CN108828092A - A kind of method of each degradation impurity in measurement fluvoxamine maleate - Google Patents
A kind of method of each degradation impurity in measurement fluvoxamine maleate Download PDFInfo
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- CN108828092A CN108828092A CN201810653275.3A CN201810653275A CN108828092A CN 108828092 A CN108828092 A CN 108828092A CN 201810653275 A CN201810653275 A CN 201810653275A CN 108828092 A CN108828092 A CN 108828092A
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- NIBZLPXTLOYHKF-UYRXBGFRSA-N COCCCC/C(/c1ccc(C(F)(F)F)cc1)=N/OCN Chemical compound COCCCC/C(/c1ccc(C(F)(F)F)cc1)=N/OCN NIBZLPXTLOYHKF-UYRXBGFRSA-N 0.000 description 1
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- 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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- 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 invention discloses a kind of methods of each impurity in measurement fluvoxamine maleate, this method is orientable to destroy out impurity II, impurity III and impurity IV, and interferes impurity small, does not influence the positioning of each impurity, impurity III is solved in USP41-NF36 vulnerable to interference, the problem of impurity IV lacks accuracy.I.e. under common experimental conditions, it can get the positioning of impure II, impurity III and impurity IV for impurity in HPLC system, simultaneously, since impurity V is between impurity II and principal component, the method of the present invention can control the separating degree between impurity II and principal component not less than 4.0, it is ensured that the separating degree between impurity II, impurity V and fluvoxamine maleate peak can meet the requirements.The method of the present invention is with strong points, accuracy is high, while is avoided again using valuableness and being difficult to the impurity reference substance bought, so that method is easy to popularize, has good application value.
Description
Technical field
The present invention relates to a kind of methods of each degradation impurity in measurement fluvoxamine maleate.
Background technique
Fluvoxamine maleate acts on the serotonin reuptake inhibitor of cranial nerve cell, is clinically used for antidepression.
There is production both at home and abroad at present.
The chemical structure of fluvoxamine maleate and its impurity I~V is as shown in table 1, about fluvoxamine maleate impurity
Control method, USP41-NF36, BP2018, JP17 record, this uncharged kind of Chinese Pharmacopoeia, existing standard of becoming a full member
YBH34112005 (raw material) and YBH33832005 (piece).
The structural formula of table 1 fluvoxamine maleate and impurity
In current standard, BP2018 using fluvoxamine maleate system usability reference substance (comprising impurity I, impurity II,
Impurity III and impurity V), the positioning of IV reference substance of impurity, it is with strong points, accuracy is high, sensitivity and separating degree might as well, but due to
Britain's impurity reference substance Buying Cycle is long, and price is high, causes purchase difficult, to limit the popularization of method.
JP17 positions each impurity using relative retention time, and the amount of each impurity, the method are calculated using correction factor
It is easy to be interfered by unknown impuritie, the phenomenon that location difficulty occurs.USP 41-NF36 then takes fluvoxamine maleate 6mg to 25ml
In volumetric flask, 120 DEG C are heated 10 minutes, after being cooled to room temperature plus 3.0ml hydrochloric acid, water-bath 10 minutes, while the Malaysia 50mg is added
Sour Fluvoxamine, constant volume.System destruction experiment can destroy out impurity II, impurity III, be positioned using relative retention time, and use school
Positive divisor calculates impurity content.But it finds during the experiment, the impurity III (relative retention time 0.50~0.53) destroyed out
There is a unknown peak (relative retention time 0.40~0.45) in front, relative retention time and impurity III relatively (see Fig. 1),
Be likely difficult to determine when being positioned with relative retention time which be impurity III (especially when in test sample in III appearance time of impurity
When only one neighbouring peak, it is difficult to which judgement is unknown impuritie or impurity III), and this method only adopts another degradation impurity IV
It is positioned with relative retention time, lacks accuracy.So the method for USP (United States Pharmacopeia) can not be applicable in completely.
