CN106198766A - A kind of avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof - Google Patents
A kind of avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof Download PDFInfo
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- CN106198766A CN106198766A CN201510097960.9A CN201510097960A CN106198766A CN 106198766 A CN106198766 A CN 106198766A CN 201510097960 A CN201510097960 A CN 201510097960A CN 106198766 A CN106198766 A CN 106198766A
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Abstract
The present invention designs the HPLC (high performance liquid chromatography) of a kind of avanaphil and preparation thereof, belongs to pharmaceutical analysis technical field.This HPLC (high performance liquid chromatography) chromatographic column: selecting octadecyl silane is the chromatographic column of filler: specification is 4.6mm*150mm, 5um, 4.6mm*200mm, 5um, 4.6mm*250mm, 5um, 4.6mm*150mm, 3.5um, 4.6mm*200mm, 3.5um, 4.6mm*250mm, 3.5um；Flowing is acetonitrile mutually: buffer salt=30～70: 70～30；Flow velocity 0.5～1.5ml/min；Column temperature 30～40 DEG C；UV-detector wavelength: 200～300nm；Sampling volume: 5～50ul.The HPLC (high performance liquid chromatography) of the avanaphil of the present invention is with common chromatograph of liquid, and equipment requirements is the highest, and two media that flowing is selected mutually are commonly easy to get, feasibility is high, operating process is simple and convenient, and the suitability is good, can be widely applied to avanaphil and preparation thereof.
Description
Technical field
The invention belongs to pharmaceutical analysis technical field, in particular to a kind of avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof.
Background technology
Avanaphil (Avanafil), chemistry entitled 4-[(3-chloro-4-methoxy benzyl) amino]-2-[2-(methylol)-1-pyrrolidinyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine Methanesulfomide, CAS accession number is 330784-47-9.Chemical structural formula is as follows:
Avanafil is a kind of PDE5 (PDE5) inhibitor, is the research project transferred the possession of from day Honda limit Rhizoma Sparganii drugmaker of Vivus company.For treating male erectile dysfunction (ED), listing on April 27th, 2012, dosage form is tablet (specification 50mg, 100mg and 200mg)
Avanaphil is that a kind of PDE5 inhibitor can effectively suppress the degraded of cGMP in penis, makes the level of the cGMP in penis increase, causes the smooth muscle of cavernous body of penis to loosen and promote the inflow of blood, it is possible in making penis, blood flow increases.
At present, avanaphil and preparation thereof the most do not list, and the analysis method of this crude drug and preparation thereof there is no document report.In order to ensure the follow-up research and development of avanaphil and the quality of production, need the quality of crude drug and preparation thereof is controlled.Therefore, research obtains Related substances separation and the detection method of assay of a kind of avanaphil, and this seems the most urgent for medicine manufacture.
Summary of the invention
For solving above-mentioned technical problem, it is an object of the invention to provide a kind of feasibility high, operating process is simple and convenient, and the suitability is good, can be widely applied to the high efficiency liquid phase chromatographic analysis method of avanaphil and preparation thereof.
The technical scheme proposed to solve above-mentioned technical problem is: the HPLC (high performance liquid chromatography) of a kind of avanaphil, and step is as follows:
(1) high-efficient liquid phase chromatogram condition is: chromatographic column: selecting octadecyl silane is the chromatographic column of filler, specification is 4.6mm*150mm, 5um, 4.6mm*200mm, 5um, 4.6mm*250mm, 5um, 4.6mm*150mm, 3.5um, 4.6mm*200mm, 3.5um or 4.6mm*250mm, 3.5um；
Flowing phase: acetonitrile and water mixing composition, volume proportion is acetonitrile: buffer salt=30～70: 70～30；
Buffer salt is one or more in phosphate, acetate salt buffer system；
Buffer salinity is 1～100mmol/L；
Flow velocity: 0.5～1.5mL/min；
Column temperature: 30～40 DEG C；
UV-detector wavelength: 200nm～300nm；
Sampling volume: 5～50uL；
(2) preparation sample solution, wherein sample is avanaphil raw material and tablet thereof；
(3) measure peak area, calculate sample purity and content.
