CN107266394A - Sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application - Google Patents
Sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application Download PDFInfo
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- CN107266394A CN107266394A CN201710659158.3A CN201710659158A CN107266394A CN 107266394 A CN107266394 A CN 107266394A CN 201710659158 A CN201710659158 A CN 201710659158A CN 107266394 A CN107266394 A CN 107266394A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
Abstract
The invention discloses sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application.The impurity V, VI that the present invention is provided has epoxy caution structure, and present inventor has detected both impurity in the pressure light degradation experiment of sarpogrelate hydrochloride bulk drug, Salmonella reversion test shows that two kinds of impurity are the positive, and genetoxic risk is very high.According to the control requirement of genetoxic impurity in medicine, both genetoxic impurity should be included in quality standard and be monitored, and the genetoxic impurity V, VI that the present invention is provided can be used as impurity reference substance in the quality control of sarpogrelate hydrochloride bulk drug or preparation.The preparation method that the present invention is provided can disposably be prepared into impurity V, VI, and purity is more than 98%；The detection method that the present invention is provided effectively can separate impurity genetoxic V, VI with Sarpogrelate, impurity I, II, III, IV, and separating degree is all higher than 1.5, and tailing factor is in prescribed limit.
Description
Technical field
The invention belongs to Control of drug quality field, and in particular to sarpogrelate hydrochloride genetoxic impurity V, VI and its
Preparation method, detection method, application.
Background technology
In Japanese Initial Public Offering, trade name Anplag is a kind of 5-HT2 receptor blocks to Sarpogrelate hydrochloride tablets within 1993
Agent, can suppress platelet aggregation, suppress vessel retraction, with anti thrombotic action and improvement microcirculation.Its indication is to change
The all symptoms of ischemic such as ulcer, pain and creeping chill caused by kind chronic arterial occlusion disease.
At present, the quality research of sarpogrelate hydrochloride bulk drug and its preparation is related to following four kinds of light degradation impurity：
Applicant have previously been provided a kind of method that one kettle way prepares sarpogrelate hydrochloride light degradation impurity I, II, III, IV
(application number 2017106469276), this method prepares the degraded containing impurity I, II, III, IV by one kettle way degraded and mixed
Compound, then by the disposable isolated impurity I, II, III, IV of high-speed countercurrent chromatography, purity is more than 98%, Ke Yiyong
Make impurity reference substance, and total recovery is more than 80%, raw material availability is high, and step is few, efficiency high, and its high speed adverse current chromatogram figure is such as
Shown in Fig. 1.Applicant is identified that the unknown chromatographic peak of two of which 1,2 being found to be two kinds has potential heredity poison
Property impurity (there is epoxy caution structure, reference can be made to " caution structure of genetoxic impurity, Chinese Journal of New Drugs 2014 year the
The phase of volume 23 the 18th "), and to have detected both miscellaneous in the pressure light degradation experiment of sarpogrelate hydrochloride bulk drug by applicant
Matter, further Salmonella reversion test shows that two kinds of impurity are the positive.(medicine is required according to the control of genetoxic impurity in medicine
The assessment and control of genetoxic impurity in product, Chinese Journal of Modern Applied Pharmacy in September, 2014 the 9th phase of volume 31), should be by both
Impurity is included in quality standard and is monitored.
The content of the invention
Present invention aims at provide sarpogrelate hydrochloride genetoxic impurity V, VI and preparation method thereof, detection method,
Using.