Domestic standard (raw material and tablet) positions impurity II using relative retention time, while by impurity I, impurity III, miscellaneous
Matter IV and impurity V are controlled as other impurities, and it is consistent with JP17 that there are problems, and method specific aim, accuracy are insufficient.By
It is difficult to buy in impurity III, impurity IV, V reference substance of impurity, and these impurity are that fluvoxamine maleate is necessarily degraded production
Object, if to improve, Control of Impurities specific aim is insufficient in the variety and quality standard or method is difficult to universal status, must just seek
A kind of convenient and fast mode is sought, to guarantee to obtain easily in daily checkout procedure containing impurity II, impurity III and impurity IV
Solution, positioned for material impurities related in the kind test analysis.
Summary of the invention
In order to make up method specificity and accuracy problem in existing examination criteria, while avoiding being difficult to buy because of reference substance
Or price is prohibitively expensive and method is caused to be difficult to the shortcomings that carrying out.Finding a kind of can obtain impurity under the conditions of common laboratory
II, impurity III and impurity IV, the simple pathway for reducing interference impurity simultaneously, to solve the positioning of the husky bright middle impurity of maleic acid volt fluorine
Problem makes the measurement of impurity have specific aim.
The purpose of the present invention is to provide a kind of methods of each degradation impurity in measurement fluvoxamine maleate.
The technical solution adopted by the present invention is that：
The method of each impurity, includes the following steps in a kind of measurement fluvoxamine maleate：
1) fluvoxamine maleate and maleic acid standard items are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100
DEG C heating 0.8~2h, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution；
Fluvoxamine maleate sample to be measured is taken, is configured to test solution with mobile phase；Test solution dilution is taken to make
For reference substance solution；
2) above-mentioned destruction solution, test solution, reference substance solution are subjected to liquid chromatographic detection respectively；
3) interpretation of result：If occurring in the chromatogram of test solution and destroying impurity II, III or IV chromatography in solution
The consistent impurity peaks of behavior then illustrate that there are corresponding impurity II, III or IV in sample to be tested；If sample to be tested need to be further calculated
The content of middle impurity I, II, III, IV, V, then calculated as the following formula：
Wherein f is correction factor of each impurity I~V relative to fluvoxamine maleate；Wherein impurity A be impurity I, II, III, IV or
Ⅴ；
The structural formula of the impurity I, II, III, IV, V is respectively And its enantiomerism
Body,
Further, in step 1), maleic acid and fluvoxamine maleate standard items and mass ratio are 0.5~2.0：1.
Further, in step 1), the mobile phase is 40~50%v/v methanol solution, or for containing 1~1.5%m/v
The solution-methyl alcohol of diammonium hydrogen phosphate and 0.2~0.3%m/v sodium heptanesulfonate, wherein containing 1~1.5%m/v diammonium hydrogen phosphate and
The pH value of the solution of 0.2~0.3%m/v sodium heptanesulfonate is 2.8~3.2, and the volume ratio of itself and methanol is 45~55：45
~55.
Further, in step 1), the concentration of fluvoxamine maleate sample is 0.8~2mg/ in the test solution
ml。
Further, in step 1), the concentration of fluvoxamine maleate sample is 0.8~2 μ g/ in the reference substance solution
ml。
Further, in step 3), correction factor f preparation method is：
I, II, III, IV, V standard items of fluvoxamine maleate and fluvoxamine maleate impurity are taken, are configured to one respectively
The solution of serial various concentration carries out liquid chromatogram to the solution of all various concentrations with 2~5 different chromatographic columns respectively respectively
Detection, returns peak area y with concentration x, obtains the regression equation of each group detection, and calculates miscellaneous in the case of different chromatographic columns
Correction factor of the matter I~V relative to fluvoxamine maleate takes being averaged for correction factor in the case of all different chromatographic column columns
Value obtains the correction factor f of impurity I~V respectively.