Preferably, described proportion of mobile phase is acetonitrile: buffer salt=40～50: 60～50, and column temperature is 40 DEG C, and flow velocity is 1.0ml/min, and sampling volume is 20uL, and described UV-detector wavelength is 220nm.
Preferably, buffer salt is acetate buffer salt system.
Preferably, buffer salinity is 5～50mmol/L
Preferably, described avanaphil preparation is excellent for tablet.
The present invention solves the application in avanaphil quality research of the HPLC (high performance liquid chromatography) that another solution is that described avanaphil that above-mentioned technical problem proposes.
The invention has the beneficial effects as follows:
(1) the analysis method that the present invention provides, according to Chinese Pharmacopoeia 2010 editions, Method Of Accomplishment is verified, tests including the test of system adaptive, specificity (Degrading experiment), stability test, linear test, recovery test, precision and ruggedness etc..Verifying through these, the analysis method that the present invention provides is practical reliable, and stability is preferable.
(2) present invention identifies 3 known impurities from avanaphil, including the intermediate 1 in synthesis technique, intermediate 2 and intermediate 3, raw material and preparation are carried out strong Degrading experiment simultaneously, degradation impurity have also been obtained and efficiently separates, separating degree is more than 1.5, main peak peak purity is preferable, and the method can be with effectively evaluating avanaphil and the quality of preparation thereof.
(3) using common chromatograph of liquid, equipment requirements is the highest.
(4) two media that flowing is selected mutually are commonly easy to get, and feasibility is high.
(5) operating process is simple and convenient.
(6) suitability is good, can be widely applied to the quality control of avanaphil and formulation samples thereof.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of the avanaphil raw material of embodiment one
Fig. 2 is the high-efficient liquid phase chromatogram of the avanaphil material content mensuration reference substance of embodiment two
Fig. 3 is the high-efficient liquid phase chromatogram of the avanaphil tablet of embodiment three
Fig. 4 is the high-efficient liquid phase chromatogram of the avanaphil tablet blank auxiliary of embodiment three
Fig. 5 is the high-efficient liquid phase chromatogram of the avanaphil system suitability solution of embodiment one
Detailed description of the invention
Below in conjunction with accompanying drawing, embodiment of the present invention is described further in detail.
Embodiment one
Avanaphil raw material Related substances separation
Instrument and chromatographic condition:
Chromatographic column: Agilent C 18；4.6mmX 150mm, 3.5um
Flowing phase: acetonitrile: 50mmol/L phosphate buffer=40: 60
Detection wavelength: 220nm
Flow velocity: 1.0ml/min
Column temperature: 40 DEG C
Sampling volume: 20uL
High performance liquid chromatograph: Japan's Shimadzu LC-20A, PDA detector
Experimental procedure:
Solution is prepared:
Take avanaphil crude drug appropriate, accurately weighed, add flowing phased soln and dilution is made in every 1ml containing about 0.5～the solution of 1mg, as Related substances separation need testing solution；Precision measures need testing solution 1ml, puts in 100ml measuring bottle, add flowing phase dilution to scale, shake up, as reference substance solution；Precision measures need testing solution and each 20ul of reference substance solution injects chromatograph of liquid, records chromatogram, as it is shown in figure 1, calculate its purity according to the Self-control method being not added with correction factor.
System suitability solution: it is appropriate that accurately weighed intermediate 1, intermediate 2 and intermediate 3 make reference substance by oneself, adds flowing phased soln, finally it is configured to the impurity mixed solution that every 1ml is containing 10～20ug, precision measures 20ul and enters chromatograph of liquid, records chromatogram, as shown in Figure 5.
Detecting according to the method described above, result is as follows:
Table 1 system adapts to the separating degree test of solution
According to table 1 it can be seen that in avanaphil raw material each impurity can be separated efficiently, separating degree is all higher than 1.5, and peak shape is good, and peak purity is good, and theoretical cam curve is more than 2000, and tailing factor is less than 1.5, conformance with standard.
Avanaphil material purity is 99.81%, and the most miscellaneous is 0.19%.From avanaphil, identify 1 known impurities, for synthetic intermediate 3, raw material and preparation are carried out strong Degrading experiment simultaneously, degradation impurity have also been obtained and efficiently separates, separating degree is more than 1.5, and main peak purity is preferable, and the present invention can be with effectively evaluating avanaphil and the quality of preparation thereof.
