CN105929030B - The detection method of organic impurities in a kind of piperazine Ma Selin - Google Patents
The detection method of organic impurities in a kind of piperazine Ma Selin Download PDFInfo
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- CN105929030B CN105929030B CN201510958090.XA CN201510958090A CN105929030B CN 105929030 B CN105929030 B CN 105929030B CN 201510958090 A CN201510958090 A CN 201510958090A CN 105929030 B CN105929030 B CN 105929030B
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- 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
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Abstract
The present invention provides a kind of detection methods of organic impurities in piperazine Ma Selin, including：High performance liquid chromatography detection is carried out to piperazine Ma Selin, mobile phase during the high performance liquid chromatography detection includes water phase and organic phase, the water phase is the aqueous solution of acid, the organic phase is the organic solution of acid, and the acid in acid and organic phase in the water phase includes formic acid, trifluoroacetic acid or phosphoric acid；Solvent in the organic solution includes methanol or acetonitrile；The organic impurities is the compound of structure shown in Formulas I.The detection method of organic impurities in piperazine Ma Selin provided by the invention, the water phase of predetermined substance and organic phase composition mobile phase are used during carrying out high performance liquid chromatography detection to piperazine Ma Selin, this mobile phase can preferably detach organic impurities, and method provided by the invention is enable accurately to detect the organic impurities in piperazine Ma Selin.In addition, the detection method of organic impurities is stable in piperazine Ma Selin provided by the invention, reproducible, specificity is strong.
Description
Technical field
The present invention relates to a kind of detection methods of organic impurities in piperazine Ma Selin technical fields more particularly to piperazine Ma Selin.
Background technology
Whole world parkinsonian about 7 million to one 10,000,000 at present, China just have 2,600,000, rank first in the world, often
Year will also increase by 100,000 neopathy patients.50% or more parkinsonian once had mental symptom (PDP).These spirit
Symptom is mainly shown as illusion and vain hope, this carrys out bigger challenge to the treatment of parkinsonian and tourniquet.Acadia
(Acadia Pharmaceuticals) is absorbed in for nervous system and relevant maincenter positioned at one of San Diego, USA
The biopharmaceutical company of nerve problems disease research new treatment, piperazine Ma Selin/Mo Fanselin (common names：
Pimavanserin, trade name：Nuplazid) be the independent research of drugmaker of Acadia patent medicine, for treat pa gold
Sen Shi disease mental symptoms are non-dopamine neurotransmitter similar to object, can be more without influencing with selective exclusion five hydroxytryptamine 2A receptors
The effect of bar amine.Piperazine Ma Selin/Mo Fanselin (Pimavanserin, Nuplazid) was in 3 U.S. Huo food of September in 2014
Drug Administration (FDA), which authorizes, breaks through sex therapy certification.Breaking through sex therapy certification is created by FDA, it is intended to which acceleration is opened
Hair and the new drug for examining serious or life-threatening the disease for the treatment of.Acadia (Acadia) drugmaker will be in the end of the year 2014
Forward direction FDA submits the New Drug Application of piperazine Ma Selin/Mo Fanselin (Pimavanserin).
Impurity in drug refers to the substance of any influence pharmaceutical purity, including organic impurities, inorganic impurity and residual solvent.
The research of inorganic impurity and residual solvent and detection method are relatively ripe, and the versatility of method is stronger, control standard
Compare and define, from the point of view of drug evaluation practice, inorganic impurity and residual solvent have obtained preferably in declaring registration drug
Research and control.Compared with inorganic impurity and residual solvent, the research and control of organic impurities are more complex, in point of impurity
Determined from identification, impurity source analysis, impurity safety research, the limit of impurities etc. is required for the structure in conjunction with drug special
The a large amount of thoroughgoing and painstaking research of the progress such as point, preparation process, storage-stable, clinical application feature.
The organic impurities with structure shown in Formulas I can be introduced in piperazine Ma Selin medicine production process：
The structure of this organic impurities and the structure of piperazine Ma Selin are extremely close, can seriously affect the purity of drug, be
Determine qualified or not one of the key factor of drug.Therefore, the content of organic impurities in piperazine Ma Selin is accurately detected for control
Drug product quality has great importance.
Currently, yet there are no to organic impurities is detected in piperazine Ma Selin relevant report.
Invention content
In view of this, the purpose of the present invention is to provide a kind of detection method of organic impurities in piperazine Ma Selin, the present invention
The method of offer can accurately detect the organic impurities in piperazine Ma Selin.