Further, in step 3), impurity I, II, III, IV, V divides relative to the correction factor f of fluvoxamine maleate
It Wei 1.1,1.0,1.0,0.36,0.89.
It is a kind of for measuring the destruction solution of each impurity in fluvoxamine maleate, the preparation method of the destruction solution is：
Fluvoxamine maleate and maleic acid standard items are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100 DEG C of heating 0.8
~2h, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution.
Further, the relationship between destruction overall solution volume and fluvoxamine maleate standard items dosage is：Every 10ml
The dosage for destroying fluvoxamine maleate standard items in solution is 10~20mg.
The application described above that solution is destroyed in detection fluvoxamine maleate impurity II, III or IV.
The beneficial effects of the invention are as follows：
(1) this patent is avoided using impurity reference substance for the specific aim and accuracy of improvement method to improvement method
Popularization, spy invents a kind of measuring method of each degradation impurity in fluvoxamine maleate for measuring fluvoxamine maleate
Degradation impurity in raw material and tablet.
(2) the method for the present invention is orientable destroys out impurity II, impurity III and impurity IV, and interferes impurity small, does not influence each
The positioning of impurity solves in USP41-NF36 system suitability solution impurity III vulnerable to interference, and impurity IV lacks accuracy
Problem.I.e. under common experimental conditions, it can get impure II, impurity III and impurity IV and determine for impurity in HPLC system
Position, simultaneously as impurity V, between impurity II and principal component, the method for the present invention can control between impurity II and principal component
Separating degree be not less than 4.0, it is ensured that the separating degree between impurity II, impurity V and fluvoxamine maleate peak can meet the requirements.
(3) the method for the present invention is with strong points, accuracy is high, while is avoided again using valuableness and being difficult to the impurity bought control
Product have good application value so that method is easy to popularize.
Detailed description of the invention
Fig. 1 uses the map of USP41-NF36 system suitability destruction methods detection；
Fig. 2 is the system map that solution is destroyed obtained by the method for the present invention；
Fig. 3 is test sample map.
Specific embodiment
A kind of method of each impurity in measurement fluvoxamine maleate,
1) fluvoxamine maleate and maleic acid standard items are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100
DEG C heating 0.8~2h, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution；
Fluvoxamine maleate sample to be measured is taken, is configured to test solution with mobile phase；Test solution dilution is taken to make
For reference substance solution；
2) above-mentioned destruction solution, test solution, reference substance solution are subjected to liquid chromatographic detection respectively；
3) interpretation of result：If occurring in the chromatogram of test solution and destroying impurity II, III or IV chromatography in solution
The consistent impurity peaks of behavior then illustrate that there are corresponding impurity II, III or IV in sample to be tested；If sample to be tested need to be further calculated
The content of middle impurity I, II, III, IV, V, then calculated as the following formula：
Wherein f
Correction factor for each impurity I~V relative to fluvoxamine maleate；Wherein impurity A is impurity I, II, III, IV or V；
The structural formula of the impurity I, II, III, IV, V is respectively And its enantiomerism
Body,
Preferably, in step 1), maleic acid and fluvoxamine maleate standard items and mass ratio are 0.5~2.0：1.
Preferably, in step 1), the solvent is in 45~95%v/v methanol solution, 45~95%v/v ethanol solution
At least one.
Preferably, in step 1), the relationship destroyed between overall solution volume and fluvoxamine maleate standard items dosage is：
The dosage that every 10ml destroys fluvoxamine maleate standard items in solution is 10~20mg.
Preferably, in step 1), the alkali in sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide at least
It is a kind of.
Preferably, in step 1), the acid is selected from least one of hydrochloric acid, nitric acid, sulfuric acid.
Preferably, in step 1), the mobile phase is 40~50%v/v methanol solution, or for containing 1~1.5%m/v phosphorus
The solution-methyl alcohol of sour hydrogen diammonium and 0.2~0.3%m/v sodium heptanesulfonate, wherein containing 1~1.5%m/v diammonium hydrogen phosphate and 0.2
The pH value of the solution of~0.3% m/v sodium heptanesulfonate is 2.8~3.2, and the volume ratio of itself and methanol is 45~55：45~
55。
It preferably, is mobile phase solution or 40~50%v/v first for diluting the diluent of test solution in step 1)
Alcoholic solution.
