CN107271592A - A kind of hydrochloric acid draws the liquid chromatogram method for detecting purity of western separated from impurities associated therewith for pyrrole - Google Patents
A kind of hydrochloric acid draws the liquid chromatogram method for detecting purity of western separated from impurities associated therewith for pyrrole Download PDFInfo
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- CN107271592A CN107271592A CN201710426288.2A CN201710426288A CN107271592A CN 107271592 A CN107271592 A CN 107271592A CN 201710426288 A CN201710426288 A CN 201710426288A CN 107271592 A CN107271592 A CN 107271592A
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- Prior art keywords
- pyrrole
- hydrochloric acid
- western
- impurity
- draws
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- 239000012535 impurity Substances 0.000 title claims abstract description 111
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 98
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 238000000034 method Methods 0.000 title claims abstract description 28
- 239000007788 liquid Substances 0.000 title claims abstract description 16
- 239000012071 phase Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000000337 buffer salt Substances 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010828 elution Methods 0.000 claims abstract description 3
- 239000000945 filler Substances 0.000 claims abstract description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000000523 sample Substances 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 25
- 238000012360 testing method Methods 0.000 claims description 24
- 238000001514 detection method Methods 0.000 claims description 23
- 239000013558 reference substance Substances 0.000 claims description 17
- ROBLTDOHDSGGDT-UHFFFAOYSA-M sodium;pentane-1-sulfonate Chemical compound [Na+].CCCCCS([O-])(=O)=O ROBLTDOHDSGGDT-UHFFFAOYSA-M 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 238000007689 inspection Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 3
- YFSUTJLHUFNCNZ-UHFFFAOYSA-M 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctane-1-sulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F YFSUTJLHUFNCNZ-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 210000005252 bulbus oculi Anatomy 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 2
- 239000012488 sample solution Substances 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- REFMEZARFCPESH-UHFFFAOYSA-M sodium;heptane-1-sulfonate Chemical compound [Na+].CCCCCCCS([O-])(=O)=O REFMEZARFCPESH-UHFFFAOYSA-M 0.000 claims 1
- 238000011084 recovery Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 5
- 229960003962 trifluridine Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KGHYQYACJRXCAT-UHFFFAOYSA-N tipiracil hydrochloride Chemical group Cl.N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 KGHYQYACJRXCAT-UHFFFAOYSA-N 0.000 description 2
- MREIFUWKYMNYTK-UHFFFAOYSA-N 1H-pyrrole Chemical compound C=1C=CNC=1.C=1C=CNC=1 MREIFUWKYMNYTK-UHFFFAOYSA-N 0.000 description 1
- QVEDOQSCNLZPJX-UHFFFAOYSA-N 1h-pyrimidine-2,4-dione;hydrochloride Chemical compound Cl.O=C1C=CNC(=O)N1 QVEDOQSCNLZPJX-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 101710132082 Pyrimidine/purine nucleoside phosphorylase Proteins 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 1
- 102000005497 Thymidylate Synthase Human genes 0.000 description 1
- YGXVNFMRNNRJJE-UHFFFAOYSA-N [Na].CCCCCCC Chemical compound [Na].CCCCCCC YGXVNFMRNNRJJE-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000009658 destructive testing Methods 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical class O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- -1 second eyeball Chemical compound 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000004154 testing of material Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 229960001740 tipiracil hydrochloride Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 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
-
- 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
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)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention discloses the liquid chromatogram method for detecting purity that hydrochloric acid draws western separated from impurities associated therewith for pyrrole, chromatographic column of this method using octadecylsilane chemically bonded silica as filler, using a certain proportion of buffer salt ion pair organic phase as mobile phase, hydrochloric acid is quantitative determined in the way of gradient elution and draws west and its about the content of material for pyrrole, so that effectively control hydrochloric acid draws the quality in west for pyrrole.The inventive method has the advantages that specificity is strong, the degree of accuracy is high, easy to operate.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of analysis detection of medicine, particularly a kind of hydrochloric acid draws west for pyrrole
The liquid chromatogram method for detecting purity of separated from impurities associated therewith.
