CN108982695A - The method that derivatization HPLC method measures azido compound in drug or in which mesosome - Google Patents
The method that derivatization HPLC method measures azido compound in drug or in which mesosome Download PDFInfo
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- CN108982695A CN108982695A CN201810852355.1A CN201810852355A CN108982695A CN 108982695 A CN108982695 A CN 108982695A CN 201810852355 A CN201810852355 A CN 201810852355A CN 108982695 A CN108982695 A CN 108982695A
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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
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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
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
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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
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The present invention provides the methods of azido compound in a kind of derivatization HPLC method measurement drug or in which mesosome, first under experimental temperature, 5 ~ 60min of reaction is performed the derivatization to azido compound using biphenyl acyl chloride derivatization reagent, reaction solution is detected as sample；Using the derivative reaction liquid of above-mentioned generation as sample, derivatization product is measured between 220 ~ 300nm using HPLC-DAD method, to realize the quantitative detection to azido compound in drug or its synthetic intermediate.The present invention can be avoided drug or synthetic intermediate itself bring matrix interference, the residual quantity that a kind of high sensitivity, specificity are strong, simple general-purpose Derivatization Method measures azide in drug or its synthetic intermediate then in HPLC method is established, the sensitivity and specificity of azido compound detection method are improved.
Description
Technical field
The invention belongs to drug assay techniques fields, and in particular to a kind of derivatization HPLC method is intermediate to drug or its synthesis
The analyzing detecting method of azide in body.
Background technique
With gradually perfecting for genotoxicity impurity regulation, national drug administration department gets over the regulatory requirements of genotoxicity impurity
Come higher.In recent years, in the application for quotation of product, since defect is increasingly caused by genotoxicity Control of Impurities irregularity
It is more.Sufficient genotoxicity impurity research has become the key of product success listing[1].Genotoxicity impurity may
DNA mutation, chromosome breakage or DNA recombination, this kind of impurity is caused to be also possible to lead to the generation of human tumor[2-4].Meanwhile base
Because toxic impurities property is active, stability is poor, it is therefore necessary to establish that specificity is strong, analysis method of high sensitivity is to monitor medicine
Genotoxicity impurity residual in object.
Azido compound is common one of gene poison impurity, while being also the key intermediate during pharmaceutical synthesis,
Such as cefoperazone sodium, Cefamandole Nafate, Valsartan, Candesartan, Zidovudine.Such compound is able to suppress cell color
The activity of plain oxidizing ferment and a variety of enzymes, and lead to the exception of phosphorylation and cellular respiration[5-6], main acute toxic action is can
Cause antiotasis extremely to reduce, therefore must be strictly controlled in medicine production process drug and its intermediate azide
Content.
In all kinds of analysis methods, HPLC method is because its separation efficiency is high, selectivity is high, method is simple, it is fast etc. to analyze speed
The prefered method that advantage becomes laboratory, pharmaceutical factory quality controls.But since some genotoxicity impurity UV absorptions are weaker, detection
Limit is lower, is directly detected with HPLC method and is unable to reach required testing goal there is shortcomings and deficiencies.Also there is report in document
Road measures azide using the method that 3,5- dinitrobenzoyl chloride and DBA (alkynes) are aided with HPLC as derivatization reagent[7-8],
But this method is frequently run onto the problem of two aspects during practical application: 1) sensitivity is not high enough, to Azide
Meet demand is difficult in the case that analyte detection bound requirements are relatively low；2) 3,5- dinitrobenzoyl chloride is formed with azido compound
Derivative it is sometimes similar compared with other compositional polarities in sample, the retention time in HPLC also relatively, detection
Result be interfered.
1.Snodin,D.J.,Elder,D.P.Genotoxic impurities part 1:general overview.
2.Benigni,R.,Bossa,C.Mechaisms of chemical carcinogenicity and
mutagenicity:a review with implications for predictive toxicology[J].Chem
Rev,2011,111(4):2507-2536.
