CN105929030A - Detection method of organic impurity in pimavanserin - Google Patents
Detection method of organic impurity in pimavanserin Download PDFInfo
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Abstract
The invention provides detection method of organic impurity in pimavanserin. The method includes the steps of: conducting HPLC detection on pimavanserin, wherein the mobile phase in the HPLC detection process includes an aqueous phase and an organic phase, the aqueous phase is aqueous solution of acid, the organic phase is organic solution of acid; the acids in the aqueous phase and organic phase include formic acid, trifluoroacetic acid, or phosphoric acid; solvents in the organic solution include methanol or acetonitrile; and the organic impurities are compounds as shown in formula I. The detection method of organic impurity in pimavanserin uses a mobile phase formed by the aqueous phase and organic phase of specific substances for high performance liquid chromatography detection process on pimavanserin; the mobile phase can better separate the organic impurities, so that the method provided by the invention can accurately detect the organic impurities in pimavanserin. In addition, the detection method of organic impurity in pimavanserin has good stability, reproducibility and strong specificity.
Description
Technical field
The present invention relates to piperazine Ma Selin technical field, particularly relate to the inspection of organic impurities in a kind of piperazine Ma Selin
Survey method.
Background technology
At present whole world parkinsonian about 7 million to one 10,000,000, China just has 2,600,000, occupies generation
Boundary first, the most also to increase by 100,000 neopathy patients.The parkinsonian of more than 50% once had
Mental symptom (PDP).These mental symptoms mainly show as hallucination and vain hope, and this gives parkinsonian
Treatment and nursing bring bigger challenge.Acadia (Acadia Pharmaceuticals) is in the U.S.
One of Santiago is absorbed in and newly treats for nervous system and relevant central nervous system disorder disease research
The biopharmaceutical company of method, a piperazine Ma Selin/Mo Fanselin (common name: Pimavanserin, trade name:
Nuplazid) it is the patent drugs of drugmaker of Acadia independent research, is used for treating parkinson spirit
Symptom, is similar to thing for non-dopamine neurotransmitter, can with selective exclusion five hydroxytryptamine 2A receptor not shadow
Ring the effect of dopamine.Piperazine Ma Selin/Mo Fanselin (Pimavanserin, Nuplazid) is in 2014
Year JIUYUE 3 Huo U.S. food Drug Administration (FDA) authorizes breakthrough therapy certification.Breakthrough treatment
Method certification is created by FDA, it is intended to accelerates exploitation and examines the serious or life-threatening disease for the treatment of
New drug.Acadia (Acadia) drugmaker will in 2014 the end of the year forward direction FDA submit piperazine Ma Selin/
The new drug application of Mo Fanselin (Pimavanserin).
Impurity in medicine refers to any material affecting pharmaceutical purity, including organic impurities, inorganic impurity and
Residual solvent.Inorganic impurity and the research of residual solvent and detection method are the most ripe, method logical
Stronger by property, control standard also the most clearly, from the point of view of drug evaluation is put into practice, inorganic impurity and residual
Solvent has obtained preferable research and control in declaring registration medicine.With inorganic impurity and residual solvent
Comparing, the research of organic impurities is more complex with control, in isolation identification, the impurity source point of impurity
The aspects such as analysis, impurity safety research, the limit of impurities determine, be required for bound drug construction features,
Preparation technology, storage-stable, clinical practice feature etc. carry out substantial amounts of intensive research.
Piperazine Ma Selin medicine production process can introduce the organic impurities with structure shown in Formulas I:
The structure of this organic impurities and the structure of piperazine Ma Selin are the most close, can badly influence medicine
Purity, is to determine one of whether qualified key factor of medicine.Therefore, accurate detection piperazine Ma Selin has
The content of machine impurity has great importance for controlling drug product quality.
At present, yet there are no the relevant report that organic impurities in piperazine Ma Selin is detected.
Summary of the invention
In view of this, it is an object of the invention to provide the detection method of organic impurities in a kind of piperazine Ma Selin,
The method that the present invention provides can accurately detect the organic impurities in piperazine Ma Selin.
The invention provides the detection method of organic impurities in a kind of piperazine Ma Selin, including:
Piperazine Ma Selin is carried out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；
Flowing during the detection of described high performance liquid chromatography includes that aqueous phase and organic facies, described aqueous phase are acid mutually
Aqueous solution, described organic facies is the organic solution of acid, and the acid in described aqueous phase and the acid in organic facies include
Formic acid, trifluoroacetic acid or phosphoric acid；Solvent in described organic solution includes methanol or acetonitrile；Described organic
Impurity is the compound of structure shown in Formulas I:
Preferably, the mass concentration of aqueous acid is 0.05%～0.15%.