The present invention is achieved by following technical scheme：
The genetoxic impurity V, VI of following chemical constitution：
The preparation method of above-mentioned genetoxic impurity V, VI, including：
Step S1, light degradation：
The dissolving of sarpogrelate hydrochloride water is configured to sarpogrelate hydrochloride solution, prior to 80-90 DEG C high-temperature process 1-2 is small
When, then successively in 1,200,000 lux CWF light irradiation 4-6 hours, 200 watts of hours/square metre ultraviolet fluorescent lamp
Irradiate 3-5 hours, the solution concentrated frozen of degraded is finally obtained into degradation of mixture to dry；
Step S2, high speed adverse current chromatogram separation：
Above-mentioned degradation of mixture is dissolved as sample solution with isometric stationary phase and mobile phase, with ethyl acetate-second
Alcohol-water-formic acid (4:1:5:0.025, v/v/v/v) it is two-phase solvent system, upper phase is stationary phase, and lower phase is mobile phase, in master
Under the conditions of machine rotating speed 800r/min, flow velocity 2.0mL/min, Detection wavelength 272nm, flow point is collected according to chromatogram, is concentrated and dried
Obtain impurity V, VI.
Preferably, high speed adverse current chromatogram is used as separating pipe, diameter 2.3mm, separation using multilayer polytetrafluoroethylarticles helix tube
Volume 230mL, β value is 0.5-0.8.
Preferably, high speed adverse current chromatogram separation column temperature is 35 DEG C.
Preferably, preferably 85 DEG C of high-temperature process is handled 1.5 hours.
Preferably, photo-irradiation treatment preferred scheme is：Prior to 1,200,000 lux CWF light irradiation 5 hours, then
In 200 watts of hours/square metre Ultraluminescence light irradiation 4 hours.
The detection method of above-mentioned genetoxic impurity V, VI, including following chromatographic parameter：
Chromatographic column：Octadecylsilane chemically bonded silica (C18) chromatographic column；
Mobile phase：A phases are tetrahydrofuran-aqueous solution that concentration expressed in percentage by volume is 0.2%；
B phases are tetrahydrofuran-acetonitrile solution that concentration expressed in percentage by volume is 0.2%；
Elution program：0-5min, 5%B phase；5-10min, 5% → 35%B phase；10-30min, 35% → 65%B phase；
30-32min, 65% → 100%B phase；32-35min, 100%B phase；35-37min, 100% → 5%B phase；37-40min, 5%
B phases；Flow velocity is 1.0mL/min；
Column temperature：34-36℃；Detection wavelength：272±2nm.
Preferably, the specification of the chromatographic column is long 250mm, internal diameter 4.6mm, 5 μm of packing material size.
Preferably, the preferred ZORBAX SB-C18 posts of chromatographic column.
Genetoxic impurity V, VI is used as impurity reference substance in the quality control of sarpogrelate hydrochloride bulk drug or preparation
Purposes.
Advantages of the present invention：
1st, the invention provides the impurity V, VI (there is epoxy caution structure) that two kinds have potential genetoxic, and
Present inventor has detected both impurity in the pressure light degradation experiment of sarpogrelate hydrochloride bulk drug, further
Salmonella reversion test shows that two kinds of impurity are the positive, and genetoxic risk is very high.According to the control of genetoxic impurity in medicine
System requires that both genetoxic impurity should be included in quality standard and be monitored, the genetoxic impurity V of the invention provided,
VI can be used as impurity reference substance in the quality control of sarpogrelate hydrochloride bulk drug or preparation；
2nd, the preparation method that the present invention is provided can disposably prepare impurity V, VI, and purity is more than 98%；The preparation
Method can also prepare other four kinds of impurity I, II, III, IV, efficiency high simultaneously；
3rd, the detection method that provides of the present invention can effectively by impurity genetoxic V, VI and Sarpogrelate, impurity I, II,
IIIth, IV separation, separating degree is all higher than 1.5, and tailing factor is in prescribed limit.
Brief description of the drawings
Fig. 1 is the high-speed counter-current separation chromatography figure of sarpogrelate hydrochloride Photodegradation Products；
Fig. 2 is the separation chromatography figure of Sarpogrelate and impurity I, II, III, IV, V, VI；Wherein A is mixed reference substance solution
Chromatogram, B is sarpogrelate hydrochloride+mixed reference substance solution chromatogram, and C is pressure light degradation solution chromatogram.
Embodiment
Technical scheme is further described with reference to specific embodiment.
