CN110514759A - The detection method of azido compound in a kind of candesartan Cilexetil - Google Patents
The detection method of azido compound in a kind of candesartan Cilexetil Download PDFInfo
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- CN110514759A CN110514759A CN201910771596.8A CN201910771596A CN110514759A CN 110514759 A CN110514759 A CN 110514759A CN 201910771596 A CN201910771596 A CN 201910771596A CN 110514759 A CN110514759 A CN 110514759A
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- acetonitrile
- sulfuric acid
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- candesartan cilexetil
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- 238000001514 detection method Methods 0.000 title claims abstract description 46
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 21
- -1 azido compound Chemical class 0.000 title claims abstract description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 45
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000010828 elution Methods 0.000 claims abstract description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 8
- 239000012085 test solution Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 7
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 5
- 238000004090 dissolution Methods 0.000 claims abstract description 5
- 239000000706 filtrate Substances 0.000 claims abstract description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims abstract description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 20
- 238000010829 isocratic elution Methods 0.000 claims description 6
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 4
- 229960000932 candesartan Drugs 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 abstract description 20
- 238000004458 analytical method Methods 0.000 abstract description 6
- 239000000377 silicon dioxide Substances 0.000 abstract description 3
- 150000001540 azides Chemical class 0.000 description 25
- 239000013558 reference substance Substances 0.000 description 24
- 239000003085 diluting agent Substances 0.000 description 10
- 238000011084 recovery Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000012490 blank solution Substances 0.000 description 5
- 238000001212 derivatisation Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- NNOHXABAQAGKRZ-UHFFFAOYSA-N 3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1 NNOHXABAQAGKRZ-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000004098 cellular respiration Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 238000011022 operating instruction Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The present invention relates to chemicals analysis technical field, the detection method of azido compound in specifically a kind of candesartan Cilexetil.Detection method is to take candesartan Cilexetil bulk pharmaceutical chemicals product to be tested, after acetonitrile ultrasonic dissolution is added, is diluted using aqueous sulfuric acid；The volume ratio of the acetonitrile and sulfuric acid water is 40:60 ~ 60:40；It is filtered after shake well, takes filtrate stand-by as test solution；Chromatographic column uses acetonitrile-aqueous sulfuric acid for mobile phase A using octadecylsilane chemically bonded silica as stationary phase, and acetonitrile-water is that Mobile phase B carries out gradient elution, carries out HPLC detection, records map.Using detection method of the invention, it can quickly and easily separate and quantitative determine the sodium azide in candesartan Cilexetil, to effectively control the quality of candesartan Cilexetil product.
Description
Technical field
The present invention relates to chemicals analysis technical field, the detection of azido compound in specifically a kind of candesartan Cilexetil
Method.
Technical background
Candesartan Cilexetil is the pro-drug of Candesartan, and in the gastrointestinal tract, it can be hydrolyzed to quick and completely bank
Ground sand is smooth.Candesartan is Angiotensin II AT1 receptor antagonist, antagonism and in conjunction with vascular smooth muscle AT1 receptor
The vasoconstrictor effects of Angiotensin II are a kind of long-acting receptor antagonists to reduce peripheral vascular resistance.
Azido compound is one of the key intermediate during candesartan Cilexetil pharmaceutical synthesis, since it is able to suppress carefully
The activity of born of the same parents' chromo-oxidase and a variety of enzymes, and lead to the exception of phosphorylation and cellular respiration, main Study on Acute Toxic Effects is energy
Enough cause antiotasis extremely to reduce, be common one of genotoxicity impurity, therefore must be stringent in medicine production process
Control the content of azide in drug and its intermediate.
Jin meter Cong etc. (Determination of residual sodium azide in binder-azide by high performance liquid chromatograph, analysis instrument, 1999
1 phase, 38-40) it reports using citric acid sodium citrate buffer solution extraction adhesive sample, extract liquor is concentrated to use 3,5- bis-
Nitrobenzoyl chloride (DNBC) carries out ultraviolet derivative under mildly acidic conditions.
Chinese patent CN201810852355.1 discloses Azide in derivatization HPLC method measurement drug or in which mesosome
Close object method, specifically disclose using biphenyl acyl chloride derivatization reagent to azido compound perform the derivatization reaction 5 ~
60min, reaction solution are detected as sample；Using the derivative reaction liquid of above-mentioned generation as sample, HPLC-DAD method is utilized
Derivatization product is measured between 220-300nm, and azido compound in drug or its synthetic intermediate is quantified to realize
Detection.But operation is performed the derivatization using this method needs, complex steps take a long time.
