CN108333272A - The method of LC-MSMS method separation determination PAS and its related impurities - Google Patents
The method of LC-MSMS method separation determination PAS and its related impurities Download PDFInfo
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- CN108333272A CN108333272A CN201810173832.1A CN201810173832A CN108333272A CN 108333272 A CN108333272 A CN 108333272A CN 201810173832 A CN201810173832 A CN 201810173832A CN 108333272 A CN108333272 A CN 108333272A
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- G—PHYSICS
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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
- G01N30/02—Column chromatography
Abstract
The invention belongs to medicinal chemistry arts, and in particular to a kind of method of LC MSMS method separation determination PAS and its related impurities.The chromatographic column used in the method is to use aqueous acetic acid and acetonitrile solution to carry out gradient elution for mobile phase using octyl silane group silica gel as filler, be detected into tandem mass spectrum detector；The related impurities include m-nitrobenzene sulfonic acid and metanilic acid.This method can detect the content of PAS intermediate nitro benzene sulfonic acid and metanilic acid simultaneously, the screening of mobile phase type, the optimization of eluent gradient, the selection of chromatographic column, eliminate interference of the PAS to metanilic acid and nitre benzene sulfonic acid, so that the rate of recovery that limit is added is more than 95%, and detection limit has reached 0.4ng/ml.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of LC-MSMS methods separation determination PAS and its
The method of related impurities.
Background technology
Tuberculosis is the chronic infectious disease caused by mycobacterium tuberculosis infection, and the Chinese scientific name of tubercle bacillus is tuberculosis branch bar
Bacterium (M.tuberculosis).Containing lipid in Mycobacterium tuberculosis cell wall, lipid can prevent thalline loss of moist, therefore to dry
Dry resistance is especially strong.It is adhered on dust and keeps infectiousness 8-10 days, can survive in dry phlegm 6-8 months.Tuberculosis point
The variations such as form, bacterium colony, virulence, immunogenicity and drug resistance can occur for branch bacillus.Currently, treatment lungy mostly uses Li Fu
Flat, isoniazid, ethambutol, streptomysin are First Line drug.Rifampin can reduce the generation of drug resistance with isoniazid.
To severe infections, can be heightened the effect of a treatment with pyrazinamide and rifampin and isoniazid with reducing the generation of drug resistance.
The entitled 4- amino-2-hydroxybenzoic acids of PAS chemistry, fusing point are 135-145 DEG C, are treating tuberculosis branches
The drug of bacillus, PAS can delay generation of the mycobacterium tuberculosis to isoniazid and streptomycin resistance, make
May be to inhibit folic acid synthesis (but confrontation folic acid compound is without synergistic effect) and/or inhibit the life of cell wall mycobacteria with mechanism
The synthesis of long element makes the iron of mycobacterium tuberculosis take in and reduces, to reach bacteriostasis.PAS is only to branch bar
Bacterium is effective, and tubercle bacillus can generate rapidly drug resistance when being used alone, therefore this product must be shared with other anti-tubercular drugs.
The preparation method of PAS bulk pharmaceutical chemicals report at present there are mainly two types of method：One is be with phenylacetic acid
Material synthesis obtains PAS；Another kind is to obtain PAS through hydroxylation by meta-aminophenol.
In document Journal of the American Chemical Society [1948,70 (4), 1665-1666]
It is raw material to report with phenylacetic acid, PAS is obtained by the reaction through 6 steps, equation is as follows：
Patent DE50835 is reported prepares PAS by raw material of meta-aminophenol, and reactional equation is as follows：
It is noted that PAS is a very unstable compound, it is all quicker to light, heat, oxygen
Sense, at 40 DEG C or more, PAS aqueous solution or its hydrochloride meeting decarboxylize are degraded into impurity m-aminophenol, are in
Brown solution.
According to technological line analysis, it is possible to create the process contaminants of metanilic acid and nitre benzene sulfonic acid, the impurity contain
There is genotoxicity caution structure, according to the requirement of ICH, needs strictly to control such impurity, limit 0.8ppm.Using
Conventional HPLC-UV method sensitivity cannot be satisfied testing requirements, therefore, next there is an urgent need to provide a kind of method of high sensitivity
Detect genotoxicity caution structure impurity in aminosalicylic acid.