Background technology
Hydrochloric acid draws the west main component then drawn as Compound Tablet Trifluridine hydrochloric acid for pyrrole in western movie for pyrrole, uses
Type or relapsing advanced colorectal cancer can not be cut off in treatment, Trifluridine hydrochloric acid draws western movie to be replaced by Trifluridine and hydrochloric acid for pyrrole
Pyrrole draws west composition, and Trifluridine monophosphate metabolin can mix DNA, and by suppressing the activation plays of thymidylate synthetase, it is anti-swollen
Absorb good after knurl curative effect, oral administration, but easily degraded by the Thymidine phosphorylase of liver；Hydrochloric acid draws west to be bent fluorine for pyrrole
The competitive inhibitor of uridine digestive enzyme, it is possible to reduce the degraded of Trifluridine, strengthens its activity.
Hydrochloric acid draws west for pyrrole, and English name is tipiracil hydrochloride, and chemical name is chloro- the 6- ((2- of 5-
Imines pyrroles -1- bases) methyl) pyrimidine -2,4 (1H, 3H)-dione hydrochloride, molecular formula is C9H12Cl2N4O2, No. CAS:
183204-72-0, chemical structural formula is as follows：
The adverse reaction that medicine is produced in Clinical practice has outside the Pass except the pharmacological activity with principal component, with being deposited in medicine
Impurity also have much relations.To ensure the security of clinical application, the impurity in strict control medicine is needed.Through retrieval,
Have no that hydrochloric acid draws Patents or the open source literature report of west and its Related substance method for pyrrole at present.According to its technique,
The conditions such as property, the destructive testing of compound replace pyrrole to draw west and its have about the analysis method of material to set up a kind of hydrochloric acid
Significance.
The content of the invention
Draw the liquid chromatogram of western separated from impurities associated therewith pure for pyrrole it is an object of the invention to provide a kind of hydrochloric acid
Spend detection method, this method answers specificity good, can will likely degradation impurity, may residual initiation material and intermediate and master
Composition is effectively separated, and sensitivity is high, can be applied to the Control of Impurities that hydrochloric acid draws west for pyrrole.
Main flow prepares hydrochloric acid and draws western synthesis technique as follows for pyrrole：
Process route：
The present inventor draws western synthesis technique and degraded situation for above-mentioned hydrochloric acid for pyrrole, preferentially identifies 6 impurity, point
Not Wei impurity 1, impurity 2, impurity 3, impurity 4, impurity 5, the chemical constitution of impurity 6 and source be shown in Table 1：
The impurity structure of table 1 and source
The present invention is screened to chromatographic condition, can be efficiently separated 6 impurity, be established Related substance side
Method, between principal component and each relevant material, can reach baseline separation between each relevant material, reach the mesh of foregoing invention
's.
The technical solution adopted by the present invention is as follows：A kind of hydrochloric acid draws west and its about the analysis method of material for pyrrole, and it is mainly walked
Suddenly include：
(1) system suitability solution is configured：Hydrochloric acid is taken to draw western sample and each impurity reference substance appropriate for pyrrole, respectively with methanol or stream
Dynamic phased soln sample, is configured to every lmL hydrochloric molten for western and 0.01~1.5mg of each impurity reference substance the system suitability of pyrrole drawing
Liquid；
(1) take hydrochloric acid to draw western sample appropriate for pyrrole, respectively with methanol or mobile phase sample dissolution, be configured to that every lmL is hydrochloric to be replaced
Pyrrole draws 0.1~1.5mg of west sample solution；
(2) take each impurity reference substance appropriate respectively, respectively with methanol or mobile phase sample dissolution, be configured to every lmL containing each impurity
0.01~0.1mg reference substance solution；
(3) detected that testing conditions are using RPLC：Mobile phase is the p- organic phase of buffer salt-ion,
Gradient elution method is as follows：
(4) it is 0.5~1.5mL/min to set flow rate of mobile phase, and Detection wavelength is 180~250nm, and chromatographic column column oven temperature is
20~40 DEG C, sample size is 5~30 μ L.
(5) hydrochloric acid is calculated for pyrrole drawing west and its about the content of material with impurity reference substance external standard method.