Preferably, the mass concentration of the organic solution of described acid is 0.05%～0.15%.
Preferably, the mass ratio of described aqueous phase and organic facies is (50～60): (50～40).
Preferably, the flow velocity of the phase that flows during described efficient Liquid Detection is
0.5mL/min～1.5mL/min.
Preferably, the mode of gradient elution is used to make flowing communicate during the detection of described high performance liquid chromatography
Crossing chromatographic column, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 45%～55% by 80%～90%,
Organic facies mass content in flowing mutually is brought up to 45%～55% by 10%～20%；
At 25min～35min, aqueous phase mass content in flowing mutually is reduced to 10%～0 by 45%～55%,
Organic facies mass content in flowing mutually is brought up to 90%～100% by 45%～55%；
At 35min～38min, aqueous phase mass content in flowing mutually keeps 10%～0, and organic facies is at stream
Mass content in moving mutually keeps 90%～100%；
At 38min～40min, aqueous phase mass content in flowing mutually is brought up to 80%～90% by 10%～0,
Organic facies mass content in flowing mutually is reduced to 10%～20% by 90%～100%；
At 40min～45min, aqueous phase mass content in flowing mutually keeps 80%～90%, and organic facies exists
Mass content in flowing mutually keeps 10%～20%.
Preferably, the chromatographic column used during the detection of described high performance liquid chromatography is C8 chromatographic column or C18
Chromatographic column.
Preferably, the chromatographic column column temperature during the detection of described high performance liquid chromatography is 25 DEG C～45 DEG C.
Preferably, the detector during the detection of described high performance liquid chromatography is UV-detector.
Preferably, the detection wavelength during the detection of described high performance liquid chromatography is 200nm～240nm.
In the piperazine Ma Selin that the present invention provides, the detection method of organic impurities, carries out high-efficient liquid to piperazine Ma Selin
Aqueous phase and organic facies composition flowing phase, this flowing phase of predetermined substance is used during the detection of phase chromatograph
Can preferably separate organic impurities, the method enabling the present invention to provide accurately detects piperazine horse
Organic impurities in color woods.Additionally, the detection method of organic impurities is steady in the piperazine Ma Selin of present invention offer
Fixed, reproducible, specificity is strong.
Accompanying drawing explanation
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, below will be to reality
Execute the required accompanying drawing used in example or description of the prior art to be briefly described, it should be apparent that below,
Accompanying drawing in description is only embodiments of the invention, for those of ordinary skill in the art, not
On the premise of paying creative work, it is also possible to obtain other accompanying drawing according to the accompanying drawing provided.
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 of the piperazine Ma Selin that the embodiment of the present invention 1 prepares；
Fig. 3 is the high-efficient liquid phase chromatogram obtained after the embodiment of the present invention 2 detects piperazine Ma Selin；
Fig. 4 is the high-efficient liquid phase chromatogram obtained after the embodiment of the present invention 3 detects piperazine Ma Selin；
Fig. 5 is the high-efficient liquid phase chromatogram obtained after the embodiment of the present invention 4 detects piperazine Ma Selin；
Fig. 6 is the high-efficient liquid phase chromatogram obtained after comparative example 1 of the present invention detects piperazine Ma Selin.
Detailed description of the invention
Technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that institute
The embodiment described is only a part of embodiment of the present invention rather than whole embodiments.Based on this
Embodiment in bright, those of ordinary skill in the art are obtained under not making creative work premise
Every other embodiment, broadly falls into the scope of protection of the invention.