There is no the methods using LC-MSMS detection metanilic acid and nitre benzene sulfonic acid at present, therefore provide a kind of
Simply, separating degree is good, method of high sensitivity can more accurately ensure PAS and its preparation it is quality controllable, and most
The safe and effective of product is determined eventually.
Invention content
In view of this, the purpose of the present invention is to provide a kind of LC-MSMS methods separation determination PAS and its phases
The method for closing impurity.The method can detect containing for PAS intermediate nitro benzene sulfonic acid and metanilic acid simultaneously
Amount, detection limit have reached 0.4ng/ml.
To achieve the above object, the technical scheme is that：
The method of LC-MSMS (Liquid Chromatography-Tandem Mass Spectrometry) method separation determination PAS and its related impurities, institute
It is using octyl silane group silica gel as filler, using aqueous acetic acid (mobile phase A) and second to state the chromatographic column used in method
Nitrile aqueous solution (Mobile phase B) is that mobile phase carries out gradient elution, is detected into tandem mass spectrum detector；The related impurities
Including m-nitrobenzene sulfonic acid and metanilic acid.
Further, the percent by volume in the aqueous acetic acid shared by acetic acid is 0.1%.
Further, the percent by volume in the acetonitrile solution shared by acetonitrile is 90%.
Further, the condition setting of the gradient elution is as follows：
Flow rate of mobile phase is 0.3-0.5ml/min.
As a preferred embodiment, the condition setting of the gradient elution is as follows：
Flow rate of mobile phase is 0.4ml/min.
Pass through the optimization of eluent gradient, the screening of mobile phase type, the selection of chromatographic column, exclusion in the method for the present invention
Interference of the PAS to metanilic acid and nitre benzene sulfonic acid so that the rate of recovery that limit is added is more than 95%,
And detection limit has reached the extremely low concentration of 0.4ng/ml.
Further, the method for the LC-MSMS methods separation determination PAS and its related impurities, specifically include with
Lower step：
1) inner mark solution is prepared：It takes p-methyl benzenesulfonic acid solubilizer to dissolve and dilutes, obtain inner mark solution；
2) test solution is prepared：Test sample is taken, 0.1mlN is added, adds again after N- dimethylacetylamides and inner mark solution
Solvent is dissolved and is diluted, and obtains test solution；
3) reference substance solution is prepared：M-nitrobenzene sulfonic acid and metanilic acid are taken respectively, and 0.1mlN, N- dimethyl is added
Solubilizer is dissolved and is diluted after acetamide and inner mark solution, obtains reference substance solution；
4) reference substance solution and test solution sample introduction in liquid chromatograph are taken respectively, are examined using tandem mass spectrum detector
It surveys, records chromatogram, the content of m-nitrobenzene sulfonic acid and metanilic acid is calculated by internal standard method.
As a preferred embodiment, in the above method, sampling volume is 20 μ l.
Further, the solvent is the acetonitrile solution that acetonitrile percent by volume is 20%.
Further, in step 1) inner mark solution a concentration of 1ng/ml；A concentration of 1230 μ of test solution in step 2)
g/ml-1270μg/ml。
As a preferred embodiment, in step 2) test solution a concentration of 1250 μ g/ml.
Mobile phase original ratio contains 80% water phase, and the organic Phase Proportion of test solution is excessively high, has apparent solvent effect
It answers, interference measurement, so in test solution process for preparation, a small amount of n,N-dimethylacetamide is added and increases to amino
The phenomenon that salicylic dissolubility has dropped organic Phase Proportion that test solution prepares solvent, greatly reduces solvent interference.
In the above method, percent by volume of the n,N-dimethylacetamide in test solution or reference substance solution is
1%.
Further, in step 4) chromatographic column of liquid chromatograph specification be 250 × 4.6mm, 5.0 μm；The chromatographic column
Post case temperature is 25-35 DEG C.
As a preferred embodiment, the chromatographic column post case temperature is 30 DEG C.
Further, in step 4) tandem mass spectrum detector condition：Electric spray ion source (ESI), using anion MRM moulds
Formula detects；Ion source temperature is 550 DEG C, and spray voltage is -3000v, and atomization gas (Gas1) is 15psi；Gas curtain gas (Curtain
Gas) it is 12psi.