Preferably, in step 1), the concentration of fluvoxamine maleate sample is 0.8~2mg/ in the test solution
ml。
Preferably, in step 1), the concentration of fluvoxamine maleate sample is 0.8~2 μ g/ in the reference substance solution
ml。
Preferably, in step 3), correction factor f preparation method is：
I, II, III, IV, V standard items of fluvoxamine maleate and fluvoxamine maleate impurity are taken, are configured to one respectively
The solution of serial various concentration carries out liquid chromatogram to the solution of all various concentrations with 2~5 different chromatographic columns respectively respectively
Detection, returns peak area y with concentration x, obtains the regression equation of each group detection, and calculates miscellaneous in the case of different chromatographic columns
Correction factor of the matter I~V relative to fluvoxamine maleate takes being averaged for correction factor in the case of all different chromatographic column columns
Value obtains the correction factor f of impurity I~V respectively.
Preferably, in step 3), impurity I, II, III, IV, V is distinguished relative to the correction factor f of fluvoxamine maleate
It is 1.1,1.0,1.0,0.36,0.89.
It is a kind of for measuring the destruction solution of each impurity in fluvoxamine maleate, the preparation method of the destruction solution is：
Fluvoxamine maleate and maleic acid standard items are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100 DEG C of heating 0.8
~2h, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution.
Preferably, maleic acid and fluvoxamine maleate standard items and mass ratio are 0.5~2.0：1.
Preferably, the solvent in 45~95%v/v methanol solution, 45~95%v/v ethanol solution at least one
Kind.
Preferably, the relationship between destruction overall solution volume and fluvoxamine maleate standard items dosage is：Every 10ml is broken
The dosage of fluvoxamine maleate standard items is 10~20mg in bad solution.
Preferably, the alkali is selected from least one of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide.
Preferably, the acid is selected from least one of hydrochloric acid, nitric acid, sulfuric acid.
The application described above that solution is destroyed in detection fluvoxamine maleate impurity II, III or IV, impurity II, III,
IV structural formula is as described above.
The present invention is further illustrated combined with specific embodiments below.
The method of each degradation impurity in a kind of measurement fluvoxamine maleate of embodiment 1
Impurity I (being shown in Table 1) is process impurity in fluvoxamine maleate；Impurity II~V (being shown in Table 1) is degradation impurity,
It can be degraded out in various degree under each failure condition；According to product structure characteristic, wherein impurity II, III impurity IV of impurity,
Impurity V is main degradation impurity.Show that impurity can be destroyed out using fluvoxamine maleate reference substance by each breaking test
II, impurity III and impurity IV.And pass through repetition test, fluvoxamine maleate reference substance is destroyed using the method for the present invention
When, interference impurity it is smaller (from figure 1 it appears that when using USP destruction methods, have before impurity III one with its peak area
Comparable Interference Peaks can cause location interference；And from figure 2 it can be seen that destroying impurity III in solution obtained by the method for the present invention
Peak area it is much bigger than the peak of front, not will cause location interference), can get impure II, impurity III and impurity IV is
Applicability solution of uniting is used for the positioning of principal degradation impurity.