The invention provides the detection method of organic impurities in a kind of piperazine Ma Selin, including:
Piperazine Ma Selin is carried out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；
Flowing during the detection of described high performance liquid chromatography includes that aqueous phase and organic facies, described aqueous phase are acid mutually
Aqueous solution, described organic facies is the organic solution of acid, and the acid in described aqueous phase and the acid in organic facies include
Formic acid, trifluoroacetic acid or phosphoric acid；Solvent in described organic solution includes methanol or acetonitrile；Described organic
Impurity is the compound of structure shown in Formulas I:
The present invention carries out high performance liquid chromatography detection to piperazine Ma Selin.Described piperazine Ma Selin is come by the present invention
Source does not has special restriction, can be bought by market and obtain, it is possible to use side well known to those skilled in the art
Method prepares.In an embodiment of the present invention, the preparation method of described piperazine Ma Selin is:
The compound of structure shown in the compound of structure shown in formula 1 and formula 2 is reacted, obtains piperazine horse
Color woods, shown piperazine Ma Selin has a structure shown in Formula II:
In an embodiment of the present invention, the compound of structure shown in the compound of structure shown in formula 1 and formula 2
The temperature of reaction is 20 DEG C～30 DEG C.In an embodiment of the present invention, the compound of structure shown in formula 1 and formula
The time of the compound reaction of structure shown in 2 is 1 hour～2 hours.In an embodiment of the present invention, formula 1
Shown in the compound of shown structure and formula 2, the mol ratio of the compound of structure is 1:1.The present invention is to formula 1 institute
Show that shown in the compound of structure and formula 2, the source of the compound of structure does not has special restriction, can be by market
Buy and obtain, it is possible to prepare according to method well known to those skilled in the art.Enforcement in the present invention
In example, shown in described formula 1, the preparation method of the compound of structure is:
The compound of structure shown in the compound of structure shown in formula 3 and formula 4 is reacted, obtains formula 1
The compound of shown structure:
In an embodiment of the present invention, the compound of structure shown in the compound of structure shown in formula 3 and formula 4
The temperature of reaction is 10 DEG C～35 DEG C.In an embodiment of the present invention, the compound of structure shown in formula 3 and formula
The time of the compound reaction of structure shown in 4 is 1 hour～2 hours.In an embodiment of the present invention, formula 3
Shown in the compound of shown structure and formula 4, the mass ratio of the compound of structure is 1:1.3.The present invention is to formula 3
Shown in the compound of shown structure and formula 4, the source of the compound of structure does not has special restriction, can be by city
Field is bought and is obtained.
In the present invention, the detection of described high performance liquid chromatography, with liquid for flowing phase, uses high pressure infuser system
System, will have the flowing phase pumps such as single solvent or the mixed solvent of different proportion, the buffer of opposed polarity
Enter the chromatographic column equipped with fixing phase, after each composition is separated in post, enter detector and detect, from
And realize the analysis to sample.
In the present invention, the flowing during the detection of described high performance liquid chromatography includes aqueous phase and organic facies mutually.
In the present invention, described aqueous phase is aqueous acid, and the acid in described aqueous phase includes formic acid, trifluoroacetic acid
Or phosphoric acid.In an embodiment of the present invention, the acid in described aqueous phase includes formic acid or trifluoroacetic acid；Separately
In outer embodiment, the acid in described aqueous phase includes trifluoroacetic acid.
In an embodiment of the present invention, the mass concentration of described aqueous acid is 0.05%～0.15%；?
In other embodiment, the mass concentration of described aqueous acid is 0.08%～0.12%；In other reality
Executing in example, the mass concentration of described aqueous acid is 0.1%.In an embodiment of the present invention, described water
It is the trifluoroacetic acid aqueous solution of 0.1% for mass concentration mutually.
In the present invention, described organic facies be acid organic solution, the acid in described organic facies include formic acid,
Trifluoroacetic acid or phosphoric acid, the solvent in described organic solution includes methanol or acetonitrile.In the present invention, institute
State the acid in organic facies and the acid in aqueous phase need to use same acid.In an embodiment of the present invention, described
Solvent in organic solution includes acetonitrile.In an embodiment of the present invention, the matter of the organic solution of described acid
Amount concentration is 0.05%～0.15%；In other examples, the mass concentration of the organic solution of described acid
It is 0.08%～0.12%；In a further embodiment, the mass concentration of the organic solution of described acid is 0.1%.
In an embodiment of the present invention, described organic facies be mass concentration be the acetonitrile solution of the trifluoroacetic acid of 0.1%.
In an embodiment of the present invention, the mass ratio of described aqueous phase and organic facies is (50～60): (50～40)；
In other examples, the mass ratio of described aqueous phase and organic facies is (52～58): (48～42)；
In other examples, the mass ratio of described aqueous phase and organic facies is (54～56): (46～44)；
In a further embodiment, the mass ratio of described aqueous phase and organic facies is 55.5:45.5.
In an embodiment of the present invention, the flow velocity of the phase that flows during described efficient Liquid Detection is
0.5mL/min～1.5mL/min；In other examples, flow during described efficient Liquid Detection phase
Flow velocity be 0.8mL/min～1.2mL/min；In a further embodiment, described efficient Liquid Detection process
The flow velocity of middle flowing phase is 1mL/min.
