMP-03 14.15mg, IMP-04 are weighed respectively
15.85mg, IMP-05 18.67mg, IMP-06 16.73mg, IMP-07 14.44mg are set in 50ml measuring bottle, add diluent molten
Scale is solved and be diluted to, each impurity stock solution is obtained.
Impurity mixing reference substance stock solution: take IMP-01, IMP-02, IMP-03, IMP-04, IMP-05, IMP-06 and
Each 2ml of IMP-07 impurity stock solution, sets in 20ml measuring bottle, and diluent is added and dissolves and be diluted to scale, shakes up to obtain the final product.
Test solution: weighing carbetocin 20.08mg, sets 20ml measuring bottle, adds diluent to dissolve and is diluted to quarter
Degree, as test solution.
Reference substance solution: by 500 times of dilution agent of dilution of test solution, as contrast solution (0.2%).
Accuracy solution: weigh carbetocin 20.86mg, 20.67mg, 20.57mg, 20.46mg, 20.88mg,
20.59mg is set respectively in 6 20ml measuring bottles, each that mixing reference substance stock solution 1ml is added, and is dissolved with diluent and is diluted to quarter
Degree, shakes up to obtain the final product.
Accuracy test result
Conclusion: 6 parts of accuracy solution measurement results are shown: IMP-01, IMP-02, IMP-03, IMP-04, IMP-05, IMP-06
With the IMP-07 rate of recovery in 90% ~ 108% range, RSD value is respectively less than 5%, and accuracy meets regulation.
Claims (11)
1. a kind of carbetocin efficient liquid phase detection method, which is characterized in that use chromatographic condition as follows: with phenyl bonded silica
Glue is chromatographic column filler, using UV detector, selects acetonitrile and buffer is mobile phase, gradient elution；The wherein gradient
Elution, mode are as follows: 0~35 minute, it was 20% that acetonitrile, which elutes ratio, and 35~50 minutes, acetonitrile eluted ratio 20% ~ 50%,
50~55 minutes, it was 50% that acetonitrile, which elutes ratio,；Detection wavelength is 220nm；Flow velocity is 1.0ml/min；Sampling volume is 20 μ
l；Column temperature is 35 ~ 40 DEG C.
2. detection method according to claim 1, which is characterized in that the buffer is selected from: sodium hexanesulfonate buffering
Liquid, sodium heptanesulfonate buffer, preferably sodium heptanesulfonate buffer.
3. detection method according to claim 1, which is characterized in that the chromatographic column be selected from:
Waters XBridge BEH Phenyl 4.6*100mm 5μm；
Agilent ZORBAX SB-Phenyl 4.6*75mm 3.5μm；
Phenomenex Luna Phenyl-Hexyl 4.6*100mm 3μm。
4. detection method according to claim 1, it is characterised in that: the gradient elution mode is 0~35 minute, second
It is 20% that nitrile, which elutes ratio,；35~50 minutes, acetonitrile eluted ratio 20% ~ 50%；50~55 minutes, acetonitrile eluted ratio and is
50%.
5. detection method according to claim 1, it is characterised in that: Detection wavelength 220nm.
6. detection method according to claim 1, it is characterised in that: flow velocity 1.0ml/min.
7. detection method according to claim 1, it is characterised in that: sampling volume is 20 μ l.
8. detection method according to claim 1, it is characterised in that: column temperature is 35 ~ 40 DEG C.