By taking fluvoxamine maleate raw material as an example, illustrate that the method for the present invention respectively drops in routine check fluvoxamine maleate
Solve the concrete operations in impurity work：
1) it takes fluvoxamine maleate standard items (there is supply in the country) about 15mg, in top set empty bottle, maleic acid 10mg is added,
With methanol-water (volume ratio 55:45) mixed solution 2ml makes to dissolve, and adds 0.2mol/L sodium hydroxide solution 1ml, sealing, water
Bath heating (95~100 DEG C) 1.5 hours is taken out, and is let cool to room temperature, is added 1mol/L hydrochloric acid solution 1ml, heating water bath (95~
100 DEG C) 2 minutes, it lets cool to room temperature, is transferred in 10ml measuring bottle, with methanol-water (55:45) mixed solution is diluted to scale, shakes
It is even, that is, the mixed solution of fluvoxamine maleate impurity II, impurity III, Fluvoxamine and impurity IV is obtained, is applicable in as system
Property solution (hereinafter referred to as destruction solution).
It is above-mentioned to destroy out impurity II, impurity III and impurity IV, it both can satisfy positioning and need and do not have to purchase impurity control
Product, and can solve the problem of impurity positioning is disturbed in USP (United States Pharmacopeia) method.
2) it takes fluvoxamine maleate raw material (lot number S13060802) to be measured in right amount, (contains 1.25% phosphoric acid hydrogen with mobile phase
Solution (with phosphorus acid for adjusting pH value to 3.0)-methanol of diammonium and 0.275% sodium heptanesulfonate, the two volume ratio is 45:55) match
The test solution of every ml system raw material of fluvoxamine maleate containing 1.5mg is made；
Test solution is taken, is diluted with mobile phase and the husky bright standard items containing 1.5 μ g maleic acids volt fluorine in every 1ml is made
Solution shakes up, as reference substance solution.
3) it takes above-mentioned destruction solution, test solution, reference substance solution to be injected separately into liquid chromatograph, analyzes.It destroys molten
Liquid measures fluvoxamine maleate impurity III, IV chromatographic peak of impurity II, Fluvoxamine and impurity, and the separating degree of each chromatographic peak is answered
Greater than 4.0 (see Fig. 2).Occurs Fluvoxamine chromatographic peak in reference substance solution.In addition to there is measured object fluorine volt in test solution
Outside the chromatographic peak of Sha Ming, in fact it could happen that the chromatographic peak of impurity III, II, V, IV and impurity I, it is also possible to not occur the chromatography of impurity
Peak, this depends on the quality of product.The chromatogram of this test solution is as shown in figure 3, contain impurity II~V, wherein retaining
The chromatographic peak that time is 14.823 is impurity III, and the chromatographic peak that retention time is 21.972 is impurity II, and retention time is
The chromatographic peak that 24.389 chromatographic peak is impurity V, retention time is 38.769 is impurity IV.
4) result calculates
In the chromatogram of test solution, if there is consistent miscellaneous with II, III, IV chromatographic behavior of impurity in destruction solution
Mass peak then illustrates that there are corresponding impurity II, III or IV in test solution to be measured；Although impurity I and V destroy solution in not
Occur, but can be positioned by relative retention time.If containing for impurity I, II, III, IV, V in sample to be tested need to be further calculated
Amount, then calculated as the following formula：
In formula：F is each impurity phase for the correction factor (f) of fluvoxamine maleate, solves the accuracy of defects inspecting
Problem.
Specific assay method is as follows for above-mentioned correction factor (f) and relative retention time：
Fluvoxamine maleate and external impurity reference substance (fluvoxamine maleate impurity I, II, III, IV, V) are bought,
Using 3 different cultivars chromatographic column (ZORBAX Eclipse Plus C8, Thermo BDS HYPERSIL C8,
Kromasil KR100-5C8), it is shown in Table 2.Take fluvoxamine maleate and external impurity reference substance fluvoxamine maleate impurity
I, II, III, IV, V is appropriate, and a series of concentration are prepared within the scope of 0.5ug/ml to 21ug/ml, and precision measures solution 20ul, into
Sample is recorded chromatogram, is returned with concentration (x) to peak area (y), obtain regression equation, and calculate each impurity phase for horse
Carry out the sour husky bright correction factor of volt fluorine, while calculating each impurity and being averaged relative retention time (R).Specific value see the table below 2.
