CN108254455A - A kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance - Google Patents
A kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance Download PDFInfo
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- CN108254455A CN108254455A CN201711284741.7A CN201711284741A CN108254455A CN 108254455 A CN108254455 A CN 108254455A CN 201711284741 A CN201711284741 A CN 201711284741A CN 108254455 A CN108254455 A CN 108254455A
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Abstract
The invention belongs to analytical chemistry fields, and in particular to a kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance, the analysis condition of the method are：Chromatographic column uses octadecylsilane chemically bonded silica as stationary phase, and isocratic elution is carried out by mobile phase of the mixed liquor of ammonium dihydrogen phosphate and organic solvent.The method of the present invention has the advantages that compared with prior art：Roflumilast can be effectively separated and be quantitative determined impurity that may be present, specificity is strong, high sensitivity, accuracy are good, so as to effectively control the product quality of roflumilast and its preparation, drug safety is improved, the formulation for roflumilast and its preparation quality standard provides foundation.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular to a kind of related substance of high effective liquid chromatography for measuring roflumilast
Method.
Background technology
Chronic obstructive pulmonary disease (COPD) is a kind of common disease characterized by duration flow limitation, is the whole world
In the range of one of the highest disease of morbidity and mortality.As the roflumilast of phosphodiesterase 4 (PDE-4) inhibitor, energy
Inflammatory reaction signal is blocked to transmit, reduces inflammatory mediator release, and then inhibit the damages of the breathing problems to lung tissue such as COPD.
Food and Drug Adminstration of the US (FDA) and European drug administration (EMEA) are respectively on March 1st, 2011 and 2011
Ratify the Roflumilast tablet of Forest companies 28 days 2 months year for reducing the breaking-out or deterioration of severe COPD symptom
Frequency, to mitigate the cough of patient and the excessive symptom of respiratory tract mucus.
Roflumilast (Roflumilast), entitled N- (3,5- dichloropyridine -4- the bases) -3- (cyclo propyl methoxy) of chemistry -
4- (difluoro-methoxy) benzamide；Molecular formula is C17H14Cl2F2N2O3；Chemical structural formula is as follows：
What starting material, intermediate, by-product and the storage introduced during the compound is synthesized generated in the process
The related substance such as catabolite if content is larger, may influence curative effect of medication, be detrimental to health, need to carry out stringent matter
Amount control.Specifying information it includes impurity is shown in Table 1.
Title and chemical structural formula of 1 roflumilast of table in relation to substance
So far, the statutory standards such as European Pharmacopoeia, United States Pharmacopeia, British Pharmacopoeia, Japanese Pharmacopoeia and Chinese Pharmacopoeia are not yet recorded
Roflumilast；The detection method in relation to substance still has much room for improvement in the pertinent literature and patent delivered at present.To ensure sieve fluorine
Department is special and its preparation safely, effectively with it is quality controllable, seek it is a kind of it is simple and fast, specificity is strong, high sensitivity, accuracy are good
Detection method be particularly important.
Invention content
In consideration of it, the present invention provides a kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance, this method
Impurity that may be present in roflumilast can be effectively separated and be quantitative determined, specificity is strong, high sensitivity, accuracy
It is good, so as to effectively control the product quality of roflumilast and its preparation, drug safety is improved, is roflumilast and its preparation matter
The formulation of amount standard provides foundation.
To achieve the above object, technical solution provided by the invention is as follows.
A kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance, with ammonium dihydrogen phosphate and organic molten
The mixed liquor of agent is mobile phase, carries out isocratic elution in octadecylsilane chemically bonded silica chromatographic column, used in sample dissolution
Dilution is mobile phase.
The related substance of the roflumilast includes：Roflumilast is in relation to one kind in substance A, B, C, D, E, F, G or several
Kind (being shown in Table 1).
A concentration of 0.004~0.02mol/L of the ammonium dihydrogen phosphate, pH value are 3.0~3.6.
The organic solvent is methanol and acetonitrile.