The present invention provides a kind of detection methods of organic impurities in piperazine Ma Selin, including：
High performance liquid chromatography detection is carried out to piperazine Ma Selin, obtains the content of organic impurities in piperazine Ma Selin；It is described efficient
Mobile phase during liquid chromatographic detection includes water phase and organic phase, and the water phase is the aqueous solution of acid, and the organic phase is
The organic solution of acid, the acid in acid and organic phase in the water phase includes formic acid, trifluoroacetic acid or phosphoric acid；The organic solution
In solvent include methanol or acetonitrile；The organic impurities is the compound of structure shown in Formulas I：
Preferably, the mass concentration of sour aqueous solution is 0.05%~0.15%.
Preferably, the mass concentration of the organic solution of the acid is 0.05%~0.15%.
Preferably, the mass ratio of the water phase and organic phase is (50~60)：(50~40).
Preferably, the flow velocity of mobile phase is 0.5mL/min~1.5mL/min in the efficient liquid phase detection process.
Preferably, mobile phase is made to pass through chromatography by the way of gradient elution during the high performance liquid chromatography detection
The process of column, the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 45%~55% by 80%~90%, organic
Mutually the mass content in mobile phase is increased to 45%~55% by 10%~20%；
In 25min~35min, mass content of the water phase in mobile phase is reduced to 10%~0 by 45%~55%, organic
Mutually the mass content in mobile phase is increased to 90%~100% by 45%~55%；
In 35min~38min, mass content of the water phase in mobile phase keeps 10%~0, and organic phase is in mobile phase
Mass content keeps 90%~100%；
In 38min~40min, mass content of the water phase in mobile phase is increased to 80%~90% by 10%~0, organic
Mutually the mass content in mobile phase is reduced to 10%~20% by 90%~100%；
In 40min~45min, mass content of the water phase in mobile phase keeps 80%~90%, and organic phase is in mobile phase
In mass content keep 10%~20%.
Preferably, the chromatographic column used during the high performance liquid chromatography detection is C8 chromatographic columns or C18 chromatographic columns.
Preferably, the chromatographic column column temperature during the high performance liquid chromatography detection is 25 DEG C~45 DEG C.
Preferably, the detector during the high performance liquid chromatography detection is UV detector.
Preferably, the Detection wavelength during the high performance liquid chromatography detection is 200nm~240nm.
The detection method of organic impurities in piperazine Ma Selin provided by the invention carries out high performance liquid chromatography inspection to piperazine Ma Selin
During survey using predetermined substance water phase and organic phase composition mobile phase, this mobile phase can to organic impurities carry out compared with
Good separation, enables method provided by the invention accurately to detect the organic impurities in piperazine Ma Selin.In addition, the present invention provides
Piperazine Ma Selin in organic impurities detection method it is stable, reproducible, specificity is strong.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The embodiment of invention for those of ordinary skill in the art without creative efforts, can also basis
The attached drawing of offer obtains other attached drawings.
Fig. 1 is the preparation technology flow chart of piperazine Ma Selin in the embodiment of the present invention 1；
Fig. 2 is the nmr spectrum for the piperazine Ma Selin that the embodiment of the present invention 1 is prepared；
Fig. 3 is that the embodiment of the present invention 2 detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin；
Fig. 4 is that the embodiment of the present invention 3 detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin；
Fig. 5 is that the embodiment of the present invention 4 detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin；
Fig. 6 is that comparative example 1 of the present invention detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin.
Specific implementation mode
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
The every other embodiment that technical staff is obtained without making creative work belongs to the model that the present invention protects
It encloses.