The present invention passes through the external impurity reference substance of purchase simultaneously, measures the correction factor of each impurity, is adopted by correction factor
With Self-control method, the amount of each degradation impurity can be accurately detected, solve the problems, such as that cost of determination is expensive in BP2018.
2 impurity I~V of table is relative to the husky bright correction factor (f) of maleic acid volt fluorine and averagely relative retention time (R)
The present embodiment is respectively 0.11% to II~V content of impurity that sample to be tested finally measures, 0.15%, 0.03%,
0.05%, impurity removal I is not detected, is shown in Table 3.
The content of each impurity in 3 sample to be tested of table
The above results explanation measures each impurity phase for fluvoxamine maleate by a simple breaking test
Correction factor, so that in daily inspection work, the fluvoxamine maleate reference substance (state that can be easy to get by one
Inside have supply), the content of each impurity in measured object accurately and is targetedly measured, to effectively control the quality of product.
The method of each degradation impurity in a kind of measurement fluvoxamine maleate of embodiment 2
1) it takes fluvoxamine maleate standard items (there is supply in the country) about 15mg, in top set empty bottle, maleic acid 10mg is added,
With methanol-water (volume ratio 55:45) mixed solution 2ml makes to dissolve, and adds 0.2mol/L potassium hydroxide solution 1ml, sealing, water
Bath heating (95~100 DEG C) 2 hours is taken out, and is let cool to room temperature, is added 1mol/L nitric acid solution 1ml, heating water bath (95~
100 DEG C) 3 minutes, it lets cool to room temperature, is transferred in 10ml measuring bottle, with methanol-water (45:55) mixed solution is diluted to scale, shakes
It is even, i.e. the mixed solution of acquisition fluvoxamine maleate impurity II, impurity III, fluvoxamine maleate and impurity IV, as being
It unites applicability solution (hereinafter referred to as destruction solution).
It is above-mentioned to destroy out impurity II, impurity III and impurity IV, it both can satisfy positioning and need and do not have to purchase impurity control
Product, and can solve the problem of impurity positioning is disturbed in USP (United States Pharmacopeia) method.
2) fluvoxamine maleate raw material (lot number S13012411) to be measured is taken in right amount, (50%v/v methanol is molten with mobile phase
Liquid) it is configured to the test solution of every husky bright raw material of ml system maleic acid containing 2mg volt fluorine；
Take test solution, be diluted with mobile phase be made in every 1ml it is molten containing 2 μ g fluvoxamine maleate standard items
Liquid shakes up, as reference substance solution.
3) it takes above-mentioned destruction solution, test solution, reference substance solution to be injected separately into liquid chromatograph, analyzes.It destroys molten
Liquid measures the husky bright impurity III of maleic acid volt fluorine, IV chromatographic peak of impurity II, Fluvoxamine and impurity, and the separating degree of each chromatographic peak is answered
Greater than 4.0.Occurs fluvoxamine maleate chromatographic peak in reference substance solution.In addition to there is measured object fluorine volt in test solution
Outside the chromatographic peak of Sha Ming, in fact it could happen that the chromatographic peak of impurity III, II, V, IV and impurity I, it is also possible to not occur the chromatography of impurity
Peak, this depends on the quality of product.
4) result calculates
In the chromatogram of test solution, if there is consistent miscellaneous with II, III, IV chromatographic behavior of impurity in destruction solution
Mass peak then illustrates that there are corresponding impurity II, III or IV in test solution to be measured；Although impurity I and V destroy solution in not
Occur, but can be positioned by relative retention time.If containing for impurity I, II, III, IV, V in sample to be tested need to be further calculated
Amount, then calculated as the following formula：
In formula：F is correction factor (f) of each impurity phase for fluvoxamine maleate, and impurity I, II, III, IV, V is opposite
In the correction factor f of fluvoxamine maleate be respectively 1.1,1.0,1.0,0.36,0.89.
The present embodiment is as shown in table 4 to the testing result of sample to be tested.Destruction methods of the present invention to the positioning of each impurity with
British Pharmacopoeia is consistent with the result of impurity reference substance localization method.