In an embodiment of the present invention, gradient elution can be used during the detection of described high performance liquid chromatography
Mode makes flowing mutually by chromatographic column, to improve post effect, to improve the sensitivity of detector.The present invention's
In embodiment, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 45%～55% by 80%～90%,
Organic facies mass content in flowing mutually is brought up to 45%～55% by 10%～20%；?
25min～35min, aqueous phase mass content in flowing mutually is reduced to 10%～0 by 45%～55%, organic
Mass content in flowing mutually is brought up to 90%～100% by 45%～55%；At 35min～38min,
Aqueous phase mass content in flowing mutually keeps 10%～0, and organic facies mass content in flowing mutually keeps
90%～100%；At 38min～40min, aqueous phase mass content in flowing mutually is brought up to by 10%～0
80%～90%, organic facies mass content in flowing mutually is reduced to 10%～20% by 90%～100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 80%～90%, and organic facies is in flowing phase
In mass content keep 10%～20%.
In other examples, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 47%～53% by 82%～88%,
Organic facies mass content in flowing mutually is brought up to 47%～53% by 12%～18%；?
25min～35min, aqueous phase mass content in flowing mutually is reduced to 8%～2% by 47%～53%, organic
Mass content in flowing mutually is brought up to 92%～98% by 47%～53%；At 35min～38min, water
Mass content in flowing mutually keeps 8%～2%, and organic facies mass content in flowing mutually keeps
92%～98%；At 38min～40min, aqueous phase mass content in flowing mutually is brought up to by 8%～2%
82%～88%, organic facies mass content in flowing mutually is reduced to 12%～18% by 92%～98%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 82%～88%, and organic facies is in flowing phase
In mass content keep 12%～18%.
In other examples, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 49%～51% by 84%～86%,
Organic facies mass content in flowing mutually is brought up to 49%～51% by 14%～16%；?
25min～35min, aqueous phase mass content in flowing mutually is reduced to 4%～6% by 49%～51%, organic
Mass content in flowing mutually is brought up to 94%～96% by 49%～51%；At 35min～38min, water
Mass content in flowing mutually keeps 4%～6%, and organic facies mass content in flowing mutually keeps
94%～96%；At 38min～40min, aqueous phase mass content in flowing mutually is brought up to by 4%～6%
84%～86%, organic facies mass content in flowing mutually is reduced to 16%～14% by 94%～96%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 84%～86%, and organic facies is in flowing phase
In mass content keep 14%～16%.
In a further embodiment, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 50% by 85%, and organic facies exists
Mass content in flowing mutually is brought up to 50% by 15%；At 25min～35min, aqueous phase is in flowing mutually
Mass content be reduced to 0 by 50%, organic facies flowing mutually in mass content brought up to by 50%
100%；At 35min～38min, aqueous phase mass content in flowing mutually keeps 0, and organic facies is in flowing
Mass content in mutually keeps 100%；At 38min～40min, aqueous phase mass content in flowing mutually by
0 brings up to 85%, and organic facies mass content in flowing mutually is reduced to 15% by 100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 85%, organic facies matter in flowing mutually
Amount content keeps 15%.
In an embodiment of the present invention, the chromatographic column used during the detection of described high performance liquid chromatography is C8
Chromatographic column or C18 chromatographic column；In other examples, make during the detection of described high performance liquid chromatography
Chromatographic column be C18 chromatographic column.
In an embodiment of the present invention, the chromatographic column column temperature during the detection of described high performance liquid chromatography is
25 DEG C～45 DEG C；In other examples, the chromatographic column column temperature during the detection of described high performance liquid chromatography
It it is 30 DEG C～40 DEG C；In a further embodiment, the chromatographic column post during the detection of described high performance liquid chromatography
Temperature is 32 DEG C～38 DEG C；In a further embodiment, the chromatographic column during the detection of described high performance liquid chromatography
Column temperature is 34 DEG C～36 DEG C；In a further embodiment, the chromatograph during the detection of described high performance liquid chromatography
Post column temperature is 35 DEG C.
In an embodiment of the present invention, the detector during the detection of described high performance liquid chromatography is ultraviolet inspection
Survey device.In an embodiment of the present invention, the detection wavelength during the detection of described high performance liquid chromatography is
200nm～240nm；In other examples, the detection ripple during the detection of described high performance liquid chromatography
A length of 210nm～230nm；In a further embodiment, the inspection during the detection of described high performance liquid chromatography
Surveying wavelength is 215mm～225nm；In a further embodiment, during the detection of described high performance liquid chromatography
Detection wavelength be 218nm～220nm.