3) mobile phase As are phosphate buffer (pH2.0) and 0.1% sodium pentanesulfonate, and Mobile phase B is methanol；Mobile phase is washed
De- gradient sets as follows:
| Time (min) | A phases (%) | B phases (%) |
| 0.00 | 95.0 | 5.0 |
| 5.00 | 95.0 | 5.0 |
| 30.00 | 90.0 | 10.0 |
| 55.00 | 85.0 | 15.0 |
| 65.00 | 40.0 | 60.0 |
| 80.00 | 40.0 | 60.0 |
| 80.10 | 95.0 | 5.0 |
| 105.00 | 95.0 | 5.0 |
As described in step (3), using octadecylsilane chemically bonded silica as chromatographic column filler, using Diode Array Detector
Device, using gradient elution program；
] as described in step (3), chromatographic column selects Shimadzu Intersil ODS-3C18
It is preferred that, in step (3), 250mm*4.6mm*5 μm of the model of chromatographic column
As described in step (3), the one kind of organic phase in following compound：Methanol, second eyeball, propyl alcohol, isopropanol；
It is preferred that, in step (3), organic phase is methanol.
As described in step (3), the one kind of buffer salt solution in following buffer salt：Phosphate, formates, acetic acid
Salt, citrate, perchlorate；
It is preferred that, in step (3), buffer salt solution is phosphate buffer
It is preferred that, in step (3), the pH of phosphate buffer is 2.0；
As described in step (3), the one kind of ion-pairing agent in following ion-pairing agent：Perfluorooctane sulfonate, heptane
Sodium sulfonate, dodecyl sodium sulfate, sodium pentanesulfonate etc.；
It is preferred that, in step (3), ion-pairing agent is sodium pentanesulfonate；
It is preferred that, in step (3), the solubility of sodium pentanesulfonate is 0.1%；
It is preferred that, in step (4), Detection wavelength is preferably 200~220nm,
It is preferred that, in step (4), Detection wavelength is preferably 210nm,
It is preferred that, in step (4), flow velocity is preferably 0.8~1.2ml/min,
It is preferred that, in step (4), flow velocity is preferably 1.0ml/min,
It is preferred that, in step (4), chromatographic column column temperature is preferably 30~40 DEG C,
It is preferred that, in step (4), chromatographic column column temperature is preferably 35 DEG C,
It is preferred that, in step (4), sample size is preferably 10~20 μ L.
It is preferred that, in step (4), sample size is preferably 10 μ L.
It is an advantage of the invention that：The hydrochloric acid of the present invention draws the liquid chromatogram purity detecting of western separated from impurities associated therewith for pyrrole
Method, specificity is good, can will likely degradation impurity, may residual initiation material and intermediate effectively separated with principal component,
And sensitivity is high, the Control of Impurities that hydrochloric acid draws west for pyrrole can be applied to.
Brief description of the drawings
Fig. 1：Impurity 1 positions collection of illustrative plates；
Fig. 2：Impurity 2 positions collection of illustrative plates；
Fig. 3：Impurity 3 positions collection of illustrative plates；
Fig. 4：Impurity 4 positions collection of illustrative plates；
Fig. 5：Impurity 5 positions collection of illustrative plates；
Fig. 6：Impurity 6 positions collection of illustrative plates；
Fig. 7：Hydrochloric acid draws west positioning collection of illustrative plates for pyrrole；
Fig. 8：System suitability collection of illustrative plates；
Fig. 9：Quantitative limit collection of illustrative plates；
Figure 10：Test limit collection of illustrative plates；
Figure 11：Flow velocity 0.8ml/min collection of illustrative plates；
Figure 12：Flow velocity 1.2ml/min collection of illustrative plates；
Figure 13：33 DEG C of collection of illustrative plates of column temperature；
Figure 14：37 DEG C of collection of illustrative plates of column temperature.
Embodiment
The test sample that is used in the present invention in embodiment, equipment are known product.