The present invention provides a kind of detection methods of organic impurities in piperazine Ma Selin, including：
High performance liquid chromatography detection is carried out to piperazine Ma Selin, obtains the content of organic impurities in piperazine Ma Selin；It is described efficient
Mobile phase during liquid chromatographic detection includes water phase and organic phase, and the water phase is the aqueous solution of acid, and the organic phase is
The organic solution of acid, the acid in acid and organic phase in the water phase includes formic acid, trifluoroacetic acid or phosphoric acid；The organic solution
In solvent include methanol or acetonitrile；The organic impurities is the compound of structure shown in Formulas I：
The present invention carries out high performance liquid chromatography detection to piperazine Ma Selin.The present invention is to the source of the piperazine Ma Selin without spy
Different limitation can be bought by market and be obtained, method well known to those skilled in the art can also be used and be prepared.The present invention's
In embodiment, the preparation method of the piperazine Ma Selin is：
The compound of structure shown in the compound of structure shown in formula 1 and formula 2 is reacted, piperazine Ma Selin is obtained, it is shown
Piperazine Ma Selin has structure shown in Formula II：
In an embodiment of the present invention, the temperature of the compound reaction of structure shown in the compound of structure and formula 2 shown in formula 1
It is 20 DEG C~30 DEG C.In an embodiment of the present invention, the compound reaction of structure shown in the compound of structure and formula 2 shown in formula 1
Time be 1 hour~2 hours.In an embodiment of the present invention, the change of structure shown in the compound of structure and formula 2 shown in formula 1
The molar ratio for closing object is 1:1.The present invention does not have the source of the compound of structure shown in the compound of structure shown in formula 1 and formula 2
Special limitation can be bought by market and be obtained, can be also prepared according to method well known to those skilled in the art.In the present invention
Embodiment in, the preparation method of the compound of structure shown in the formula 1 is：
The compound of structure shown in the compound of structure shown in formula 3 and formula 4 is reacted, structure shown in formula 1 is obtained
Compound：
In an embodiment of the present invention, the temperature of the compound reaction of structure shown in the compound of structure and formula 4 shown in formula 3
It is 10 DEG C~35 DEG C.In an embodiment of the present invention, the compound reaction of structure shown in the compound of structure and formula 4 shown in formula 3
Time be 1 hour~2 hours.In an embodiment of the present invention, the change of structure shown in the compound of structure and formula 4 shown in formula 3
The mass ratio for closing object is 1：1.3.The present invention does not have the source of the compound of structure shown in the compound of structure shown in formula 3 and formula 4
There is special limitation, can be bought and be obtained by market.
In the present invention, the high performance liquid chromatography detection, using high pressure transfusion system, will have using liquid as mobile phase
The mobile phases such as the single solvent of opposed polarity or the mixed solvent of different proportion, buffer solution are pumped into the chromatographic column equipped with stationary phase,
It after each ingredient is detached in column, is detected into detector, to realize the analysis to sample.
In the present invention, the mobile phase during the high performance liquid chromatography detection includes water phase and organic phase.In this hair
In bright, the water phase is the aqueous solution of acid, and the acid in the water phase includes formic acid, trifluoroacetic acid or phosphoric acid.In the reality of the present invention
It applies in example, the acid in the water phase includes formic acid or trifluoroacetic acid；In a further embodiment, the acid in the water phase includes three
Fluoroacetic acid.
In an embodiment of the present invention, the mass concentration of the aqueous solution of the acid is 0.05%~0.15%；In others
In embodiment, the mass concentration of the aqueous solution of the acid is 0.08%~0.12%；In a further embodiment, the water of the acid
The mass concentration of solution is 0.1%.In an embodiment of the present invention, the water phase is the trifluoroacetic acid that mass concentration is 0.1%
Aqueous solution.
In the present invention, the organic phase is the organic solution of acid, and the acid in the organic phase includes formic acid, trifluoroacetic acid
Or phosphoric acid, the solvent in the organic solution includes methanol or acetonitrile.In the present invention, in the acid and water phase in the organic phase
Acid need to use same acid.In an embodiment of the present invention, the solvent in the organic solution includes acetonitrile.The present invention's
In embodiment, the mass concentration of the organic solution of the acid is 0.05%~0.15%；In other examples, it is described acid
The mass concentration of organic solution is 0.08%~0.12%；In a further embodiment, the quality of the organic solution of the acid is dense
Degree is 0.1%.In an embodiment of the present invention, the organic phase is the acetonitrile solution for the trifluoroacetic acid that mass concentration is 0.1%.
In an embodiment of the present invention, the mass ratio of the water phase and organic phase is (50~60)：(50~40)；At other
Embodiment in, the mass ratio of the water phase and organic phase is (52~58)：(48~42)；In other examples, described
The mass ratio of water phase and organic phase is (54~56)：(46~44)；In a further embodiment, the matter of the water phase and organic phase
Amount is than being 55.5：45.5.
In an embodiment of the present invention, in the efficient liquid phase detection process mobile phase flow velocity be 0.5mL/min~
1.5mL/min；In other examples, in the efficient liquid phase detection process mobile phase flow velocity be 0.8mL/min~
1.2mL/min；In a further embodiment, the flow velocity of mobile phase is 1mL/min in the efficient liquid phase detection process.