In an embodiment of the present invention, in described piperazine Ma Selin, the detection method of organic impurities is:
Piperazine Ma Selin is carried out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；
Described high performance liquid chromatography detection during flowing mutually in aqueous phase be mass concentration be the trifluoroacetic acid of 0.1%
Aqueous solution, organic facies be mass concentration be the acetonitrile solution of the trifluoroacetic acid of 0.1%, chromatographic column is C18 color
Spectrum post, chromatogram column temperature is 35 DEG C, and flow rate of mobile phase is 1mL/min, and detector is UV-detector,
Detection wavelength is 218nm, and flowing during the detection of described high performance liquid chromatography uses the side of gradient elution mutually
Formula passes through chromatographic column, and the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 50% by 85%, and organic facies exists
Mass content in flowing mutually is brought up to 50% by 15%；At 25min～35min, aqueous phase is in flowing mutually
Mass content be reduced to 0 by 50%, organic facies flowing mutually in mass content brought up to by 50%
100%；At 35min～38min, aqueous phase mass content in flowing mutually keeps 0, and organic facies is in flowing
Mass content in mutually keeps 100%；At 38min～40min, aqueous phase mass content in flowing mutually by
0 brings up to 85%, and organic facies mass content in flowing mutually is reduced to 15% by 100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 85%, organic facies matter in flowing mutually
Amount content keeps 15%.
According to the method for the regulation in 2015 editions pharmacopeia general rules 0512, the piperazine horse color that the detection present invention provides
The system suitability of the detection method of organic impurities in woods, when the main peak recorded after recording repeatedly sample introduction retains
Between, main peak area, organic impurities peak retention time, organic impurities peak area and the separation of organic impurities
Degree；Testing result shows, in the piperazine Ma Selin that the present invention provides the detection method peak shape of organic impurities good,
Height stable, repeated, specificity are strong.
According to the method for regulation in 2015 editions pharmacopeia general rules 9101, in the piperazine Ma Selin that the present invention is provided
The detection method of organic impurities carries out recovery of standard addition experiment, and testing result shows, the piperazine that the present invention provides
In Ma Selin, the detection method testing result of organic impurities is accurate, it is possible to measuring in piperazine Ma Selin accurately has
The content of machine impurity.
Raw material used in following example of the present invention is commercial goods.
Embodiment 1
Preparing piperazine Ma Selin according to the technological process shown in Fig. 1, Fig. 1 is piperazine horse in the embodiment of the present invention 1
The preparation technology flow chart of color woods；
The compound of structure shown in the compound of structure shown in formula 3 that mol ratio is 1:1.3 and formula 4 is existed
Carry out the reaction of 1.5 hours at 25 DEG C, obtain the compound of structure shown in formula 1；
By the compound of structure shown in the compound of structure shown in formula 1 that mol ratio is 1:1 and formula 2 at 25 DEG C
Under carry out the reaction of 1 hour, obtain piperazine Ma Selin.
The piperazine Ma Selin preparing the embodiment of the present invention 1 carries out magnetic resonance detection, and testing result is such as
Shown in Fig. 2, Fig. 2 is the nmr spectrum of the piperazine Ma Selin that the embodiment of the present invention 1 prepares, by
Fig. 2 understands, and the piperazine Ma Selin that the embodiment of the present invention 1 prepares has the structure shown in Formula II.
Embodiment 2
The piperazine Ma Selin preparing the embodiment of the present invention 1 carries out high performance liquid chromatography detection, described height
Effect liquid phase chromatogram detection during flowing mutually in aqueous phase be mass concentration be 0.1% trifluoroacetic acid water-soluble
Liquid, organic facies be mass concentration be the acetonitrile solution of the trifluoroacetic acid of 0.1%, chromatographic column is C18 chromatographic column,
Chromatogram column temperature is 35 DEG C, and flow rate of mobile phase is 1mL/min, and detector is UV-detector, detects ripple
A length of 218nm, flows during the detection of described high performance liquid chromatography and uses the mode of gradient elution to pass through mutually
Chromatographic column, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 50% by 85%, and organic facies exists
Mass content in flowing mutually is brought up to 50% by 15%；At 25min～35min, aqueous phase is in flowing mutually
Mass content be reduced to 0 by 50%, organic facies flowing mutually in mass content brought up to by 50%
100%；At 35min～38min, aqueous phase mass content in flowing mutually keeps 0, and organic facies is in flowing
Mass content in mutually keeps 100%；At 38min～40min, aqueous phase mass content in flowing mutually by
0 brings up to 85%, and organic facies mass content in flowing mutually is reduced to 15% by 100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 85%, organic facies matter in flowing mutually
Amount content keeps 15%.