The second object of the present invention is to provide the reagent set of a kind of separation determination PAS and its related impurities
Object is closed, the reagent composition is made of mobile phase A, Mobile phase B and n,N-dimethylacetamide；The mobile phase A is acetic acid
Aqueous solution, the percentage in aqueous acetic acid shared by acetic acid are 0.1%；The Mobile phase B is acetonitrile solution, acetonitrile solution
Percentage shared by middle acetonitrile is 90%；The related impurities include m-nitrobenzene sulfonic acid and metanilic acid.
Percent by volume of the DMAC N,N' dimethyl acetamide in test solution or reference substance solution is in separation determination
1%.
The beneficial effects of the present invention are：
1) method of LC-MSMS methods separation determination PAS and its related impurities provided by the invention, this method
Can detect simultaneously the content of PAS intermediate nitro benzene sulfonic acid and metanilic acid and it is easy to operate, separating degree is good,
Specificity is strong, high sensitivity, can accurately ensure the quality controllable of PAS and its preparation, and finally determine product
Safely and effectively.
2) it is excluded by the screening of mobile phase type, the optimization of eluent gradient, the selection of chromatographic column in the method for the present invention
Interference of the PAS to metanilic acid and nitre benzene sulfonic acid so that the rate of recovery that limit is added is more than 95%,
And detection limit has reached the extremely low concentration of 0.4ng/ml.
3) in detection process, the organic Phase Proportion of test solution is excessively high, has apparent solvent effect, interference measurement, institute
The dissolving that a small amount of n,N-dimethylacetamide increases PAS in test solution process for preparation, is added
Property, the phenomenon that having dropped organic Phase Proportion that test solution prepares solvent, greatly reduce solvent interference.
Description of the drawings
Fig. 1 is the second order ms figure of m-nitrobenzene sulfonic acid.
Fig. 2 is the second order ms figure of metanilic acid.
Fig. 3 is the second order ms figure of p-methyl benzenesulfonic acid.
Fig. 4 is LOD-1 (0.5ng/ml).
Fig. 5 is LOD-2.
Fig. 6 is LOD-3.
Fig. 7 is blank solvent chromatogram.
Fig. 8 is internal standard chromatogram.
Fig. 9 is reference substance chromatogram (1ng/ml).
Figure 10 is test sample chromatogram.
Figure 11 is that test solution adds standard solution chromatogram (1ng/ml).
Specific implementation mode
Hereinafter reference will be made to the drawings, and the preferred embodiment of the present invention is described in detail.Tool is not specified in preferred embodiment
The experimental method of concrete conditions in the establishment of a specific crime, usually according to normal condition, illustrated embodiment are to preferably be said to present disclosure
It is bright, but be not that present disclosure is only limitted to illustrated embodiment.So those skilled in the art are according to foregoing invention
Content carries out nonessential modifications and adaptations to embodiment, still falls within protection scope of the present invention.
Determining instrument：Mass spectrum：API3000, liquid phase：LC-20A
Liquid phase chromatogram condition
Chromatographic column：Agilent XDB-C8 250 × 4.6mm, 5 μm；
Mobile phase：0.1% aqueous acetic acid (mobile phase A), 90% acetonitrile solution (Mobile phase B)；
Flow velocity：0.4ml/min.
The condition and parameter of tandem mass spectrum detector：Electric spray ion source (ESI), using anion MRM mode detections；From
Source temperature is 550 DEG C, and spray voltage is -3000v, and atomization gas (Gas1) is 15psi；Gas curtain gas (Curtain Gas) is
12psi；Residence time：200msce Resolution Q1:Unit, Resolution Q3:Unit, compound ions are to being shown in figure
1~Fig. 3.