Example 1：
Checking draws western sample, each impurity reference substance information (confirming its structure by detection) with hydrochloric acid for pyrrole.
| Title | Lot number | Source | Purity (HPLC methods) |
| Hydrochloric acid draws west for pyrrole | 160820-2 | Self-control | / |
| Impurity 1 | 20151101 | Shenzhen brilliance bio tech ltd | 97.6% |
| Impurity 2 | 20150809 | Shenzhen brilliance bio tech ltd | 99.5% |
| Impurity 3 | 20150809 | Shenzhen brilliance bio tech ltd | 98.2% |
| Impurity 4 (starting material I) | BH-B62078-150729 | Shanghai Hanhong Chemical Industry Co., Ltd. | 99.3% |
| Impurity 5 (starting material II) | BH-B45026-151217 | Shanghai Hanhong Chemical Industry Co., Ltd. | 99.9% |
| Impurity 6 (intermediate) | 20160823 | Self-control | 99.8% |
Verify with each impurity stock solution, impurity reference substance solution, system suitability solution, need testing solution compound method
Detection method：
Instrument：Agilent high performance liquid chromatograph is equipped with PDAD
Chromatographic column：250mm*4.6mm*5 μm of Shimadzu Intersil ODS-3C18 models
Mobile phase A：The sodium pentanesulfonate of phosphate buffer (pH 2.0)+0.1% (weighs 19.7g disodium hydrogen phosphate dodecahydrates
With pipette 12ml phosphoric acid into 1L water, with disodium hydrogen phosphate adjust pH to 2.0, add 1g sodium pentanesulfonate)
Mobile phase B：Methanol
Gradient：
| Time (min) | A phases (%) | B phases (%) |
| 0.00 | 95.0 | 5.0 |
| 5.00 | 95.0 | 5.0 |
| 30.00 | 90.0 | 10.0 |
| 55.00 | 85.0 | 15.0 |
| 65.00 | 40.0 | 60.0 |
| 80.00 | 40.0 | 60.0 |
| 80.10 | 95.0 | 5.0 |
| 105.00 | 95.0 | 5.0 |
Detection wavelength：210nm
Column temperature：35℃
Flow velocity 1.0ml/min
Sample size：10μl
According to above-mentioned testing conditions, precision measures the μ l of system suitability solution 10 injection liquid chromatographs and detected, as a result accords with
Close and require, precision measures need testing solution and each 10 μ l injections liquid chromatograph of contrast solution is detected, is calculated by external standard method
The content of west and its impurity is drawn for pyrrole for hydrochloric acid in solution, result data see the table below
Calculation formula：
Impurity content=(ASample×V×ZIt is flat)/MSample
In formula：ASampleFor the peak area of measured object in test sample,
MSampleFor the sample weighting amount of test sample
V is the extension rate of test sample
ZIt is flatThe ratio of concentration and peak area for measured object reference substance
The hydrochloric acid of table 1 draws the relevant material testing result in west for pyrrole：
As can be seen that sample measurement result meets the requirements in from the above, retention time, separating degree, theoretical cam curve etc. are
Meet the requirements, detection data are reliable, illustrate that this method can be used for detection hydrochloric acid and draw west and its impurity for pyrrole.
Method validation
Specificity is tested
Detection method：Ibid.
Hydrochloric acid is prepared respectively for the western need testing solution of pyrrole drawing and each relevant material reference substance solution, and hydrochloric acid draws west and each for pyrrole
Mixed solution and blank solvent solution about material, take 10 μ l to inject liquid chromatograph and are detected respectively.Hydrochloric acid replaces pyrrole
Western and each impurity separating degree is drawn to the results are shown in Table 2, collection of illustrative plates is shown in Fig. 1-8.
The hydrochloric acid of table 2 draws western and each impurity separating degree result for pyrrole
| Title | Impurity positions retention time | Biased sample retention time | Separating degree | Theoretical cam curve |
| Impurity 5 | 6.326 | 6.325 | - | 9763 |
| Hydrochloric acid draws west for pyrrole | 10.247 | 10.254 | 11.51 | 9294 |
| Impurity 4 | 14.735 | 14.748 | 4.21 | 14665 |
| Impurity 2 | 28.422 | 28.431 | 24.36 | 32125 |
| Impurity 1 | 30.894 | 30.914 | 3.84 | 35416 |
| Impurity 3 | 32.749 | 32.965 | 2.74 | 35957 |
| Impurity 6 | 37.163 | 37.176 | 5.91 | 34661 |
Conclusion：Blank solvent is noiseless to main peak, and each impurity peaks separating degree meets the requirements, noiseless to main peak.