The liquid chromatogram shown in Fig. 3, Fig. 3 is obtained after piperazine Ma Selin is carried out high performance liquid chromatography detection
High-efficient liquid phase chromatogram (the content in Fig. 3 table obtained after detecting piperazine Ma Selin for the embodiment of the present invention 2
For the data that chromatogram is corresponding), from the figure 3, it may be seen that the method that the embodiment of the present invention 2 provides can detect
Going out the organic impurities in piperazine Ma Selin with Formulas I structure, impurity peaks enough reaches baseline with piperazine Ma Selin peak energy and divides
From, peak shape is preferable.
According to the method described in technique scheme, in the piperazine Ma Selin that the detection embodiment of the present invention 2 provides
The system suitability of the detection method of organic impurities, testing result is as shown in table 1, and table 1 is that the present invention is real
Execute the system suitability of the method for detecting impurities that example 2 provides.
The system suitability of the method for detecting impurities that table 1 embodiment of the present invention 2 provides
As shown in Table 1, in the piperazine Ma Selin that the embodiment of the present invention 2 provides, the detection method of organic impurities is steady
Height fixed, repeated, specificity are strong.
According to the method described in technique scheme, the piperazine Ma Selin that the embodiment of the present invention 2 is provided is had
The detection method of machine impurity carries out recovery of standard addition experiment, and experimental result is as shown in table 2, and table 2 is this
The recovery of standard addition of the method for detecting impurities that bright embodiment 2 provides.
The recovery of standard addition of the method for detecting impurities that table 2 embodiment of the present invention 2 provides
Note: in table 4, L, M, H represent the amount of addition organic impurities from low to high, 1,2,3 represent that addition is different amounts of miscellaneous
Matter is parallel does 3 times.
As shown in Table 2, the detection method inspection of organic impurities in the piperazine Ma Selin that the embodiment of the present invention 2 provides
Survey result is accurate.
Embodiment 3
The piperazine Ma Selin preparing the embodiment of the present invention 1 carries out high performance liquid chromatography detection, described height
Effect liquid phase chromatogram detection during flowing mutually in aqueous phase be mass concentration be the aqueous formic acid of 0.1%, have
Machine is mutually for the acetonitrile solution of formic acid that mass concentration is 0.1%, and chromatographic column is C18 chromatographic column, chromatographic column temperature
Degree is 30 DEG C, and flow rate of mobile phase is 0.8mL/min, and detector is UV-detector, and detection wavelength is
210nm, flows during the detection of described high performance liquid chromatography and uses the mode of gradient elution to pass through chromatograph mutually
Post, the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 55% by 90%, and organic facies exists
Mass content in flowing mutually is brought up to 45% by 10%；At 25min～35min, aqueous phase is in flowing mutually
Mass content be reduced to 0 by 55%, organic facies flowing mutually in mass content brought up to by 45%
100%；At 35min～38min, aqueous phase mass content in flowing mutually keeps 0, and organic facies is in flowing
Mass content in mutually keeps 100%；At 38min～40min, aqueous phase mass content in flowing mutually by
0 brings up to 90%, and organic facies mass content in flowing mutually is reduced to 10% by 100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 90%, organic facies matter in flowing mutually
Amount content keeps 10%.
The liquid chromatogram shown in Fig. 4, Fig. 4 is obtained after piperazine Ma Selin is carried out high performance liquid chromatography detection
The high-efficient liquid phase chromatogram obtained after detecting piperazine Ma Selin for the embodiment of the present invention 3, as shown in Figure 4, this
The method that inventive embodiments 3 provides is capable of detecting when the organic impurities in piperazine Ma Selin with Formulas I structure, miscellaneous
Mass peak and piperazine Ma Selin peak energy enough reach baseline separation, and peak shape is preferable.
According to the method described in technique scheme, in the piperazine Ma Selin that the detection embodiment of the present invention 3 provides
The system suitability of the detection method of organic impurities, testing result is as shown in table 3, and table 3 is that the present invention is real
Execute the system suitability of the method for detecting impurities that example 3 provides.