Embodiment
The method of LC-MSMS method separation determination PAS and its related impurities,
1, concrete operation method：
Test sample 12.5mg is taken, it is accurately weighed, it sets in 10ml measuring bottles, 0.1mlN is added, N- dimethylacetylamides are accurate
Measurement inner mark solution 1.0ml (take p-methyl benzenesulfonic acid appropriate, it is accurately weighed, it is dissolved with 20% acetonitrile solution and quantifies dilution system
At the solution containing 10ng in every 1ml) it sets in 10ml measuring bottles, it is dissolved with 20% acetonitrile solution and is quantitatively diluted to scale, shaken up, made
For test solution；Take m-nitrobenzene sulfonic acid and metanilic acid reference substance appropriate, it is accurately weighed, it is molten with 20% acetonitrile solution
It solves and quantifies dilution and the solution containing 10ng in every 1ml is made, precision measures solution 1.0ml, sets in 10ml measuring bottles, then accurate amount
Inner mark solution 1.0ml is taken, is set in the same measuring bottle, 0.1mlN is added, N- dimethylacetylamides are diluted to 20% acetonitrile solution
Scale shakes up, as a contrast product solution.According to high performance liquid chromatography (Chinese Pharmacopoeia 0,512 first method of version general rule in 2015)
It measures, is stationary phase (5 μm of 250mm*4.6mm) with eight alkyl linked silica gel；Using 0.1% glacial acetic acid aqueous solution as mobile phase
A, using 90% acetonitrile solution as Mobile phase B, gradient elution, column temperature is 30 DEG C, flow velocity 0.4ml/min.
Condition of gradient elution：
Electric spray ion source (ESI), using anion MRM mode detections, ion source temperature is 550 DEG C, spray voltage is-
3000v, atomization gas (Gas1) are 15；Gas curtain gas (Curtain Gas) is 12, and ion information see the table below.Take reference substance molten respectively
Liquid and 20 μ l sample introductions of test solution, record chromatogram.Test solution intermediate nitro benzene sulfonic acid and metanilic acid difference
It is not greater than reference substance solution intermediate nitro benzene sulfonic acid and metanilic acid and internal standard peak area with the ratio of internal standard peak area
Ratio (0.00008%).
2, testing result：
Blank solvent does not interfere m-nitrobenzene sulfonic acid, metanilic acid and interior target to measure in the detection；Internal standard is not done
Disturb the measurement of m-nitrobenzene sulfonic acid and metanilic acid；Reference substance solution sample introduction repeatability is good, sees Fig. 7~Fig. 9.
3, the detection of detection limit m-nitrobenzene sulfonic acid and metanilic acid is limited to 0.5ng/ml, is equivalent to aminosalicyclic
The impurity of the 0.4ppm of acid can be detected, and signal-to-noise ratio is more than 3, sees Fig. 4~Fig. 6.
4, Standard entertion experiment PAS does not interfere metanilic acid and nitro this sulphur measurement
Precision weighs sample 12.5mg, sets in 10ml measuring bottles, and 0.1mlN, N- dimethylacetylamides, then precision respectively is added
The internal standard stock solution (10ng/ml) and reference substance stock solution (10ng/ml) 1.0ml under specificity item are measured, is set in measuring bottle, then is added
Solvent is quantitatively diluted to scale, shakes up, and as testing liquid is added, takes 20 μ l sample introductions, records chromatogram, see Figure 11.
Precision weighs sample 12.5mg, sets in 10ml measuring bottles, and 0.1mlN, N- dimethylacetylamides is added, and precision measures special
Internal standard stock solution 1.0ml under attribute item, sets in measuring bottle, then solubilizer is quantitatively diluted to scale, shakes up, molten as test sample
Liquid takes 20 μ l sample introductions, records chromatogram, sees Figure 10.
Precision measures internal standard stock solution and reference substance stock solution 1.0ml under specificity item, sets in 10ml measuring bottles, is added
0.1mlN, N- dimethylacetylamide, solubilizer dissolve simultaneously be quantitatively diluted to scale, shake up, as a contrast product solution, take 20 μ l into
Sample records chromatogram, sees Fig. 9.
Finally illustrate, the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although with reference to compared with
Good embodiment describes the invention in detail, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the right of invention.
Claims (10)
- The method of 1.LC-MSMS method separation determination PAS and its related impurities, which is characterized in that adopted in the method Chromatographic column is using octyl silane group silica gel as filler, using aqueous acetic acid (mobile phase A) and acetonitrile solution (stream Dynamic phase B) it is that mobile phase carries out gradient elution, it is detected into tandem mass spectrum detector；The related impurities include between nitro Benzene sulfonic acid and metanilic acid.