Preferably, the mobile phase is 0.005mol/L ammonium dihydrogen phosphates (with phosphorus acid for adjusting pH value to 3.5)-first
Alcohol-acetonitrile (41:31:28).
The testing conditions of the high performance liquid chromatography are：0.8~1.2ml/min of flow velocity of mobile phase, column temperature 25~35
DEG C, 210~215nm of Detection wavelength, 10 μ l of sample size.
The method of the present invention is used for the detection of potential impurity in roflumilast and its preparation.
The method specific steps of the present invention：
This product about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml shakings is added to make dissolving, then use diluted
It to scale, shakes up, as test solution；Precision measures 1ml, puts in 100ml measuring bottles, with diluted to scale, shakes up,
As contrast solution.
Take impurity A, impurity B, impurity C, impurity D, impurity E, impurity F and impurity G reference substances each appropriate, it is accurately weighed, point
It is not dissolved with dilution and quantifies dilution and the solution that every 1ml contains 500 μ g is made, as reference substance stock solution；Precision measures 1ml,
It puts in 50ml measuring bottles, with diluted to scale, shakes up, as reference substance solution.
Roflumilast reference substance about 5mg is taken, it is accurately weighed, it puts in 10ml measuring bottles, acetonitrile 1ml shakings is added to make dissolving, then essence
It is close to add in above-mentioned each 0.2ml of impurity reference substance stock solution, it with diluted to scale, shakes up, every 1ml is made containing roflumilast
The mixed solution of each 10 μ g of 0.5mg, above-mentioned impurity, shakes up, as system suitability solution.
It is filler with octadecylsilane chemically bonded silica according to high effective liquid chromatography for measuring；With 0.005mol/L phosphoric acid
Dihydro ammonium salt solution (with phosphorus acid for adjusting pH value to 3.5)-methanol-acetonitrile (41:31:28) it is mobile phase, Detection wavelength 213nm,
Flow velocity 1.0ml/min, 30 DEG C of column temperature.10 μ l of system suitability solution are taken, inject liquid chromatograph, record chromatogram to principal component
3 times of peak retention time, the separating degree between roflumilast peak and other impurities peak should be greater than 1.5.It is molten that precision measures test sample
Liquid, contrast solution and each 10 μ l of reference substance solution are injected separately into liquid chromatograph, record chromatogram to principal component peak retention time
3 times.
The method of the present invention has the advantages that compared with prior art：
1. the method for the present invention can efficiently separate and quantitative determine related substance that may be present in roflumilast, so as to have
The quality of effect control roflumilast product, specificity is strong, high sensitivity, accuracy are good, can fully meet Related substances separation
It is required that.
2. the method for the present invention is simple and fast, roflumilast can be detached under same high-efficient liquid phase chromatogram condition and its had
Substance is closed, extent of reaction is monitored, avoids and detection method is frequently replaced in production monitoring, available for production process intermediate
Related substances separation in monitoring and finished product improves working efficiency, is suitble to the requirement of industrialized production.
In conclusion the method high sensitivity of the present invention, the potential dopant species that can be detected simultaneously are more, can control comprehensively
Related substance in roflumilast and its preparation improves drug safety, to formulate the quality of Roflumilast raw material and its preparation
Standard provides foundation.
Description of the drawings
The high-efficient liquid phase chromatogram of Fig. 1 roflumilast Related substances separation blank solutions.
The high-efficient liquid phase chromatogram of Fig. 2 roflumilast Related substances separation system suitability solution.
Fig. 3 roflumilast Related substances separation acid forced degradation tests the high-efficient liquid phase chromatogram of test solution.
Fig. 4 roflumilast Related substances separation alkali forced degradation tests the efficient liquid phase chromatic graph of test solution.
The high-efficient liquid phase chromatogram of Fig. 5 roflumilasts Related substances separation oxidation forced degradation experiment test solution.
Fig. 6 roflumilast Related substances separation illumination forced degradation tests the high-efficient liquid phase chromatogram of test solution.