The system suitability of the method for detecting impurities that table 3 embodiment of the present invention 3 provides
As shown in Table 3, in the piperazine Ma Selin that the embodiment of the present invention 3 provides, the detection method of organic impurities is steady
Height fixed, repeated, specificity are strong.
According to the method described in technique scheme, the piperazine Ma Selin that the embodiment of the present invention 3 is provided is had
The detection method of machine impurity carries out recovery of standard addition experiment, and experimental result is as shown in table 4, and table 4 is this
The recovery of standard addition of the method for detecting impurities that bright embodiment 3 provides.
The recovery of standard addition of the method for detecting impurities that table 4 embodiment of the present invention 3 provides
Note: in table 2, L, M, H represent the amount of addition organic impurities from low to high, 1,2,3 represent that addition is different amounts of miscellaneous
Matter is parallel does 3 times.
As shown in Table 4, the detection method inspection of organic impurities in the piperazine Ma Selin that the embodiment of the present invention 3 provides
Survey result is accurate.
Embodiment 4
The piperazine Ma Selin preparing the embodiment of the present invention 1 carries out high performance liquid chromatography detection, described height
Effect liquid phase chromatogram detection during flow mutually in aqueous phase be mass concentration be the phosphate aqueous solution of 0.1%, organic
Mutually for the methanol solution of phosphoric acid that mass concentration is 0.1%, chromatographic column is C8 chromatographic column, chromatogram column temperature
Being 40 DEG C, flow rate of mobile phase is 1.2mL/min, and detector is UV-detector, and detection wavelength is 230nm,
The mode using gradient elution mutually that flows during the detection of described high performance liquid chromatography is by chromatographic column, described
The process of gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 45% by 80%, and organic facies exists
Mass content in flowing mutually is brought up to 55% by 20%；At 25min～35min, aqueous phase is in flowing mutually
Mass content be reduced to 0 by 45%, organic facies flowing mutually in mass content brought up to by 55%
100%；At 35min～38min, aqueous phase mass content in flowing mutually keeps 0, and organic facies is in flowing
Mass content in mutually keeps 100%；At 38min～40min, aqueous phase mass content in flowing mutually by
0 brings up to 80%, and organic facies mass content in flowing mutually is reduced to 20% by 100%；?
40min～45min, aqueous phase mass content in flowing mutually keeps 80%, organic facies matter in flowing mutually
Amount content keeps 20%.
The liquid chromatogram shown in Fig. 5, Fig. 5 is obtained after piperazine Ma Selin is carried out high performance liquid chromatography detection
The high-efficient liquid phase chromatogram obtained after detecting piperazine Ma Selin for the embodiment of the present invention 4, as shown in Figure 5, this
The method that inventive embodiments 4 provides is capable of detecting when the organic impurities in piperazine Ma Selin with Formulas I structure, miscellaneous
Mass peak and piperazine Ma Selin peak energy enough reach baseline separation, and peak shape is preferable.
According to the method described in technique scheme, in the piperazine Ma Selin that the detection embodiment of the present invention 4 provides
The system suitability of the detection method of organic impurities, testing result is as shown in table 5, and table 5 is that the present invention is real
Execute the system suitability of the method for detecting impurities that example 4 provides.
The system suitability of the method for detecting impurities that table 5 embodiment of the present invention 4 provides
As shown in Table 1, in the piperazine Ma Selin that the embodiment of the present invention 4 provides, the detection method of organic impurities is steady
Height fixed, repeated, specificity are strong.
According to the method described in technique scheme, the piperazine Ma Selin that the embodiment of the present invention 4 is provided is had
The detection method of machine impurity carries out recovery of standard addition experiment, and experimental result is as shown in table 6, and table 6 is this
The recovery of standard addition of the method for detecting impurities that bright embodiment 4 provides.
The recovery of standard addition of the method for detecting impurities that table 6 embodiment of the present invention 4 provides
Note: in table 6, L, M, H represent the amount of addition organic impurities from low to high, 1,2,3 represent that addition is different amounts of miscellaneous
Matter is parallel does 3 times.
As shown in Table 6, the detection method inspection of organic impurities in the piperazine Ma Selin that the embodiment of the present invention 4 provides
Survey result is accurate.
Comparative example 1
The piperazine Ma Selin prepared embodiment 1 according to the method described in embodiment 2 carries out efficient liquid phase
Chromatograph detects, and as different from Example 2, using molar concentration is the KH of 20mmol/L2PO4Water-soluble
Liquid is aqueous phase, and employing acetonitrile is organic facies.