The relevant information for the high-speed counter-current chromatograph that following embodiments are used：
GS10A types high-speed counter-current chromatograph (HSCCC, Beijing Amy woods Science and Technology Ltd.), multilayer polytetrafluoroethylarticles spiral shell
Coil (diameter 2.3mm, separated volume 230mL, β value is 0.5-0.8), TBP pumps (Shanghai Tongtian Biotechnology Co., Ltd.),
8823B- UV-detectors (Beijing Bin Daying creates Science and Technology Ltd.), 3057-11 recorders (the limited public affairs of Chongqing river instrument head factory
Department).
The preparation of the light degradation impurity I, II, III, IV, V, VI of embodiment 1
The preparation method of degradation of mixture：
The dissolving of 60mg sarpogrelate hydrochlorides water is taken to be configured to 3mg/mL solution, prior to 85 DEG C high-temperature process 1.5 hours,
Again successively in 1,200,000 lux CWF light irradiation 5 hours, 200 watts of hours/square metre Ultraluminescence light irradiation 4
Hour, the solution concentrated frozen of degraded is finally obtained into degradation of mixture to dry.
The high-speed counter-current separation method of degradation of mixture：
Separation prepares ethyl acetate, alcohol and water-formic acid (4 in first 12 hours:1:5:0.025, v/v/v/v) solvent system, tool
Body compound method is：Four kinds of solvents are mixed in proportion, acutely after concussion, standing makes it be layered completely in 12 hours, in funnel
It is separated upper and lower, upper phase is used as stationary phase, and lower phase is used as mobile phase, with preceding ultrasonic half an hour.Phase 5mL is taken respectively with
Phase 5mL, after mixing using above-mentioned freeze-dried powder all dissolving (to need ultrasonic wave added to dissolve) wherein molten as the sample of high-speed counter-current
Liquid.
The upper phase (stationary phase) of ultrasound degassing in two phase solvent system is pumped into HSCCC separation with 20mL/min flow velocity
In pipe (35 DEG C of separation temperature), after upper phase is full of whole separating pipe, regulation engine speed reaches 800r/min, turns clockwise,
After after stabilization of speed, lower phase (mobile phase) is pumped into 2.0mL/min flow velocitys, Detection wavelength is 272nm.When mobile phase is from main frame mouthful
During outflow, explanation system has reached fluid dynamic equilibrium, and the 10mL sample solutions being ready for now are injected into HSCCC instrument,
Gathered data is started simultaneously at, target component is collected according to chromatogram, chromatogram is as shown in Figure 1.
The unknown nuclear-magnetism appraising datum of chromatographic peak 2：1H-NMR (DMSO-d6,600MHz), δ：2.25 (6H, N-CH3), 2.36-
2.64 (2H, N-CH2), 3.72 (3H, O-CH3), 4.06 (1H, CH-OH), 5.35 (1H ,-OH), 4.12-4.18 (2H, O-CH2),
4.24 (2H, CH-O-CH), 6.91-7.28 (8H, phenyl ring hydrogen)；ESI, m/z：344.18[M+H]+；
It is accredited as following structure：
The unknown nuclear-magnetism appraising datum of chromatographic peak 1：1H-NMR (DMSO-d6,600MHz), δ：2.52 (2H, CO-CH2), 2.73
(2H, CO-CH2), 2.65,2.90 (2H, N-CH2), 3.27 (3H, N-CH3), 3.70 (3H, O-CH3), 4.06,4.29 (2H, O-
CH2), 4.23 (2H, CH-O-CH), 5.12 (1H, O-CH), 5.54 (1H ,-NH-), 12.16 (1H ,-COOH), 6.90-7.28
(8H, phenyl ring hydrogen)；ESI, m/z：430.18[M+H]+；
It is accredited as following structure：
The corresponding flow point of each chromatographic peak is concentrated and dried to obtain impurity I, II, III, IV, V, VI, purity is all higher than 98%.