Fig. 7 roflumilast Related substances separation high temperature forced degradation tests the high-efficient liquid phase chromatogram of test solution.
In figure：1- impurity As；2- impurity Bs；3- impurity C；4- impurity D；5- impurity Es；6- impurity Fs；7- impurity G；Sieve's 8- fluorine department
It is special.
Specific embodiment
It is explained further below by embodiment and illustrates the present invention.The embodiment of the present invention is only used for that this is better described
The content rather than limitation of the present invention of invention, therefore to the simple modifications of the present invention on the basis of the method for the present invention
Or it replaces and belongs to the scope of protection of present invention.
The chromatographic condition of detection method of the present invention.
Instrument：Waters e2695 types high performance liquid chromatograph (e2695 points of 3 chromatographic work stations of Empower, Waters
From module, Waters Alliance series column oven), 2998 photodiode array detectors of Waters.
Chromatographic column：Waters Xbridge C18(4.6mm × 250mm, 5 μm).
Mobile phase：0.005mol/L ammonium dihydrogen phosphates (with phosphorus acid for adjusting pH value to 3.5)-methanol-acetonitrile (41:31:
28), isocratic elution.
Detection wavelength：213nm.
Flow velocity：1.0ml/min.
Column temperature：30℃.
Sample size：10μl.
The system suitability of 1 detection method of the present invention of embodiment.
Dilution：0.005mol/L ammonium dihydrogen phosphates (with phosphorus acid for adjusting pH value to 3.5)-methanol-acetonitrile (41:31:
28)。
Blank solution：Dilution.
The preparation of impurity reference substance stock solution：Take G pairs of impurity A, impurity B, impurity C, impurity D, impurity E, impurity F and impurity
It is each appropriate according to product, it is accurately weighed, dissolve respectively with dilution and quantify dilution solution of every 1ml containing 500 μ g is made, shaken up, i.e.,
.
Impurity positions the preparation of solution：It takes above-mentioned impurity reference substance stock solution appropriate, quantitatively dilutes system with dilution respectively
Into every 1ml contain 10 μ g solution, shake up to get.
The preparation of system suitability solution：Roflumilast reference substance about 5mg is taken, it is accurately weighed, it puts in 10ml measuring bottles, adds second
Nitrile 1ml shakings make dissolving, then the accurate above-mentioned each 0.2ml of impurity reference substance stock solution of addition, with diluted to scale, shake
It is even, be made the mixed solution of each 10 μ g of every 1ml 0.5mg containing roflumilast, above-mentioned impurity to get.
Precision measures above-mentioned blank solution, each impurity positioning solution and each 10 μ l of system suitability solution, is injected separately into liquid
Chromatography is measured according to 1 chromatographic condition of embodiment, records chromatogram.Blank solution chromatogram is shown in attached drawing 1, and system is fitted
See attached drawing 2 with property solution chromatogram.This method is shown in Table 2 to the separation situation of roflumilast and each impurity.
The separation situation of 2 roflumilast of table and each impurity
The result shows that the chromatographic peak that retention time is 14.6min is roflumilast, roflumilast and each impurity, each impurity
Between can reach and efficiently separate, separating degree is all higher than 1.5, and peak shape is preferable, and blank solution does not interfere the related substance of roflumilast
Detection.
The specificity experiment of 2 detection method of the present invention of embodiment.
Forced degradation experiment is in the strong degradation condition for simulating strong acid, highly basic, oxidation, illumination and high temperature etc., acceleration pair
Roflumilast is destroyed, it is therefore an objective to by investigating the catabolite of sample and the separation situation of main peak and known impurities, be commented
Estimate the efficiency and applicability of analysis method.
In order to preferably investigate the specificity of this method and stability, the strong of acid, alkali, oxidation, illumination and high temperature is devised
Degrading experiment processed.