The liquid chromatogram shown in Fig. 6, Fig. 6 is obtained after piperazine Ma Selin is carried out high performance liquid chromatography detection
The high-efficient liquid phase chromatogram obtained after detecting piperazine Ma Selin for comparative example 1 of the present invention, it will be appreciated from fig. 6 that this
Method impurity peaks and piperazine Ma Selin peak that invention comparative example 1 provides are not separated by, it is impossible to detect piperazine horse color
The organic impurities of woods.
As seen from the above embodiment, the invention provides the detection method of organic impurities in a kind of piperazine Ma Selin,
Including: piperazine Ma Selin is carried out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；
Flowing during the detection of described high performance liquid chromatography includes that aqueous phase and organic facies, described aqueous phase are acid mutually
Aqueous solution, described organic facies is the organic solution of acid, and described acid includes formic acid, trifluoroacetic acid or phosphoric acid；
Solvent in described organic solution includes methanol or acetonitrile；Described organic impurities is the chemical combination of structure shown in Formulas I
Thing.In the piperazine Ma Selin that the present invention provides, the detection method of organic impurities, carries out high-efficient liquid to piperazine Ma Selin
During the detection of phase chromatograph, use aqueous phase and organic facies composition flowing phase, this flowing of predetermined substance
Can preferably separate organic impurities mutually, the method enabling the present invention to provide accurately detects piperazine
Organic impurities in Ma Selin.Additionally, the detection method of organic impurities in the piperazine Ma Selin of present invention offer
Stable, reproducible, specificity is strong.
Claims (10)
1. a detection method for organic impurities in piperazine Ma Selin, including:
Piperazine Ma Selin is carried out high performance liquid chromatography detection, obtains the content of organic impurities in piperazine Ma Selin；
Flowing during the detection of described high performance liquid chromatography includes that aqueous phase and organic facies, described aqueous phase are acid mutually
Aqueous solution, described organic facies is the organic solution of acid, and the acid in described aqueous phase and the acid in organic facies include
Formic acid, trifluoroacetic acid or phosphoric acid；Solvent in described organic solution includes methanol or acetonitrile；Described organic
Impurity is the compound of structure shown in Formulas I:
Detection method the most according to claim 1, it is characterised in that the matter of described aqueous acid
Amount concentration is 0.05%～0.15%.
Detection method the most according to claim 1, it is characterised in that the organic solution of described acid
Mass concentration is 0.05%～0.15%.
Detection method the most according to claim 1, it is characterised in that described aqueous phase and organic facies
Mass ratio is (50～60): (50～40).
Detection method the most according to claim 1, it is characterised in that described efficient Liquid Detection mistake
The flow velocity of the phase that flows in journey is 0.5mL/min～1.5mL/min.
Detection method the most according to claim 1, it is characterised in that described high performance liquid chromatography is examined
The mode using gradient elution during survey makes flowing mutually by chromatographic column, and the process of described gradient elution is:
0～25min, aqueous phase mass content in flowing mutually is reduced to 45%～55% by 80%～90%,
Organic facies mass content in flowing mutually is brought up to 45%～55% by 10%～20%；
At 25min～35min, aqueous phase mass content in flowing mutually is reduced to 10%～0 by 45%～55%,
Organic facies mass content in flowing mutually is brought up to 90%～100% by 45%～55%；
At 35min～38min, aqueous phase mass content in flowing mutually keeps 10%～0, and organic facies is at stream
Mass content in moving mutually keeps 90%～100%；
At 38min～40min, aqueous phase mass content in flowing mutually is brought up to 80%～90% by 10%～0,
Organic facies mass content in flowing mutually is reduced to 10%～20% by 90%～100%；
At 40min～45min, aqueous phase mass content in flowing mutually keeps 80%～90%, and organic facies exists
Mass content in flowing mutually keeps 10%～20%.
Detection method the most according to claim 1, it is characterised in that described high performance liquid chromatography is examined
The chromatographic column used during survey is C8 chromatographic column or C18 chromatographic column.
Detection method the most according to claim 1, it is characterised in that described high performance liquid chromatography is examined
Chromatographic column column temperature during survey is 25 DEG C～45 DEG C.
Detection method the most according to claim 1, it is characterised in that described high performance liquid chromatography is examined
Detector during survey is UV-detector.
Detection method the most according to claim 1, it is characterised in that described high performance liquid chromatography
Detection wavelength during detection is 200nm～240nm.
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