In an embodiment of the present invention, the mode that gradient elution can be used during the high performance liquid chromatography detection makes stream
Dynamic phase is by chromatographic column, with the sensitivity for improving column effect, improving detector.In an embodiment of the present invention, the gradient elution
Process be：
In 0~25min, mass content of the water phase in mobile phase is reduced to 45%~55% by 80%~90%, organic
Mutually the mass content in mobile phase is increased to 45%~55% by 10%~20%；In 25min~35min, water phase is flowing
Mass content in phase is reduced to 10%~0 by 45%~55%, mass content of the organic phase in mobile phase by 45%~
55% is increased to 90%~100%；In 35min~38min, mass content holding 10%~0 of the water phase in mobile phase is organic
Mutually the mass content in mobile phase keeps 90%~100%；In 38min~40min, mass content of the water phase in mobile phase
It being increased to 80%~90% by 10%~0, mass content of the organic phase in mobile phase be reduced to 10% by 90%~100%~
20%；In 40min~45min, mass content of the water phase in mobile phase keeps 80%~90%, and organic phase is in mobile phase
Mass content keeps 10%~20%.
In other examples, the process of the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 47%~53% by 82%~88%, organic
Mutually the mass content in mobile phase is increased to 47%~53% by 12%~18%；In 25min~35min, water phase is flowing
Mass content in phase is reduced to 8%~2% by 47%~53%, mass content of the organic phase in mobile phase by 47%~
53% is increased to 92%~98%；In 35min~38min, mass content holding 8%~2% of the water phase in mobile phase is organic
Mutually the mass content in mobile phase keeps 92%~98%；In 38min~40min, mass content of the water phase in mobile phase
It being increased to 82%~88% by 8%~2%, mass content of the organic phase in mobile phase be reduced to 12% by 92%~98%~
18%；In 40min~45min, mass content of the water phase in mobile phase keeps 82%~88%, and organic phase is in mobile phase
Mass content keeps 12%~18%.
In other examples, the process of the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 49%~51% by 84%~86%, organic
Mutually the mass content in mobile phase is increased to 49%~51% by 14%~16%；In 25min~35min, water phase is flowing
Mass content in phase is reduced to 4%~6% by 49%~51%, mass content of the organic phase in mobile phase by 49%~
51% is increased to 94%~96%；In 35min~38min, mass content holding 4%~6% of the water phase in mobile phase is organic
Mutually the mass content in mobile phase keeps 94%~96%；In 38min~40min, mass content of the water phase in mobile phase
It being increased to 84%~86% by 4%~6%, mass content of the organic phase in mobile phase be reduced to 16% by 94%~96%~
14%；In 40min~45min, mass content of the water phase in mobile phase keeps 84%~86%, and organic phase is in mobile phase
Mass content keeps 14%~16%.
In a further embodiment, the process of the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 50% by 85%, and organic phase is in mobile phase
Mass content be increased to 50% by 15%；In 25min~35min, mass content of the water phase in mobile phase is reduced by 50%
To 0, mass content of the organic phase in mobile phase is increased to 100% by 50%；In 35min~38min, water phase is in mobile phase
Mass content keep 0, mass content of the organic phase in mobile phase keeps 100%；In 38min~40min, water phase is flowing
Mass content in phase is increased to 85% by 0, and mass content of the organic phase in mobile phase is reduced to 15% by 100%；
40min~45min, mass content of the water phase in mobile phase keep 85%, and mass content of the organic phase in mobile phase is kept
15%.
In an embodiment of the present invention, the chromatographic column used during the high performance liquid chromatography detection be C8 chromatographic columns or
C18 chromatographic columns；In other examples, the chromatographic column used during the high performance liquid chromatography detection is C18 chromatographic columns.
In an embodiment of the present invention, the chromatographic column column temperature during the high performance liquid chromatography detection is 25 DEG C~45
℃；In other examples, the chromatographic column column temperature during the high performance liquid chromatography detection is 30 DEG C~40 DEG C；In addition
Embodiment in, chromatographic column column temperature during the high performance liquid chromatography detection is 32 DEG C~38 DEG C；In other embodiment
In, the chromatographic column column temperature during the high performance liquid chromatography detection is 34 DEG C~36 DEG C；In a further embodiment, the height
Chromatographic column column temperature in effect liquid phase chromatogram detection process is 35 DEG C.