Sour forced degradation experiment：Roflumilast about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml shakings is added to make
Dissolving, adds 1mol/L hydrochloric acid solution 2ml, shakes up, and puts heating in 80 DEG C of water-baths and destroys 3.5h, lets cool, add 1mol/L sodium hydroxides
Solution neutralizes, and with diluted to scale, shakes up, and filters, and 10 μ l is taken to inject liquid chromatograph, records chromatogram, refers to attached
Fig. 3.
Alkali forced degradation is tested：Roflumilast about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml shakings is added to make
Dissolving, adds 0.1mol/L sodium hydroxide solution 4ml, shakes up, and puts heating in 80 DEG C of water-baths and destroys 20min, lets cool, add 0.1mol/L
Hydrochloric acid solution neutralizes, and with diluted to scale, shakes up, and filters, and 10 μ l is taken to inject liquid chromatograph, records chromatogram, in detail
See attached drawing 4.
Aoxidize forced degradation experiment：Roflumilast about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml is added to shake
Make dissolving, add 30% hydrogen peroxide solution 4ml, shake up, put heating in 80 DEG C of water-baths and destroy 6h, let cool, with diluted to quarter
Degree, shakes up, and filters, and 10 μ l is taken to inject liquid chromatograph, records chromatogram, refers to attached drawing 5.
Illumination forced degradation is tested：Roflumilast about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml is added to shake
Make dissolving, diluted is added to shake up to scale, put illumination to destroy 12h under conditions of 4500lx ± 500lx, shake up, mistake
Filter takes 10 μ l to inject liquid chromatograph, records chromatogram, refers to attached drawing 6.
High temperature forced degradation is tested：It takes roflumilast appropriate, puts 130 DEG C of baking oven heating and destroy 8h, let cool, seal, it is spare.
Roflumilast about 25mg after high temperature forced degradation of learning from else's experience experiment, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml shakings is added to make
Dissolving, with diluted to scale, shakes up, and filters, and 10 μ l is taken to inject liquid chromatograph, records chromatogram, refers to attached drawing 7.
The result shows that roflumilast is stablized under the high temperature conditions；Catabolite under acid, alkali, oxidation and illumination condition
It can be efficiently separated with roflumilast, show that the sensitivity of the chromatographic system, specificity are good.
The detection limit and quantitative limit of 3 detection method of the present invention of embodiment.
For related substance, detection limit and quantitative limit are come determining according to signal-to-noise ratio method.By 2 known concentration of embodiment
Impurity reference substance stock solution is diluted to the sample of low concentration, and the signal measured is compared with baseline noise, and calculating can be reliable
The amount of detection is about 3 with signal-to-noise ratio:1、10:1 calculates the detection limit and quantitative limit of roflumilast and each impurity respectively, as a result sees
Table 3.
The detection of table 3 limit and quantitative limit result
By table 3 as it can be seen that the sensitivity of the method for the invention is higher.
The linear and range of 4 detection method of the present invention of embodiment.
For roflumilast and its related substance, quantitative limit to not less than taken in the range of 200% index concentration 6 it is dense
Degree point is studied.Peak area of the linear relationship to measure carries out linear regression, respectively to the function construction of analyte concentration
Regression equation is obtained, the results are shown in Table 4.
4 each constituent concentration of table and peak area linear relationship result summary sheet
By table 4 as it can be seen that the method for the invention linear relationship is good.
The repetitive test of 5 detection method of the present invention of embodiment.
6 parts are prepared containing each limit of impurities concentration test sample, measures under the same conditions, calculates each impurity in 6 parts of test samples
The relative standard deviation of content.
Roflumilast about 25mg is taken, it is accurately weighed, it puts in 50ml measuring bottles, acetonitrile 5ml is added to make dissolving, is separately added into embodiment
Each each 1ml of impurity reference substance stock solution prepared in 2, and scale is diluted to diluent, it shakes up, according to the color in embodiment 1
Spectral condition is repeated 6 times the content of each impurity in detection test sample, the results are shown in Table 5.