3.Sitaram,C.,Rupakula,R.B.Determination of alkyl methanesulfonates in
doxazosin mesylate by gas chromatography mass spectrometer[J].Indian J Pharm
Sci,2011,73(1):107-110.
4.Gricar,M.,Andrensek,S.Determination of azide impurity in sartans
using reversed-phase HPLC with UV detection[J].Journal of Pharmaceutical and
Biomedical Analysis,2016,125:27–32.
5.Tsuge,T.,Kataoka,M.,Harvey,A.E.Rapid determination of cyanide and
azide in beverages by microdiffusion spectrophotometric method[J]
.Anal.Toxicol.,2011,25:228–236.
6.Hajiaghazorgy R.,Zarei,A.R.Pakdehi,S.G.A highly sensitive
spectrophotometric determination of ultra trace amounts of azide ion in water
and biological samples after preconcentration using dispersive liquid–liquid
microextraction technique[J].Anal.Chem,2014,69(8):805–811.
7.Lifang W,Chaofeng D,Weixuan C,et al.Facile derivatization of azide
ions using click chemistry for their sensitive detection with LC-MS[J]
.Chem.Commun.,2011,47,10377–10379.
8. gold medal meter Cong, Yan Jinliang, symbol opens up bright Determination of residual sodium azide in binder-azide by high performance liquid chromatograph [J]
Analysis instrument, 1999,1:38-40..
Summary of the invention
In order to solve the deficiencies in the prior art, the present invention provides azide in a kind of derivatization HPLC method measurement drug
Method.
The purpose of the present invention is achieved through the following technical solutions:
The method that derivatization HPLC method measures azido compound in drug or in which mesosome, comprising the following steps:
S1, at room temperature, using biphenyl acyl chloride derivatization reagent to azido compound perform the derivatization reaction 5~
60min, reaction solution are detected as sample；
S2, derivative is measured using HPLC-DAD method as sample between 220~300nm using change reaction solution derived from S1
Change product, to realize to the quantitative detection of generation or remaining azido compound in drug or its synthetic intermediate.
Preferably, biphenyl acyl chloride derivatization reagent is selected from biphenyl -4- acyl chlorides or the biphenyl-containing substituent group in the S1
4- acyl chlorides, structural formula difference is as follows,
Wherein, substituent X or Y are and are not limited to alkoxy, hydroxyl, the nitre of halogen, the alkyl of 1-4 carbon, 1-4 carbon
Base, amino, cyano.
Preferably, biphenyl acyl chloride derivatization reagent is preferably biphenyl -4- formyl chloride in the S1.
Preferably, the S1 derivedization reaction condition is, using acetonitrile as reaction system, biphenyl -4- formyl chloride derivatization
The additive amount of reagent is 100-700 μ L, reacts 5~60min with azido compound.
Preferably, it using acetonitrile as reaction system in the S1, by 100 μ L biphenyl -4- formyl chloride derivatization reagents and folds
Nitrogen compound is reacted, reaction time 30min.
Preferably, HPLC liquid chromatograph is used in the S2 in HPLC-DAD method, using reversed phase partition chromatography；With non-
Polar binding is mutually stationary phase, and using polarity mobile phase, Detection wavelength is 220~300nm.
Preferably, HPLC liquid chromatograph is used in the S2 in HPLC-DAD method, Detection wavelength is 250~300nm.
Preferably, Detection wavelength is between 270~295nm.
Preferably, the HPLC instrument is Shimadzu LC20AT high performance liquid chromatograph, is included in line vacuum degassing
Machine, binary gradient pump, autosampler, column oven, DAD detector and solution work station；Chromatographic column be C18 (4.6 ×
150mm, 3 μm), using octadecylsilane chemically bonded silica as packing material, using 0.1% phosphoric acid solution and acetonitrile as mobile phase, column
Temperature be 35 DEG C~40 DEG C, flow velocity be 0.6mL/min~1.5mL/min, sample volume be the 5 μ L of μ L~20, Detection wavelength be 250~
300nm。
Preferably, the drug and its synthetic intermediate are and are not limited to Cefamandole Nafate, Candesartan, Qi Duo
Husband determines compound.