Sample introduction Precision Experiment：
Detection method：Ibid
Poly-doped impurity reference substance solution continuous sample introduction 6 times, according to the calculated by peak area RSD (RSD≤2.0%) of each impurity,
It the results are shown in Table 3
The sample introduction Precision Experiment result of table 3
Conclusion：This method sample introduction precision meets the requirements.
Quantitative limit, test limit experiment：
Detection method：Ibid.
(1) impurity reference substance solution is diluted into sample detection step by step
Quantitative limit signal to noise ratio is 10:Each impurity concentration testing result when 1 is shown in Table 4, and collection of illustrative plates is shown in Fig. 9.
The quantitative limit of table 4
| Impurity title | Quantitative limit concentration | Quantitative limit/ng |
| Impurity 5 | 0.02284 | 0.2284 |
| Impurity 4 | 0.0501 | 0.501 |
| Impurity 2 | 0.213 | 2.13 |
| Impurity 1 | 0.1054 | 1.054 |
| Impurity 3 | 0.1004 | 1.004 |
| Impurity 6 | 0.05425 | 0.5425 |
Test limit signal to noise ratio is 3:Each impurity concentration testing result when 1 is shown in Table 5, and collection of illustrative plates is shown in Figure 10
The test limit of table 5
Linear test
Precision weighs each impurity reference substance in right amount, is dissolved and is diluted with 50% methanol aqueous solution, is configured to various concentrations
Solution distinguishes sample introduction and records chromatogram, using the actual concentrations of each impurity as abscissa, and peak area is ordinate, obtains each impurity
Equation of linear regression.
Detection method：Ibid.
The linear test of impurity 1 the results are shown in Table 6
Table 6：Impurity 1 is linear
The linear test of impurity 2 the results are shown in Table 7：
Table 7：Impurity 2 is linear
The linear test of impurity 3 the results are shown in Table 8：
Table 8：Impurity 3 is linear
The linear test of impurity 4 the results are shown in Table 9：
Table 9：Impurity 4 is linear
The linear test of impurity 5 the results are shown in Table 10：
Table 10：Impurity 5 is linear
The linear test of impurity 6 the results are shown in Table 11：
Table 11：Impurity 6 is linear
Conclusion：Impurity 1 is in 0.1054~11.76 μ g/ml concentration ranges, and impurity 2 is in 0.213~12.75 μ g/ml concentration
In the range of, impurity 3 is in 0.1004~12.048 μ g/ml concentration ranges, and impurity 4 is in 0.0501~12.024 μ g/ml concentration models
In enclosing, impurity 5 is in 0.02284~13.704 μ g/ml concentration ranges, and impurity 6 is in 0.05425~13.02 μ g/ml concentration ranges
Interior, linear relationship is good.
The rate of recovery is tested
Each concentration of impurities reference substance mixing storing solution is prepared, impurity is added into hydrochloric acid with (80%, 100%, 120%) concentration
Drawn for pyrrole and prepare 9 parts of need testing solutions in west altogether, calculated the rate of recovery, the results are shown in Table 12-17
Detection method：Ibid.
Table 12：The rate of recovery of impurity 1
Table 13：The rate of recovery of impurity 2
Table 14：The rate of recovery of impurity 3
Table 15：The rate of recovery of impurity 4
Table 16：The rate of recovery of impurity 5
The rate of recovery of 17 impurity of table 6
Durability is tested
(1) detection method：Only change flow velocity, other are with more than.
Flow velocity is changed into 0.8ml/min, 1.0ml/min and 1.2ml/min, with the mixed solution sample introduction of specificity, examined
The separating degree of each impurity is examined, 18 are the results are shown in Table, collection of illustrative plates is shown in 11-12.
(2) detection method：Only change column temperature, other are ibid.
Column temperature is changed into 33 DEG C, 35 DEG C, 37 DEG C, with the mixed solution sample introduction of specificity, the separating degree of each impurity is investigated,
18 are the results are shown in Table, collection of illustrative plates is shown in 13-14.