5 repetitive test result of table
By table 5 as it can be seen that the relative standard deviation of 6 detections of each impurity is respectively less than 3.0%, show that the precision of this method is good
It is good.
The accuracy test of 6 detection method of the present invention of embodiment.
The rate of recovery institute that each impurity of 80%, 100% and 120% various concentration of standard limits measures is added in test sample
.It is measured using sample-adding absorption method, the ratio between the actually measured amount and theoretical amount of each impurity in loaded sample is measured, with hundred
Divide rate expression, the results are shown in Table 6.
6 impurity recovery test result of table
By table 6 as it can be seen that the average recovery rate of each impurity is between 98.6%~101.1%, meet proof scheme requirement,
Show that this method has good accuracy.
The solution stability testing of 7 detection method of the present invention of embodiment.
Roflumilast sample is taken, 0,1,2,4,6,8,10,12h is placed at room temperature respectively according to 1 detection method of embodiment,
Chromatographic condition measures as described in embodiment 1, records peak area, investigates situation of change and the calculating of each impurity and total impurities peak area
Relative standard deviation the results are shown in Table 7.
7 test solution stability test result of table
By table 7 as it can be seen that the quantity and content of single impurity do not increase, total impurities also do not increase, show roflumilast
Test solution is stablized in 12h.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but the protection of the present invention is not limited with this
Range.It will be understood by those of ordinary skill in the art that technical scheme of the present invention can be modified or replaced equivalently,
Without departing from the essence and protection domain of technical solution of the present invention, it is intended to be within the scope of the claims of the invention.
Claims (5)
1. a kind of method of the high effective liquid chromatography for measuring roflumilast in relation to substance, which is characterized in that molten with ammonium dihydrogen phosphate
The mixed liquor of liquid and organic solvent is mobile phase, and isocratic elution is carried out in octadecylsilane chemically bonded silica chromatographic column, is dissolved
Dilution used in sample is mobile phase；
The related substance of the roflumilast includes：One or more of the related substance A of roflumilast, B, C, D, E, F, G：
。
2. the method as described in claim 1, which is characterized in that a concentration of 0.004~0.02mol/ of ammonium dihydrogen phosphate
L, pH value are 3.0~3.6.
3. the method as described in claim 1, which is characterized in that the organic solvent is methanol and acetonitrile.
4. the method as described in claim 1, which is characterized in that the mobile phase is 0.005mol/L ammonium dihydrogen phosphates
(with phosphorus acid for adjusting pH value to 3.5)-methanol-acetonitrile (41:31:28).
5. the method as described in claim 1, which is characterized in that testing conditions are：0.8~1.2ml/min of flow velocity of mobile phase,
25~35 DEG C, 210~215nm of Detection wavelength of column temperature, 10 μ l of sample size.
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| CN111380993A (en) * | 2018-12-30 | 2020-07-07 | 江苏万邦生化医药集团有限责任公司 | Method for analyzing related substances of roxasistat |
| CN111505169A (en) * | 2020-06-04 | 2020-08-07 | 山东省食品药品检验研究院 | Method for detecting benzohydroxamic acid based on ultra-high performance liquid chromatography tandem mass spectrometry and application thereof |
| CN111595974A (en) * | 2020-05-30 | 2020-08-28 | 山东希尔康泰药业有限公司 | Analysis method of roflumilast raw material medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111380993A (en) * | 2018-12-30 | 2020-07-07 | 江苏万邦生化医药集团有限责任公司 | Method for analyzing related substances of roxasistat |
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| CN111505169A (en) * | 2020-06-04 | 2020-08-07 | 山东省食品药品检验研究院 | Method for detecting benzohydroxamic acid based on ultra-high performance liquid chromatography tandem mass spectrometry and application thereof |
| CN111505169B (en) * | 2020-06-04 | 2022-04-12 | 山东省食品药品检验研究院 | Method for detecting benzohydroxamic acid based on ultra-high performance liquid chromatography tandem mass spectrometry and application thereof |
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