Preferably, the room temperature refers to the temperature that conventional analysis experiment carries out, and refers generally to 20~30 DEG C.
The beneficial effects of the present invention are embodied in: 1, drug or synthetic intermediate itself bring matrix interference are avoided, is built
Strong a kind of high sensitivity, specificity are found, in simple general-purpose pre-column derivatization HPLC measurement drug or its synthetic intermediate
The residual of azide.
2, impurity is detected by the method for chemical derivatization, improves the sensitivity and specificity of detection method.
Its principle is, since the UV absorption intensity of most drugs and its impurity is very weak, even without UV absorption, to use biphenyl
Derivatization product that acyl chloride derivatization reagent obtains because biphenyl group there are due to so that UV absorption intensity is had apparent increase.
Meanwhile biphenyl acyl chloride derivatization reagent can change the polarity of derivatization reaction product, postpone appearance time, reduce bulk pharmaceutical chemicals
In the interference of other component brings.
Detailed description of the invention
Fig. 1: the peak area of derivatization product of the invention and the relation schematic diagram of derivatization reagent dosage.
Fig. 2: relation schematic diagram when derivative reaction of the present invention between reaction temperature.
Fig. 3: relation schematic diagram when derivative reaction of the present invention is complete between reaction temperature.
Fig. 4: the present invention carries out derivatization reaction specificity schematic diagram with Cefamandole Nafate bulk pharmaceutical chemicals.
Fig. 5: the present invention carries out derivatization reaction specificity schematic diagram with Zidovudine bulk pharmaceutical chemicals.
Fig. 6: the present invention carries out derivatization reaction specificity schematic diagram with Candesartan bulk pharmaceutical chemicals.
Specific embodiment
It is specifically described technical solution of the present invention with reference to embodiments, present invention discloses a kind of surveys of derivatization HPLC method
Determine the method for azido compound in drug.It is specific to use:
Instrument: Shimadzu LC20AT high performance liquid chromatograph is included in line vacuum degasser, binary gradient pumps, automatic
Sample injector, column oven, DAD detector and solution work station；Sai Duolisi BT25S assay balance.
Reagent: sodium azide (purity: 97.9%), biphenyl -4- formyl chloride (purity: 98%), Cefamandole Nafate, candy
Sha Tan, Zidovudine.
Purified water, acetonitrile (chromatographically pure), phosphoric acid (GR).
The preparation of biphenyl -4- acyl chlorides derivatization solution: biphenyl -4- acyl chlorides about 100mg, it is accurately weighed, it sets in 10mL measuring bottle,
Scale is dissolved and be diluted to pure acetonitrile, is shaken up.
The preparation of test solution: taking Cefamandole Nafate, Candesartan or appropriate Zidovudine, and it is derivative that 100 μ L are added
Change reagent, be settled to graduation mark with acetonitrile, shake up, 25 DEG C of reaction 30min to get.
The preparation of reference substance solution: taking sodium azide reference substance about 16mg, accurately weighed, sets in 10mL volumetric flask, uses 2mL
Water dissolution after, be settled to scale with acetonitrile；The accurate 50 μ L that draw are settled to scale with acetonitrile to 10mL volumetric flask after shaking up
Line.(5 μ g/mL, in terms of Azide).
Chromatographic condition: chromatographic column is C18 (5 μm, 4.6*250mm), using octadecylsilane chemically bonded silica as packing material；
Mobile phase: using 0.1% phosphoric acid solution and acetonitrile as mobile phase, gradient elution, column temperature is 40 DEG C, flow velocity 1mL/min, sample volume
For 20 μ L, Detection wavelength 290nm.
Embodiment 1
In order to ensure derivative reaction is complete, using Candesartan as representative, the use to the derivatization reagent in system is needed
Amount, reaction time and reaction temperature are investigated.Concrete outcome is shown in Fig. 1-Fig. 3.