The liquid phase detection method of the genetoxic impurity V, VI of embodiment 2
1st, chromatographic condition
Chromatographic column：ZORBAX SB-C18 chromatographic columns (250mm × 4.6mm, 5 μm)；
Mobile phase：A phases are tetrahydrofuran-aqueous solution that concentration expressed in percentage by volume is 0.2%；
B phases are tetrahydrofuran-acetonitrile solution that concentration expressed in percentage by volume is 0.2%；
Elution program：0-5min, 5%B phase；5-10min, 5% → 35%B phase；10-30min, 35% → 65%B phase；
30-32min, 65% → 100%B phase；32-35min, 100%B phase；35-37min, 100% → 5%B phase；37-40min, 5%
B phases；Flow velocity is 1.0mL/min；
Column temperature：35℃；
Detection wavelength：272nm；
Sample size：10μL.
2nd, solution is prepared
Reference substance solution：The reference substance of impurity I, II, III, IV, V, VI is taken to be prepared with the flowing phased soln of 5%B phases respectively
The independent reference substance solution and mixed reference substance solution for being about 1 μ g/mL into concentration；
Sarpogrelate hydrochloride+mixed reference substance solution：Sarpogrelate hydrochloride, impurity I, II, III, IV, V, VI are taken respectively
Reference substance is configured to the solution that impurity concentration respectively may be about 1 μ g/mL, Sarpogrelate 1mg/mL with the flowing phased soln of 5%B phases；
Force light degradation solution：It is about the molten of 1mg/mL to take sarpogrelate hydrochloride to be configured to concentration with deionized water dissolving
Liquid, is placed in pressure light degradation chamber, in illumination 10 days under 4500 ± 500Lx intensities of illumination.
3rd, analysis result
Precision measures reference substance solution, sarpogrelate hydrochloride+mixed reference substance solution, forces the μ L of light degradation solution 10 respectively
Analyzed according to above-mentioned chromatographic condition sample introduction.As a result the chromatogram of each solution is as shown in Fig. 2 wherein A is mixed reference substance solution color
Spectrogram, B is sarpogrelate hydrochloride+mixed reference substance solution chromatogram, and C is pressure light degradation solution chromatogram.Can from Fig. 2
Go out, the detection method that provides of the present invention can effectively by impurity genetoxic V, VI and Sarpogrelate, impurity I, II, III, IV point
From separating degree is all higher than 1.5, and peak shape is good.Moreover, it is miscellaneous to have detected genetoxic in sarpogrelate hydrochloride pressure light degradation sample
Matter V, VI, according to relevant laws and regulations, both genetoxic impurity should be included in quality standard and be monitored.
Above-described embodiment is proved：
The invention provides the impurity V, VI (having epoxy caution structure) that two kinds have potential genetoxic, Er Qieben
The inventor of application has detected both impurity in the pressure light degradation experiment of sarpogrelate hydrochloride bulk drug, further
Salmonella reversion test shows that two kinds of impurity are the positive, and genetoxic risk is very high.According to the control of genetoxic impurity in medicine
System requires that both genetoxic impurity should be included in quality standard and be monitored, the genetoxic impurity V of the invention provided,
VI can be used as impurity reference substance in the quality control of sarpogrelate hydrochloride bulk drug or preparation；
The preparation method that the present invention is provided can disposably prepare impurity V, VI, and purity is more than 98%；The preparation side
Method can also prepare other four kinds of impurity I, II, III, IV, efficiency high simultaneously；
The detection method that the present invention is provided can effectively by impurity genetoxic V, VI and Sarpogrelate, impurity I, II,
IIIth, IV separation, separating degree is all higher than 1.5, and tailing factor is in prescribed limit.