In an embodiment of the present invention, the detector during the high performance liquid chromatography detection is UV detector.
In the embodiment of the present invention, the Detection wavelength during the high performance liquid chromatography detection is 200nm~240nm；In others
In embodiment, the Detection wavelength during the high performance liquid chromatography detection is 210nm~230nm；In a further embodiment,
Detection wavelength during the high performance liquid chromatography detection is 215mm~225nm；In a further embodiment, described efficient
Detection wavelength during liquid chromatographic detection is 218nm~220nm.
In an embodiment of the present invention, the detection method of organic impurities is in the piperazine Ma Selin：
High performance liquid chromatography detection is carried out to piperazine Ma Selin, obtains the content of organic impurities in piperazine Ma Selin；It is described efficient
Water phase is the trifluoroacetic acid aqueous solution that mass concentration is 0.1% in mobile phase during liquid chromatographic detection, and organic phase is matter
The acetonitrile solution of a concentration of 0.1% trifluoroacetic acid is measured, chromatographic column is C18 chromatographic columns, and chromatogram column temperature is 35 DEG C, mobile phase stream
Speed is 1mL/min, and detector is UV detector, Detection wavelength 218nm, high performance liquid chromatography detection flowing in the process
It is by chromatographic column, the process of the gradient elution by the way of gradient elution mutually：
In 0~25min, mass content of the water phase in mobile phase is reduced to 50% by 85%, and organic phase is in mobile phase
Mass content be increased to 50% by 15%；In 25min~35min, mass content of the water phase in mobile phase is reduced by 50%
To 0, mass content of the organic phase in mobile phase is increased to 100% by 50%；In 35min~38min, water phase is in mobile phase
Mass content keep 0, mass content of the organic phase in mobile phase keeps 100%；In 38min~40min, water phase is flowing
Mass content in phase is increased to 85% by 0, and mass content of the organic phase in mobile phase is reduced to 15% by 100%；
40min~45min, mass content of the water phase in mobile phase keep 85%, and mass content of the organic phase in mobile phase is kept
15%.
According to the defined method in 2015 editions pharmacopeia general rules 0512, detect organic miscellaneous in piperazine Ma Selin provided by the invention
The system suitability of the detection method of matter records the main peak retention time measured after multiple sample introduction, main peak area, organic impurities peak
The separating degree of retention time, organic impurities peak area and organic impurities；Testing result shows piperazine Ma Selin provided by the invention
The detection method peak shape of middle organic impurities is good, stable, repeatability is high, specificity is strong.
According to method specified in 2015 editions pharmacopeia general rules 9101, to organic impurities in piperazine Ma Selin provided by the invention
Detection method carries out recovery of standard addition experiment, and testing result shows the detection of organic impurities in piperazine Ma Selin provided by the invention
Method testing result is accurate, can accurately measure the content of organic impurities in piperazine Ma Selin.
Raw material used in following embodiment of the present invention is commercial goods.
Embodiment 1
It is the preparation of piperazine Ma Selin in the embodiment of the present invention 1 to prepare piperazine Ma Selin, Fig. 1 according to technological process shown in FIG. 1
Process flow chart；
It is 1 by molar ratio:The compound of structure shown in the compound of structure and formula 4 shown in 1.3 formula 3 carries out at 25 DEG C
Reaction in 1.5 hours obtains the compound of structure shown in formula 1；
It is 1 by molar ratio:The compound of structure shown in the compound of structure and formula 2 shown in 1 formula 1 carries out 1 at 25 DEG C
The reaction of hour, obtains piperazine Ma Selin.
The piperazine Ma Selin that the embodiment of the present invention 1 is prepared carries out magnetic resonance detection, testing result as shown in Fig. 2,
Fig. 2 is the nmr spectrum for the piperazine Ma Selin that the embodiment of the present invention 1 is prepared, and as shown in Figure 2, the embodiment of the present invention 1 is made
Standby obtained piperazine Ma Selin has structure shown in Formula II.