As shown in Figure 1, the peak area of derivatization product increases with the increase of derivatization reagent dosage, until biphenyl-
When 4- formyl chlorine dose is 600 μ L, peak area reaches maximum value and unchanged.As shown in Figure 2, increase reaction temperature to produce derivatization
Object peak area does not have much affect, and illustrates that the derivative reaction can be carried out quickly at room temperature.From the figure 3, it may be seen that the reaction of 30min
Time can make derivative reaction complete.
Embodiment 2
Methodology validation and application
Specificity experiment:
It is exclusive that derivatization reaction is carried out with Cefamandole Nafate bulk pharmaceutical chemicals, Zidovudine bulk pharmaceutical chemicals and Candesartan raw material respectively
It investigates, investigates and show blank solution not jamming target derivative, and the separating degree of azide derivatives peak and adjacent peak >=
1.5, illustrate that this method specificity is good, concrete outcome is with reference to shown in Fig. 4~Fig. 6.
Linearity and range:
Precision pipettes appropriate nitrine stock solution respectively, is placed in 10mL volumetric flask, is settled to graduation mark with acetonitrile, is configured to
Series of concentrations solution, performs the derivatization according to the above method, after 0.22 μm of syringe-driven filter filters, 20 μ L is taken to inject liquid phase color
Spectrometer measures the peak area of derivatization product.With nitrine concentration (ng/ml) for abscissa, derivatization peak areas (A) is vertical
Coordinate carries out linear regression analysis, and equation of linear regression and related coefficient is calculated.The results show that being folded in Cefamandole Nafate
The range of linearity of nitrogen is 6.4~38.0ng/mL, Candesartan, the range of linearity of nitrine is 6.4~38.2ng/ in Zidovudine
ML, and good linear relationship is presented, it the results are shown in Table 1.
Precision Experiment:
By bound requirements, 100% limit level standard solution is prepared, is performed the derivatization according to the above method, through 0.22 μm of needle
After the filtering of hair style filter, 20 μ L is taken to inject liquid chromatograph, repeated sample introduction 6 times, RSD is calculated with derivatization peak areas
Value, the sample introduction precision of the method is good, and RSD the results are shown in Table 1 between 0.1%~0.3%.
Stability experiment:
By bound requirements, standard solution and 100% limit level standard solution are prepared respectively, is spread out according to the above method
Biochemistry, place 0 at 25 DEG C, 2,4,6,8, after 12h, after 0.22 μm of syringe-driven filter filters, 20 μ L is taken to inject liquid phase color
Spectrometer is measured, and investigates its stability with the peak area variation of derivatization product.As can be seen from the results, derivatization product is in room temperature
When placement, the RSD mean value of peak area is less than 3% in 0~12h, i.e. derivatization product stability is good, and the results are shown in Table 1.
Detection limit and quantitative limit:
Detection limit is carried out by signal-to-noise ratio method and quantitative limit is investigated, i.e. signal-to-noise ratio 3:1 is method detection limit, and signal-to-noise ratio is
10:1 is method quantitative limit.The results show that the detection of nitrine derivatization product is limited to 2.5ng/mL in three kinds of drugs, quantitative limit exists
Between 1.5~6.4ng/mL, 1 the results are shown in Table.
Table 1: methodology experimental result table.
Accuracy experiment
For the accuracy for investigating method, sample recovery rate experiment is carried out.The drug being related to includes Cefamandole Nafate, candy
Sha Tan, Zidovudine.
By bound requirements, 50%, 100% and 150% 3 limit level standard solution is prepared, is spread out according to the above method
Biochemistry takes 20 μ L injection liquid chromatograph to be measured, calculates the rate of recovery, as a result after 0.22 μm of syringe-driven filter filters
It is shown in Table 2.