9. a kind of efficient liquid phase detection method of carbetocin bulk pharmaceutical chemicals in relation to substance, which comprises the following steps:
Step 1: the preparation of solution:
The preparation of blank solution: 20% acetonitrile solution (v/v)；
The preparation of system suitability solution: taking carbetocin bulk pharmaceutical chemicals and impurity reference substance each appropriate, dilute with 20% acetonitrile solution
It releases and mixed solution is made, as system suitability solution；
The preparation of test solution: it is appropriate to weigh carbetocin, and blank solvent is added to make to dissolve and dilute that test solution is made；
Step 2: the setting of high-efficient liquid phase chromatogram condition:
Using phenyl bonded silica as chromatographic column filler, using UV detector, selecting acetonitrile and buffer is mobile phase, and gradient is washed
De-: wherein the gradient elution, mode are as follows:
0~35 minute, it was 20% that acetonitrile, which elutes ratio,；35~50 minutes, acetonitrile eluted ratio 20% ~ 50%；50~55 minutes,
It is 50% that acetonitrile, which elutes ratio,；Detection wavelength is 220nm；Flow velocity is 1.0ml/min；Sampling volume is 20 μ l；Column temperature is 35 ~ 40
℃。
10. detection method according to claim 9, which is characterized in that the impurity are as follows:
。
11. detection method according to claim 9, which is characterized in that the preparation of the solution includes following content:
The preparation of blank solution: 20% acetonitrile solution (v/v)；
The preparation of impurity reference substance solution: weighing carbetocin impurity, and blank solvent is added to make to dissolve and dilute to be made in every 1ml
Solution containing 20 μ g, as impurity reference substance solution；
The preparation of system suitability solution: taking carbetocin bulk pharmaceutical chemicals and impurity reference substance each appropriate, dilute with 20% acetonitrile solution
It releases and mixed solution is made, as system suitability solution；
The preparation of test solution: it is appropriate to weigh carbetocin, and blank solvent is added to make to dissolve and dilute that test solution is made.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111060635A (en) * | 2019-11-27 | 2020-04-24 | 吉尔生化（上海）有限公司 | Analysis and detection method of carbetocin |
| CN111077243A (en) * | 2019-12-16 | 2020-04-28 | 成都市海通药业有限公司 | Detection method for oxytocin injection |
| CN113252807A (en) * | 2021-04-15 | 2021-08-13 | 武汉大安制药有限公司 | High performance liquid chromatography separation method for oxytocin raw material medicine related substances |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260326A (en) * | 2011-06-08 | 2011-11-30 | 成都圣诺科技发展有限公司 | Method for preparing carbetocin |
| CN102580057A (en) * | 2012-03-14 | 2012-07-18 | 南京先宇科技有限公司 | Medicine composition containing ergometrine and oxytocin analogue and preparation method |
| CN102977192A (en) * | 2012-12-06 | 2013-03-20 | 安徽工程大学 | Purification method of carbetocin |
| US20130210746A1 (en) * | 2010-09-30 | 2013-08-15 | Ferring B.V. | Pharmaceutical composition |
| CN104055732A (en) * | 2014-07-10 | 2014-09-24 | 成都天台山制药有限公司 | Carbetocin injection and preparation method thereof |
| CN104086631A (en) * | 2014-07-10 | 2014-10-08 | 成都天台山制药有限公司 | Carbetocin and preparation method thereof |
| CN106478779A (en) * | 2016-10-24 | 2017-03-08 | 合肥国肽生物科技有限公司 | A kind of preparation method of carbetocin |
-
2019
- 2019-07-17 CN CN201910643080.5A patent/CN110308222A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130210746A1 (en) * | 2010-09-30 | 2013-08-15 | Ferring B.V. | Pharmaceutical composition |
| CN104906032A (en) * | 2010-09-30 | 2015-09-16 | 辉凌公司 | Pharmaceutical composition |
| CN102260326A (en) * | 2011-06-08 | 2011-11-30 | 成都圣诺科技发展有限公司 | Method for preparing carbetocin |
| CN102580057A (en) * | 2012-03-14 | 2012-07-18 | 南京先宇科技有限公司 | Medicine composition containing ergometrine and oxytocin analogue and preparation method |
| CN102977192A (en) * | 2012-12-06 | 2013-03-20 | 安徽工程大学 | Purification method of carbetocin |
| CN104055732A (en) * | 2014-07-10 | 2014-09-24 | 成都天台山制药有限公司 | Carbetocin injection and preparation method thereof |
| CN104086631A (en) * | 2014-07-10 | 2014-10-08 | 成都天台山制药有限公司 | Carbetocin and preparation method thereof |
| CN106478779A (en) * | 2016-10-24 | 2017-03-08 | 合肥国肽生物科技有限公司 | A kind of preparation method of carbetocin |
Non-Patent Citations (1)
| Title |
|---|
| 张慧 等: "高效液相色谱法分析卡贝缩宫素及其有关杂质", 药物分析杂志, vol. 27, no. 10, pages 1553 - 1555 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111060635A (en) * | 2019-11-27 | 2020-04-24 | 吉尔生化（上海）有限公司 | Analysis and detection method of carbetocin |
| CN111077243A (en) * | 2019-12-16 | 2020-04-28 | 成都市海通药业有限公司 | Detection method for oxytocin injection |
| CN113252807A (en) * | 2021-04-15 | 2021-08-13 | 武汉大安制药有限公司 | High performance liquid chromatography separation method for oxytocin raw material medicine related substances |
| CN113252807B (en) * | 2021-04-15 | 2022-05-06 | 远大生命科学(武汉)有限公司 | High performance liquid chromatography separation method for oxytocin raw material medicine related substances |
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