The method of each degradation impurity in a kind of measurement fluvoxamine maleate of embodiment 3
1) it takes fluvoxamine maleate standard items (there is supply in the country) about 10mg, in top set empty bottle, maleic acid 20mg is added,
With alcohol-water (volume ratio 45:55) mixed solution 2ml makes to dissolve, and adds 0.2mol/L calcium hydroxide solution 1ml, sealing, water
Bath heating (95~100 DEG C) 0.8 hour is taken out, and is let cool to room temperature, is added 1mol/L nitric acid solution 1ml, heating water bath (95~
100 DEG C) 3 minutes, it lets cool to room temperature, is transferred in 10ml measuring bottle, with alcohol-water (45:55) mixed solution is diluted to scale, shakes
It is even, i.e. the husky bright impurity II of acquisition maleic acid volt fluorine, impurity III, husky bright and impurity IV the mixed solution of maleic acid volt fluorine, as being
It unites applicability solution (hereinafter referred to as destruction solution).
It is above-mentioned to destroy out impurity II, impurity III and impurity IV, it both can satisfy positioning and need and do not have to purchase impurity control
Product, and can solve the problem of impurity positioning is disturbed in USP (United States Pharmacopeia) method.
2) it takes the husky bright raw material (lot number 110) of maleic acid volt fluorine to be measured in right amount, is prepared with mobile phase (45%v/v methanol solution)
At the test solution of every ml system raw material of fluvoxamine maleate containing 0.8mg；
Take test solution, be diluted with water be made in every 1ml it is molten containing 0.8 μ g fluvoxamine maleate standard items
Liquid shakes up, as reference substance solution.
3) it takes above-mentioned destruction solution, test solution, reference substance solution to be injected separately into liquid chromatograph, analyzes.It destroys molten
Liquid measures the husky bright impurity III of maleic acid volt fluorine, impurity II, husky bright and IV chromatographic peak of impurity of volt fluorine, and the separating degree of each chromatographic peak is answered
Greater than 4.0.Occurs fluvoxamine maleate chromatographic peak in reference substance solution.In addition to there is measured object fluorine volt in test solution
Outside the chromatographic peak of Sha Ming, in fact it could happen that the chromatographic peak of impurity III, II, V, IV and impurity I, it is also possible to not occur the chromatography of impurity
Peak, this depends on the quality of product.
4) result calculates
In the chromatogram of test solution, if there is consistent miscellaneous with II, III, IV chromatographic behavior of impurity in destruction solution
Mass peak then illustrates that there are corresponding impurity II, III or IV in test solution to be measured；Although impurity I and V destroy solution in not
Occur, but can be positioned by relative retention time.If containing for impurity I, II, III, IV, V in sample to be tested need to be further calculated
Amount, then calculated as the following formula：
In formula：F is correction factor (f) of each impurity phase for fluvoxamine maleate, and impurity I, II, III, IV, V is opposite
In the correction factor f of fluvoxamine maleate be respectively 1.1,1.0,1.0,0.36,0.89.
The present embodiment is as shown in table 4 to the testing result of sample to be tested.Destruction methods of the present invention to the positioning of each impurity with
British Pharmacopoeia is consistent with the result of impurity reference substance localization method.
The method of each degradation impurity in a kind of measurement fluvoxamine maleate of embodiment 4~5
The detection method of embodiment 4~5 is with embodiment 1, respectively to other 2 batches (lot number is respectively 111,112) horses to be measured
Carry out sour Fluvoxamine raw material to be detected, 2 batches of product to be tested testing results are as shown in table 4.Destruction methods of the present invention are to each impurity
Locating effect and British Pharmacopoeia be consistent with the result of impurity reference substance localization method.