Embodiment 2
High performance liquid chromatography detection, the high-efficient liquid phase color are carried out to the piperazine Ma Selin that the embodiment of the present invention 1 is prepared
Water phase is the trifluoroacetic acid aqueous solution that mass concentration is 0.1% in mobile phase in spectrum detection process, and organic phase is mass concentration
For the acetonitrile solution of 0.1% trifluoroacetic acid, chromatographic column is C18 chromatographic columns, and chromatogram column temperature is 35 DEG C, and flow rate of mobile phase is
1mL/min, detector are UV detector, Detection wavelength 218nm, and mobile phase is adopted during the high performance liquid chromatography detection
With the mode of gradient elution by chromatographic column, the process of the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 50% by 85%, and organic phase is in mobile phase
Mass content be increased to 50% by 15%；In 25min~35min, mass content of the water phase in mobile phase is reduced by 50%
To 0, mass content of the organic phase in mobile phase is increased to 100% by 50%；In 35min~38min, water phase is in mobile phase
Mass content keep 0, mass content of the organic phase in mobile phase keeps 100%；In 38min~40min, water phase is flowing
Mass content in phase is increased to 85% by 0, and mass content of the organic phase in mobile phase is reduced to 15% by 100%；
40min~45min, mass content of the water phase in mobile phase keep 85%, and mass content of the organic phase in mobile phase is kept
15%.
Liquid chromatogram shown in Fig. 3 is obtained after carrying out high performance liquid chromatography detection to piperazine Ma Selin, Fig. 3 is that the present invention is real
It applies example 2 and detects the high-efficient liquid phase chromatogram (content in Fig. 3 tables is the corresponding data of chromatogram) obtained after piperazine Ma Selin, by scheming
3 it is found that the method that the embodiment of the present invention 2 provides is capable of detecting when the organic impurities with Formulas I structure, impurity peaks in piperazine Ma Selin
Enough reach baseline separation with piperazine Ma Selin peak energy, peak shape is preferable.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin that the detection embodiment of the present invention 2 provides
Detection method system suitability, testing result is as shown in table 1, and table 1 is the method for detecting impurities that provides of the embodiment of the present invention 2
System suitability.
The system suitability for the method for detecting impurities that 1 embodiment of the present invention 2 of table provides
As shown in Table 1, the detection method of organic impurities is stable, repeated in the piperazine Ma Selin that the embodiment of the present invention 2 provides
Height, specificity are strong.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin provided the embodiment of the present invention 2
Detection method carries out recovery of standard addition experiment, and experimental result is as shown in table 2, and table 2 is the defects inspecting that the embodiment of the present invention 2 provides
The recovery of standard addition of method.
The recovery of standard addition for the method for detecting impurities that 2 embodiment of the present invention 2 of table provides
Note：From low to high, 1,2,3 indicate that different amounts of impurity, which are added, puts down to the amount of L, M, H expression addition organic impurities in table 4
Row is done 3 times.
As shown in Table 2, the detection method testing result of organic impurities is accurate in the piperazine Ma Selin that the embodiment of the present invention 2 provides
Really.
Embodiment 3
High performance liquid chromatography detection, the high-efficient liquid phase color are carried out to the piperazine Ma Selin that the embodiment of the present invention 1 is prepared
Water phase is the aqueous formic acid that mass concentration is 0.1% in mobile phase in spectrum detection process, and organic phase is that mass concentration is
The acetonitrile solution of 0.1% formic acid, chromatographic column are C18 chromatographic columns, and chromatogram column temperature is 30 DEG C, flow rate of mobile phase 0.8mL/
Min, detector are UV detector, Detection wavelength 210nm, and mobile phase is using ladder during the high performance liquid chromatography detection
The mode of elution is spent by chromatographic column, and the process of the gradient elution is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 55% by 90%, and organic phase is in mobile phase
Mass content be increased to 45% by 10%；In 25min~35min, mass content of the water phase in mobile phase is reduced by 55%
To 0, mass content of the organic phase in mobile phase is increased to 100% by 45%；In 35min~38min, water phase is in mobile phase
Mass content keep 0, mass content of the organic phase in mobile phase keeps 100%；In 38min~40min, water phase is flowing
Mass content in phase is increased to 90% by 0, and mass content of the organic phase in mobile phase is reduced to 10% by 100%；
40min~45min, mass content of the water phase in mobile phase keep 90%, and mass content of the organic phase in mobile phase is kept
10%.
Liquid chromatogram shown in Fig. 4 is obtained after carrying out high performance liquid chromatography detection to piperazine Ma Selin, Fig. 4 is that the present invention is real
It applies example 3 and detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin, as shown in Figure 4, the method that the embodiment of the present invention 3 provides can
Detect that the organic impurities with Formulas I structure in piperazine Ma Selin, impurity peaks enough reach baseline separation, peak shape with piperazine Ma Selin peak energy
Preferably.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin that the detection embodiment of the present invention 3 provides
Detection method system suitability, testing result is as shown in table 3, and table 3 is the method for detecting impurities that provides of the embodiment of the present invention 3
System suitability.