- 2. according to the method described in claim 1, it is characterized in that, percent by volume in the aqueous acetic acid shared by acetic acid It is 0.1%.
- 3. according to the method described in claim 1, it is characterized in that, percent by volume in the acetonitrile solution shared by acetonitrile It is 90%.
- 4. according to the method described in claim 1, it is characterized in that, the condition setting of the gradient elution is as follows：Flow rate of mobile phase is 0.3-0.5ml/min.
- 5. according to claim 1-4 any one of them methods, which is characterized in that specifically include following steps：1) inner mark solution is prepared：It takes p-methyl benzenesulfonic acid solubilizer to dissolve and dilutes, obtain inner mark solution；2) test solution is prepared：Test sample is taken, solubilizer dissolving again is added after n,N-dimethylacetamide and inner mark solution And dilute, obtain test solution；3) reference substance solution is prepared：Take m-nitrobenzene sulfonic acid and metanilic acid respectively, be added n,N-dimethylacetamide and Solubilizer is dissolved and is diluted after inner mark solution, obtains reference substance solution；4) reference substance solution and test solution sample introduction in liquid chromatograph are taken respectively, are detected using tandem mass spectrum detector, Chromatogram is recorded, the content of m-nitrobenzene sulfonic acid and metanilic acid is calculated by internal standard method.
- 6. according to the method described in claim 5, it is characterized in that, the solvent is the acetonitrile that acetonitrile percent by volume is 20% Aqueous solution.
- 7. according to the method described in claim 5, it is characterized in that, in step 1) inner mark solution a concentration of 1ng/ml；Step 2) a concentration of 1230 μ g/ml-1270 μ g/ml of test solution in.
- 8. according to the method described in claim 5, it is characterized in that, the specification of the chromatographic column of liquid chromatograph is in step 4) 250 × 4.6mm, 5.0 μm；The chromatographic column post case temperature is 25-35 DEG C.
- 9. according to the method described in claim 5, it is characterized in that, in step 4) tandem mass spectrum detector condition：Electron spray Ion source (ESI), using anion MRM mode detections；Ion source temperature is 550 DEG C, and spray voltage is -3000v, atomization gas (Gas1) it is 15psi；Gas curtain gas (Curtain Gas) is 12psi.
- 10. the reagent composition of separation determination PAS and its related impurities, which is characterized in that the reagent composition It is made of mobile phase A, Mobile phase B and DMAC N,N' dimethyl acetamide；The mobile phase A is aqueous acetic acid, in aqueous acetic acid Percentage shared by acetic acid is 0.1%；The Mobile phase B is acetonitrile solution, the percentage in acetonitrile solution shared by acetonitrile It is 90%；The related impurities include m-nitrobenzene sulfonic acid and metanilic acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109799292A (en) * | 2018-12-28 | 2019-05-24 | 重庆健能医药开发有限公司 | A kind of related substance-measuring method of Mesalazine enema fluid |
| CN110133118A (en) * | 2018-12-28 | 2019-08-16 | 重庆健能医药开发有限公司 | A kind of related substance-measuring method of Mesalazine enteric-coated sustained-release tablet |
| CN110441434A (en) * | 2019-08-29 | 2019-11-12 | 重庆华邦胜凯制药有限公司 | The method of related impurities in GC-MS separation determination PAS |
| CN112924613A (en) * | 2021-01-31 | 2021-06-08 | 中南大学湘雅医院 | LC-MS/MS method for quantitatively analyzing plasma concentration of antituberculotic |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109799292A (en) * | 2018-12-28 | 2019-05-24 | 重庆健能医药开发有限公司 | A kind of related substance-measuring method of Mesalazine enema fluid |
| CN110133118A (en) * | 2018-12-28 | 2019-08-16 | 重庆健能医药开发有限公司 | A kind of related substance-measuring method of Mesalazine enteric-coated sustained-release tablet |
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| CN110441434A (en) * | 2019-08-29 | 2019-11-12 | 重庆华邦胜凯制药有限公司 | The method of related impurities in GC-MS separation determination PAS |
| CN112924613A (en) * | 2021-01-31 | 2021-06-08 | 中南大学湘雅医院 | LC-MS/MS method for quantitatively analyzing plasma concentration of antituberculotic |
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Application publication date: 20180727 |