Claims (10)
1. the genetoxic impurity VI of following chemical constitution：
2. the preparation method of genetoxic impurity VI described in claim 1, it is characterised in that including：
Step S1, light degradation：
The dissolving of sarpogrelate hydrochloride water is configured to sarpogrelate hydrochloride solution, prior to 80-90 DEG C high-temperature process 1-2 hours,
Again successively in 1,200,000 lux CWF light irradiation 4-6 hours, 200 watts of hours/square metre ultraviolet fluorescent lamp shine
Penetrate 3-5 hours, the solution concentrated frozen of degraded is finally obtained into degradation of mixture to dry；
Step S2, high speed adverse current chromatogram separation：
Above-mentioned degradation of mixture is dissolved as sample solution with isometric stationary phase and mobile phase, with ethyl acetate-ethanol-
Water-formic acid (4:1:5:0.025, v/v/v/v) it is two-phase solvent system, upper phase is stationary phase, and lower phase is mobile phase, is turned in main frame
Under the conditions of fast 800r/min, flow velocity 2.0mL/min, Detection wavelength 272nm, flow point is collected according to chromatogram, is concentrated and dried miscellaneous
Matter VI.
3. preparation method according to claim 2, it is characterised in that：High speed adverse current chromatogram uses multilayer polytetrafluoroethylarticles spiral shell
Coil is as separating pipe, diameter 2.3mm, and separated volume 230mL, β value is 0.5-0.8.
4. preparation method according to claim 2, it is characterised in that：High speed adverse current chromatogram separation column temperature is 35 DEG C.
5. preparation method according to claim 2, it is characterised in that：Preferably 85 DEG C of high-temperature process is handled 1.5 hours.
6. preparation method according to claim 2, it is characterised in that photo-irradiation treatment preferred scheme is：Prior to 120
Ten thousand lux CWF light irradiations 5 hours, then at 200 watts of hours/square metre Ultraluminescence light irradiation 4 hours.
7. the detection method of genetoxic impurity VI described in claim 1, it is characterised in that including following chromatographic parameter：
Chromatographic column：Octadecylsilane chemically bonded silica (C18) chromatographic column；
Mobile phase：A phases are tetrahydrofuran-aqueous solution that concentration expressed in percentage by volume is 0.2%；
B phases are tetrahydrofuran-acetonitrile solution that concentration expressed in percentage by volume is 0.2%；
Elution program：0-5min, 5%B phase；5-10min, 5% → 35%B phase；10-30min, 35% → 65%B phase；30-
32min, 65% → 100%B phase；32-35min, 100%B phase；35-37min, 100% → 5%B phase；37-40min, 5%B
Phase；Flow velocity is 1.0mL/min；
Column temperature：34-36℃；
Detection wavelength：272±2nm.
8. detection method according to claim 7, it is characterised in that the specification of the chromatographic column is long 250mm, internal diameter
4.6mm, 5 μm of packing material size.
9. detection method according to claim 8, it is characterised in that：The preferred ZORBAX SB-C18 posts of chromatographic column.
10. genetoxic impurity VI is used as in the quality control of sarpogrelate hydrochloride bulk drug or preparation described in claim 1
The purposes of impurity reference substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710659158.3A CN107266394A (en) | 2017-08-04 | 2017-08-04 | Sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710659158.3A CN107266394A (en) | 2017-08-04 | 2017-08-04 | Sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application |
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| CN107266394A true CN107266394A (en) | 2017-10-20 |
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| CN201710659158.3A Pending CN107266394A (en) | 2017-08-04 | 2017-08-04 | Sarpogrelate hydrochloride genetoxic impurity VI and preparation method thereof, detection method, application |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356012A (en) * | 2014-09-23 | 2015-02-18 | 山东齐都药业有限公司 | Preparation method of sarpogrelate hydrochloride photodegradation impurities |
-
2017
- 2017-08-04 CN CN201710659158.3A patent/CN107266394A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356012A (en) * | 2014-09-23 | 2015-02-18 | 山东齐都药业有限公司 | Preparation method of sarpogrelate hydrochloride photodegradation impurities |
Non-Patent Citations (1)
| Title |
|---|
| 张建礼: "盐酸沙格雷酯降解杂质的制备", 《中国抗生素杂志》 * |
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