The analysis method that the present embodiment provides, according to Chinese Pharmacopoeia 2010 editions, Method Of Accomplishment is verified, including system suitability, specificity (Degrading experiment), stability test, linear test, recovery test, precision and serviceability test.Through a series of checkings, it was demonstrated that the analysis method that the present embodiment provides is practical reliable, and stability is preferable.
Embodiment two
Avanaphil material content measures
Instrument and chromatographic condition
Chromatographic column: Agilent C 18；4.6mmX 150mm, 3.5um
Flowing phase: acetonitrile: 50mmol/L phosphate buffer=60: 40
Detection wavelength: 220nm
Flow velocity: 1.0mL/min
Column temperature: 40 DEG C
Sampling volume: 20ul
Instrument: Japan's Shimadzu LC-20A (PDA detector)
Solution is prepared
Accurately weighed avanaphil fabricated material 10mg, puts in 100ml volumetric flask, adds flowing appropriate mutually, and shaking is diluted to scale after making dissolving, shakes up, obtains test sample mother solution；Precision measures test sample mother solution 1ml, puts in 10ml measuring bottle, add flowing phase dilution to scale, shake up, as reference substance solution, precision measure 20ul inject chromatograph of liquid, record chromatogram；Another accurately weighed avanaphil self-control reference substance 10mg, puts in 100ml measuring bottle, adds flowing appropriate mutually, and shaking is diluted to scale after making dissolving, shakes up, obtains reference substance mother solution；Precision measures reference substance mother solution 1ml, puts in 10ml measuring bottle, add flowing phase dilution to scale, shake up, as reference substance solution, be measured in the same method (as shown in Figure 2), by external standard method with calculated by peak area, to obtain final product.
Content (%)=CR*AX/AR
CRConcentration for reference substance solution
AXFor need testing solution peak area
ARFor reference substance solution peak area
Detecting according to the method described above, avanaphil assay result is as follows:
Based on dry product, avanaphil material content is 99.8%.
Embodiment three
Avanaphil tablet Related substances separation
Instrument and chromatographic condition:
Chromatographic column: Agilent C 18；4.6mmX 150mm, 3.5um
Flowing phase: acetonitrile: 50mmol/L phosphate buffer=40: 60
Detection wavelength: 220nm
Flow velocity: 1.0ml/min
Column temperature: 40 DEG C
Sampling volume: 20ul
Instrument: Japan's Shimadzu LC-20A (PDA detector)
Solution is prepared:
Take avanaphil tablet, be ground to powder, take the powder after grinding appropriate, accurately weighed, add flowing phased soln and dilution is made in every 1ml containing about 0.5～the solution of 1mg, take subsequent filtrate after filtration as Related substances separation need testing solution；Precision measures need testing solution 1ml, puts in 100ml measuring bottle, add flowing phase dilution to scale, shake up, as reference substance solution；Precision measures need testing solution and each 20ul of reference substance solution injects chromatograph of liquid, records chromatogram, calculates its purity according to the Self-control method being not added with correction factor.
Detecting according to the method described above, result is as follows:
In avanaphil tablet, each impurity can be separated efficiently, and sample analysis is not interfered with by blank auxiliary and solvent.
Avanaphil tablet purity is 99.83%, and the most miscellaneous is 0.17%, and impurity cis-isomer is 0.13%.
Embodiment four
Avanaphil tablet content measures
Instrument and chromatographic condition:
Chromatographic column: Agilent C 18；4.6mmX 150mm, 3.5um
Flowing phase: acetonitrile: 50mmol/L phosphate buffer=60: 40
Detection wavelength: 220nm
Flow velocity: 1.0ml/min
Column temperature: 40 DEG C
Sampling volume: 20ul
Instrument: Japan's Shimadzu LC-20A (PDA detector)
Solution is prepared:
Taking avanaphil tablet, be ground to powder, the powder after accurately weighed grinding is appropriate (being approximately equivalent to avanaphil 10mg), puts in 100ml volumetric flask, adds flowing phased soln and is diluted to scale, obtaining test sample mother solution；Take the continuous filter 1ml after filtration to be placed in 10ml volumetric flask, add flowing phase dilution to scale, shake up, as need testing solution；Another accurately weighed avanaphil self-control reference substance 10mg, puts in 100ml measuring bottle, adds flowing appropriate mutually, and shaking is diluted to scale after making dissolving, shakes up, obtains reference substance mother solution；Precision measures reference substance mother solution 1ml, puts in 10ml measuring bottle, add flowing phase dilution to scale, shake up, as reference substance solution；Precision measures need testing solution and each 20ul of reference substance solution injects in chromatograph of liquid, records chromatogram, calculates its purity according to the Self-control method being not added with correction factor.