4 each batches of sample measurement results of table
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. the method for each impurity, includes the following steps in a kind of measurement fluvoxamine maleate：
1) fluvoxamine maleate and maleic acid standard items are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100 DEG C add
0.8~2h of heat, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution；
Fluvoxamine maleate sample to be measured is taken, is configured to test solution with mobile phase；Take test solution dilution conduct pair
According to product solution；
2) above-mentioned destruction solution, test solution, reference substance solution are subjected to liquid chromatographic detection respectively；
3) interpretation of result：If occurring in the chromatogram of test solution and destroying impurity II, III or IV chromatographic behavior in solution
Consistent impurity peaks then illustrate that there are corresponding impurity II, III or IV in sample to be tested；If need to further calculate miscellaneous in sample to be tested
The content of matter I, II, III, IV, V, then calculated as the following formula：
Wherein
F is correction factor of each impurity I~V relative to fluvoxamine maleate；Wherein impurity A is impurity I, II, III, IV or V；
The structural formula of the impurity I, II, III, IV, V is respectively And its enantiomerism
Body,
2. the method according to claim 1, wherein in step 1), maleic acid and fluvoxamine maleate standard
Product and mass ratio are 0.5~2.0：1.
3. the method according to claim 1, wherein the mobile phase is 40~50%v/v methanol in step 1)
Solution, or be the solution-methyl alcohol containing 1~1.5%m/v diammonium hydrogen phosphate and 0.2~0.3%m/v sodium heptanesulfonate, wherein containing
The pH value of the solution of 1~1.5%m/v diammonium hydrogen phosphate and 0.2~0.3%m/v sodium heptanesulfonate is 2.8~3.2, and itself and first
The volume ratio of alcohol is 45~55：45~55.
4. the method according to claim 1, wherein maleic acid fluorine lies prostrate in the test solution in step 1)
The concentration of husky bright sample is 0.8~2mg/ml.
5. the method according to claim 1, wherein maleic acid fluorine lies prostrate in the reference substance solution in step 1)
The concentration of husky bright sample is 0.8~2 μ g/ml.
6. the method according to claim 1, wherein in step 3), correction factor f preparation method is：
I, II, III, IV, V standard items of fluvoxamine maleate and fluvoxamine maleate impurity are taken, are configured to respectively a series of
The solution of various concentration carries out liquid chromatogram inspection to the solution of all various concentrations with 2~5 different chromatographic columns respectively respectively
It surveys, peak area y is returned with concentration x, obtain the regression equation of each group detection, and calculate impurity in the case of different chromatographic columns
I~V correction factor relative to fluvoxamine maleate takes the average value of correction factor in the case of all different chromatographic column columns,
The correction factor f of impurity I~V is obtained respectively.
7. the method according to claim 1, wherein impurity I, II, III, IV, V is relative to Malaysia in step 3)
The correction factor f of sour Fluvoxamine is respectively 1.1,1.0,1.0,0.36,0.89.
8. a kind of for measuring the destruction solution of each impurity in fluvoxamine maleate, which is characterized in that the system of the destruction solution
Preparation Method is：Fluvoxamine maleate standard items and maleic acid are taken, is dissolved with solvent, aqueous slkali is added, is sealed, 95~100
DEG C heating 0.8~2h, it is cooling, acid solution is added, 95~100 DEG C of 120~180s of heating obtain destruction solution.
9. destruction solution according to claim 8, which is characterized in that destroy overall solution volume and fluvoxamine maleate mark
Relationship between quasi- product dosage is：The dosage that every 10ml destroys fluvoxamine maleate standard items in solution is 10~20mg.
10. application of the destruction solution described in claim 9 in detection fluvoxamine maleate impurity II, III or IV, impurity II,
III, IV structural formula is as described in claim 1.
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| CN115656370A (en) * | 2022-10-25 | 2023-01-31 | 湖南省湘中制药有限公司 | HPLC detection method for fluvoxamine maleate, intermediate and impurities |
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Inventor after: Yu Shaowen Inventor after: Ye Xiujin Inventor after: Chen Ying Inventor before: Yu Shaowen |