The impurity separating degree result of table 18
Conclusion：Separating degree is good under the conditions of each, illustrates this method good tolerance on flow velocity and column temperature.
Claims (10)
1. a kind of hydrochloric acid draws the liquid chromatogram method for detecting purity of western separated from impurities associated therewith, its key step bag for pyrrole
Include：
1) configuration of system suitability solution：Take hydrochloric acid to draw western sample and each impurity reference substance appropriate for pyrrole, respectively with methanol or
Mobile phase sample dissolution, is configured to every lmL hydrochloric for western and 0.01~1.5mg of each impurity reference substance the system suitability of pyrrole drawing
Solution；
2) take hydrochloric acid to draw western sample appropriate for pyrrole, respectively with methanol or mobile phase sample dissolution, be configured to every lmL hydrochloric for pyrrole
Draw 0.1~1.5mg of west sample solution；
3) take each impurity reference substance appropriate respectively, respectively with methanol or mobile phase sample dissolution, be configured to every lmL containing each impurity
0.01~0.1mg reference substance solution；
4) detected that testing conditions are using RPLC：Mobile phase is the p- organic phase of buffer salt-ion, ladder
Spend elution process as follows：
5) it is 0.5~1.5mL/min to set flow rate of mobile phase, and Detection wavelength is 200~250nm, and chromatographic column column oven temperature is
20~40 DEG C, sample size is 5~30 μ L；
6) (1), (2), (3) are added in above-mentioned reaction system and detected respectively, finally with external standard method calculate hydrochloric acid replace than
Draw west and its about the content of material.
2. a kind of hydrochloric acid according to claim 1 draws the liquid chromatogram purity inspection of western separated from impurities associated therewith for pyrrole
Survey method, it is characterised in that step 4) in, using octadecylsilane chemically bonded silica as chromatographic column filler, examined using diode array
Device is surveyed, using gradient elution program.
3. a kind of hydrochloric acid according to claim 2 draws the liquid chromatogram purity inspection of western separated from impurities associated therewith for pyrrole
Survey method, chromatographic column is Shimadzu Intersil ODS-3C18,250mm*4.6mm*5 μm of model.
4. a kind of hydrochloric acid according to claim 1 draws the high performance liquid chromatography of western separated from impurities associated therewith pure for pyrrole
Spend detection method, it is characterised in that step 4) in the one kind of described organic phase in following compound：Methanol, second eyeball, third
Alcohol, isopropanol.
5. a kind of hydrochloric acid according to claim 4 draws the high performance liquid chromatography of western separated from impurities associated therewith pure for pyrrole
Spend detection method, it is characterised in that step 4) in described organic phase be methanol.
6. a kind of hydrochloric acid according to claim 1 draws the liquid chromatogram purity inspection of western separated from impurities associated therewith for pyrrole
Survey method, it is characterised in that step 4) described in one kind in following buffer salt of buffer salt solution：Phosphate, formates,
Acetate, citrate, perchlorate.
7. analysis determining method according to claim 6, it is characterised in that step 4) described in buffer salt solution be phosphoric acid
Salt buffer, pH is 2.0.
8. a kind of hydrochloric acid according to claim 1 draws the liquid chromatogram purity inspection of western separated from impurities associated therewith for pyrrole
Survey method, it is characterised in that step 4) described in one kind in following ion-pairing agent of ion-pairing agent：Perfluorooctane sulfonate,
Sodium heptanesulfonate, dodecyl sodium sulfate, sodium pentanesulfonate etc..
9. a kind of hydrochloric acid according to claim 8 draws the high performance liquid chromatography of western separated from impurities associated therewith pure for pyrrole
Spend detection method, it is characterised in that step 4) described in ion-pairing agent be 0.1% sodium pentanesulfonate.
10. a kind of hydrochloric acid according to claim 1 draws the high performance liquid chromatography of western separated from impurities associated therewith for pyrrole
Method for detecting purity, it is characterised in that step 5) described in Detection wavelength be 210nm, flow velocity is 1.0ml/min, chromatographic column column temperature
For 35 DEG C, sample size is 10 μ L.
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