Detecting according to the method described above, result is as follows:
Avanaphil tablet content is 98.45%.
Obviously, above-described embodiment is only for clearly demonstrating example, and not restriction to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here without also cannot all of embodiment be given exhaustive.And the obvious change thus extended out or variation still in protection scope of the present invention among.
Claims (4)
1. an avanaphil and the HPLC (high performance liquid chromatography) of preparation thereof, it is characterised in that step is as follows:
(1) high-efficient liquid phase chromatogram condition is: chromatographic column: selecting octadecyl silane is the chromatographic column of filler, and specification is 4.6mm*150mm,
5um, 4.6mm*200mm, 5um, 4.6mm*250mm, 5um, 4.6mm*150mm, 3.5um, 4.6mm*200mm, 3.5um or
4.6mm*250mm, 3.5um.
Flowing phase: acetonitrile and buffer salt mixing composition, volume proportion is acetonitrile: buffer salt=30～70: 70～30；
Buffer salt is one or more in phosphate, acetate and triethylamine buffer system；
Buffer salinity is 1～100mmol/L；
Flow velocity: 0.5～1.5mL/min；
Column temperature: 30～40 DEG C；
UV-detector wavelength: 200nm～300nm；
Sampling volume: 5～50uL；
(2) preparation sample solution, wherein sample is avanaphil raw material and tablet thereof；
(3) measure peak area, calculate sample purity and content.
Avanaphil the most according to claim 1 and the HPLC (high performance liquid chromatography) of preparation thereof, it is characterised in that described flowing matches
Ratio is acetonitrile: buffer salt=60: 40, and column temperature is 40 DEG C, and flow velocity is 1.0ml/min, and sampling volume is 20ul, and described UV-detector wavelength is 220nm.
The HPLC (high performance liquid chromatography) of avanaphil the most according to claim 1 and 2, it is characterised in that described avanaphil preparation is excellent
For tablet.
The application in avanaphil quality research of the HPLC (high performance liquid chromatography) of avanaphil the most according to claim 1 and preparation thereof.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
| CN109696502A (en) * | 2019-02-22 | 2019-04-30 | 重庆安格龙翔医药科技有限公司 | Benzene and the remaining method of Mesityl oxide in gas chromatographic detection avanaphil |
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
| CN113917027A (en) * | 2021-10-11 | 2022-01-11 | 山东省药学科学院 | Optical isomer separation detection method for avanafil and intermediate thereof |
| CN114280174A (en) * | 2021-12-07 | 2022-04-05 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
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| CN104557877A (en) * | 2013-10-28 | 2015-04-29 | 重庆安格龙翔医药科技有限公司 | Avanafil intermediate as well as preparation method and application thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108593805A (en) * | 2018-06-01 | 2018-09-28 | 无锡富泽药业有限公司 | The separation method and detection method of 3- chloro-4-methoxy benzylamine hydrochloride isomers |
| CN109696502A (en) * | 2019-02-22 | 2019-04-30 | 重庆安格龙翔医药科技有限公司 | Benzene and the remaining method of Mesityl oxide in gas chromatographic detection avanaphil |
| CN111208232A (en) * | 2020-01-20 | 2020-05-29 | 山东省药学科学院 | Analysis method of related substances in avanafil and preparation thereof |
| CN113917027A (en) * | 2021-10-11 | 2022-01-11 | 山东省药学科学院 | Optical isomer separation detection method for avanafil and intermediate thereof |
| CN114280174A (en) * | 2021-12-07 | 2022-04-05 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
| CN114280174B (en) * | 2021-12-07 | 2023-12-29 | 嘉实（湖南）医药科技有限公司 | Detection method of avanafil and related impurities thereof |
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