Table 2: sample recovery rate experimental result
Embodiment 3
The method established is applied to the residue detection of azide in drug.Precision weighs each drug, is respectively placed in
In 10mL volumetric flask, 600 μ L biphenyl -4- formyl chlorides are added, take 20 μ L sample introductions after reacting 30min at 25 DEG C with acetonitrile constant volume
Detection.The result shows that survey azide is not detected in three kinds of drugs.
Certainly still there are many specific embodiments by the present invention, are just not listed one by one herein.It is all using equivalent replacement or
Equivalent transformation and all technical solutions formed, all fall within the scope of protection of present invention.
Claims (10)
1. the method that derivatization HPLC method measures azido compound in drug or in which mesosome, it is characterised in that: including following step
It is rapid:
S1, at room temperature, performs the derivatization 5~60min of reaction to azido compound using biphenyl acyl chloride derivatization reagent, instead
Liquid is answered to be detected as sample；
S2, using derived from S1 change reaction solution as sample, measured between 220~300nm using HPLC-DAD method derivatization produce
Object, to realize to the quantitative detection of generation or remaining azido compound in drug or its synthetic intermediate.
2. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: biphenyl acyl chloride derivatization reagent is selected from biphenyl -4- acyl chlorides or the biphenyl -4- acyl chlorides containing substituent group in the S1,
Its structural formula difference is as follows,
Wherein, substituent X or Y are and are not limited to alkoxy, hydroxyl, nitro, the ammonia of halogen, the alkyl of 1-4 carbon, 1-4 carbon
Base, cyano.
3. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: biphenyl acyl chloride derivatization reagent is preferably biphenyl -4- formyl chloride in the S1.
4. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: the S1 derivedization reaction condition is, using acetonitrile as reaction system, biphenyl -4- formyl chloride derivatization reagent adds
Dosage is 100-700 μ L, reacts 5~60min with azido compound.
5. the method for azido compound, special in derivatization HPLC method measurement drug as claimed in claim 4 or in which mesosome
Sign is: using acetonitrile as reaction system in the S1, passing through 100 μ L biphenyl -4- formyl chloride derivatization reagents and azido compound
It is reacted, reaction time 30min.
6. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: HPLC liquid chromatograph is used in the S2 in HPLC-DAD method, using reversed phase partition chromatography；With non-polar linkage
It is mutually stationary phase, using polarity mobile phase, Detection wavelength is 220~300nm.
7. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: using HPLC liquid chromatograph in the S2 in HPLC-DAD method, Detection wavelength is 250~300nm.
8. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: the HPLC instrument is ShimadzuLC20AT high performance liquid chromatograph, is included in line vacuum degasser, binary ladder
Spend pump, autosampler, column oven, DAD detector and solution work station；Chromatographic column is C18 (4.6 × 150mm, 3 μm),
Using octadecylsilane chemically bonded silica as packing material, using 0.1% phosphoric acid solution and acetonitrile as mobile phase, column temperature is 35 DEG C~40
DEG C, flow velocity is 0.6mL/min~1.5mL/min, and sample volume is the 5 μ L of μ L~20, and Detection wavelength is 250~300nm.
9. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: the drug and its synthetic intermediate is and is not limited to Cefamandole Nafate, Candesartan, Zidovudine chemical combination
Object.
10. the method for azido compound, special in derivatization HPLC method measurement drug as described in claim 1 or in which mesosome
Sign is: room temperature refers to 20~30 DEG C of temperature that conventional analysis experiment carries out in the S1.
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| CN113866300A (en) * | 2021-09-26 | 2021-12-31 | 山东建筑大学 | Method for detecting sodium azide in medicine or intermediate thereof |
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| CN112415107A (en) * | 2021-01-21 | 2021-02-26 | 珠海润都制药股份有限公司 | Method for detecting impurities in sartan drug synthesis |
| CN113671085A (en) * | 2021-08-30 | 2021-11-19 | 珠海润都制药股份有限公司 | Method for detecting 2-azido-3-methylbutyric acid in valsartan |
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