The system suitability for the method for detecting impurities that 3 embodiment of the present invention 3 of table provides
As shown in Table 3, the detection method of organic impurities is stable, repeated in the piperazine Ma Selin that the embodiment of the present invention 3 provides
Height, specificity are strong.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin provided the embodiment of the present invention 3
Detection method carries out recovery of standard addition experiment, and experimental result is as shown in table 4, and table 4 is the defects inspecting that the embodiment of the present invention 3 provides
The recovery of standard addition of method.
The recovery of standard addition for the method for detecting impurities that 4 embodiment of the present invention 3 of table provides
Note：From low to high, 1,2,3 indicate that different amounts of impurity, which are added, puts down to the amount of L, M, H expression addition organic impurities in table 2
Row is done 3 times.
As shown in Table 4, the detection method testing result of organic impurities is accurate in the piperazine Ma Selin that the embodiment of the present invention 3 provides
Really.
Embodiment 4
High performance liquid chromatography detection, the high-efficient liquid phase color are carried out to the piperazine Ma Selin that the embodiment of the present invention 1 is prepared
Water phase is the phosphate aqueous solution that mass concentration is 0.1% in mobile phase in spectrum detection process, and organic phase is that mass concentration is 0.1%
Phosphoric acid methanol solution, chromatographic column be C8 chromatographic columns, chromatogram column temperature be 40 DEG C, flow rate of mobile phase 1.2mL/min, detection
Device is UV detector, Detection wavelength 230nm, and mobile phase is using gradient elution during the high performance liquid chromatography detection
Mode is by chromatographic column, the process of the gradient elution：
In 0~25min, mass content of the water phase in mobile phase is reduced to 45% by 80%, and organic phase is in mobile phase
Mass content be increased to 55% by 20%；In 25min~35min, mass content of the water phase in mobile phase is reduced by 45%
To 0, mass content of the organic phase in mobile phase is increased to 100% by 55%；In 35min~38min, water phase is in mobile phase
Mass content keep 0, mass content of the organic phase in mobile phase keeps 100%；In 38min~40min, water phase is flowing
Mass content in phase is increased to 80% by 0, and mass content of the organic phase in mobile phase is reduced to 20% by 100%；
40min~45min, mass content of the water phase in mobile phase keep 80%, and mass content of the organic phase in mobile phase is kept
20%.
Liquid chromatogram shown in fig. 5 is obtained after carrying out high performance liquid chromatography detection to piperazine Ma Selin, Fig. 5 is that the present invention is real
It applies example 4 and detects the high-efficient liquid phase chromatogram obtained after piperazine Ma Selin, as shown in Figure 5, the method that the embodiment of the present invention 4 provides can
Detect that the organic impurities with Formulas I structure in piperazine Ma Selin, impurity peaks enough reach baseline separation, peak shape with piperazine Ma Selin peak energy
Preferably.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin that the detection embodiment of the present invention 4 provides
Detection method system suitability, testing result is as shown in table 5, and table 5 is the method for detecting impurities that provides of the embodiment of the present invention 4
System suitability.
The system suitability for the method for detecting impurities that 5 embodiment of the present invention 4 of table provides
As shown in Table 1, the detection method of organic impurities is stable, repeated in the piperazine Ma Selin that the embodiment of the present invention 4 provides
Height, specificity are strong.
According to the method described in above-mentioned technical proposal, organic impurities in the piperazine Ma Selin provided the embodiment of the present invention 4
Detection method carries out recovery of standard addition experiment, and experimental result is as shown in table 6, and table 6 is the defects inspecting that the embodiment of the present invention 4 provides
The recovery of standard addition of method.
The recovery of standard addition for the method for detecting impurities that 6 embodiment of the present invention 4 of table provides
Note：From low to high, 1,2,3 indicate that different amounts of impurity, which are added, puts down to the amount of L, M, H expression addition organic impurities in table 6
Row is done 3 times.
As shown in Table 6, the detection method testing result of organic impurities is accurate in the piperazine Ma Selin that the embodiment of the present invention 4 provides
Really.
Comparative example 1
High performance liquid chromatography detection is carried out to the piperazine Ma Selin that embodiment 1 is prepared according to the method described in embodiment 2,
As different from Example 2, use molar concentration for the KH of 20mmol/L2PO4Aqueous solution is water phase, uses acetonitrile for organic phase.
Liquid chromatogram shown in fig. 6 is obtained after carrying out high performance liquid chromatography detection to piperazine Ma Selin, Fig. 6 is ratio of the present invention
The high-efficient liquid phase chromatogram obtained after piperazine Ma Selin is detected compared with example 1, it will be appreciated from fig. 6 that the method impurity that comparative example of the present invention 1 provides
Peak and the peaks piperazine Ma Selin are not separated by, and can not detect the organic impurities of piperazine Ma Selin.
As seen from the above embodiment, the present invention provides a kind of detection methods of organic impurities in piperazine Ma Selin, including：It is right
Piperazine Ma Selin carries out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；The high performance liquid chromatography inspection
Mobile phase during survey includes water phase and organic phase, and the water phase is the aqueous solution of acid, and the organic phase is the organic molten of acid
Liquid, the acid include formic acid, trifluoroacetic acid or phosphoric acid；Solvent in the organic solution includes methanol or acetonitrile；It is described organic
Impurity is the compound of structure shown in Formulas I.The detection method of organic impurities in piperazine Ma Selin provided by the invention, to piperazine Ma Selin
During carrying out high performance liquid chromatography detection, the water phase using predetermined substance and organic phase composition mobile phase, this mobile phase
Organic impurities can preferably be detached, so that method provided by the invention is accurately detected organic in piperazine Ma Selin
Impurity.In addition, the detection method of organic impurities is stable in piperazine Ma Selin provided by the invention, reproducible, specificity is strong.
Claims (9)
1. the detection method of organic impurities in a kind of piperazine Ma Selin, including：
High performance liquid chromatography detection is carried out to piperazine Ma Selin, obtains the content of organic impurities in piperazine Ma Selin；The efficient liquid phase
Mobile phase in chromatography detection process includes water phase and organic phase, and the water phase is the aqueous solution of acid, and the organic phase is sour
Organic solution, the acid in acid and organic phase in the water phase includes formic acid, trifluoroacetic acid or phosphoric acid；In the organic solution
Solvent includes methanol or acetonitrile；The organic impurities is the compound of structure shown in Formulas I：
Mobile phase is set to pass through chromatographic column by the way of gradient elution during the high performance liquid chromatography detection, the gradient is washed
De- process is：
In 0~25min, mass content of the water phase in mobile phase is reduced to 45%~55% by 80%~90%, and organic phase exists
Mass content in mobile phase is increased to 45%~55% by 10%~20%；
In 25min~35min, mass content of the water phase in mobile phase is reduced to 10%~0 by 45%~55%, and organic phase exists
Mass content in mobile phase is increased to 90%~100% by 45%~55%；
In 35min~38min, mass content of the water phase in mobile phase keeps 10%~0, quality of the organic phase in mobile phase
Content keeps 90%~100%；
In 38min~40min, mass content of the water phase in mobile phase is increased to 80%~90% by 10%~0, and organic phase exists
Mass content in mobile phase is reduced to 10%~20% by 90%~100%；
In 40min~45min, mass content of the water phase in mobile phase keeps 80%~90%, and organic phase is in mobile phase
Mass content keeps 10%~20%.
2. detection method according to claim 1, which is characterized in that the mass concentration of the aqueous solution of the acid is 0.05%
~0.15%.
3. detection method according to claim 1, which is characterized in that the mass concentration of the organic solution of the acid is
0.05%~0.15%.
4. detection method according to claim 1, which is characterized in that the mass ratio of the water phase and organic phase be (50~
60)：(50~40).
5. detection method according to claim 1, which is characterized in that the stream of mobile phase in the efficient liquid phase detection process
Speed is 0.5mL/min~1.5mL/min.
6. detection method according to claim 1, which is characterized in that used during the high performance liquid chromatography detection
Chromatographic column is C8 chromatographic columns or C18 chromatographic columns.
7. detection method according to claim 1, which is characterized in that the chromatography during the high performance liquid chromatography detection
Column column temperature is 25 DEG C~45 DEG C.
8. detection method according to claim 1, which is characterized in that the detection during the high performance liquid chromatography detection
Device is UV detector.
9. detection method according to claim 1, which is characterized in that the detection during the high performance liquid chromatography detection
Wavelength is 200nm~240nm.
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