Summary of the invention
In consideration of it, the purpose of the present invention is to provide a kind of detection method of azido compound in candesartan Cilexetil, the party
Method can be separated quickly and easily and quantitative determine the sodium azide in candesartan Cilexetil, so that effectively control candesartan Cilexetil produces
The quality of product, this method is in system suitability, specificity, detection property and the side such as the quantitative, range of linearity, the rate of recovery, repeatability
Face complies fully with standard and has the new detection method compared with high durability.
The present invention adopts the following technical scheme:
The detection method of azido compound in a kind of candesartan Cilexetil, this method include taking candesartan Cilexetil bulk pharmaceutical chemicals product to be tested,
It after acetonitrile ultrasonic dissolution is added, is diluted using aqueous sulfuric acid, the volume ratio of the acetonitrile and sulfuric acid water is 40:60-60:40；
It is filtered after shake well, takes filtrate stand-by as test solution；Chromatographic column using octadecylsilane chemically bonded silica as stationary phase,
Use acetonitrile-aqueous sulfuric acid for mobile phase A, acetonitrile-water is that Mobile phase B carries out gradient elution, carries out HPLC detection, record figure
Spectrum.
Preferably, the ratio between volume of acetonitrile and aqueous sulfuric acid is 40:60 in the mobile phase A.
Preferably, the ratio between volume of acetonitrile and water is 90:10 in the Mobile phase B.
Preferably, the aqueous sulfuric acid is 0.0009mol/L sulfuric acid solution.
Preferably, the temperature of the stationary phase is 28-32 DEG C, and the flow velocity of the mobile phase is 0.6-0.8 mL/min.
Preferably, the Detection wavelength of the HPLC detection is 205nm.
Preferably, the sample volume of the HPLC detection is 50 μ l.
Preferably, in the gradient elution, mobile phase A and Mobile phase B are with volume percent, elution program are as follows:
0-15min, mobile phase A and Mobile phase B volume ratio are 100:0, carry out isocratic elution；
15-16min, mobile phase A and Mobile phase B volume ratio are 10:90 by linear gradient, carry out linear gradient elution；
16-30min, mobile phase A and Mobile phase B volume ratio are 10:90, carry out isocratic elution；
30-31min, mobile phase A and Mobile phase B volume ratio are 100:10 by linear gradient, carry out linear gradient elution；
31-40min, mobile phase A and Mobile phase B volume ratio are 100:0, carry out isocratic elution.
The present invention provides a kind of detection methods of azido compound in candesartan Cilexetil, compared with prior art, this hair
Bright method can be separated quickly and easily and quantitative determine the sodium azide in candesartan Cilexetil, to effectively control Candesartan
The quality of ester product, and this method is in system suitability, specificity, detection property and the quantitative, range of linearity, the rate of recovery, repetition
Property etc. comply fully with standard and have compared with high durability new detection method.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention for those of ordinary skill in the art without creative efforts, can be with
It obtains other drawings based on these drawings.
Attached drawing 1 is sodium azide ultraviolet spectrogram；
Attached drawing 2 is to detect blank solution liquid chromatogram using the method for the present invention；
Attached drawing 3 is to detect reference substance solution liquid chromatogram using the method for the present invention；
Attached drawing 4 is using the molten liquid chromatogram of the method for the present invention system suitability；
Attached drawing 5 is the linear relationship chart of sodium azide.
Specific embodiment
In order to preferably illustrate the content of the invention, below by specific embodiment to further verifying of the invention.It is special
Illustrate herein, embodiment is only that more directly description is of the invention, they are a part of the invention, cannot be to structure of the present invention
At any restrictions.
Detection method in accordance with the present invention, wherein aqueous sulfuric acid: aqueous sulfuric acid is to measure 18ml concentration to be
0.05mol/L sulfuric acid solution is added to the aqueous sulfuric acid that 0.0009mol/L is configured in 1000ml purified water.Diluent: it adopts
The volume ratio for using acetonitrile and sulfuric acid water is 40:60 as diluent.
Embodiment 1: the HPLC detection of candesartan Cilexetil bulk pharmaceutical chemicals
Using detection method of the present invention, specific embodiment is as follows:
Instrument: Waters e2695-2489 high performance liquid chromatograph
Chromatographic column: octadecylsilane chemically bonded silica is filler (Waters Atlantis T3 C18 4.6*250mm, 5 μm)
Mobile phase A: using the ratio between volume of acetonitrile and aqueous sulfuric acid is 40:60 as mobile phase A.
Mobile phase B: using the ratio between volume of acetonitrile and water is 90:10 as Mobile phase B.
Gradient elution is carried out by such as the following table 1:
1 elution program of table
Column temperature: 30 DEG C
Flow velocity: 0.7ml/min
Sample volume: 50 μ l
Detection wavelength: 205nm
Work station: Empower 3
Test solution: precision weighs candesartan Cilexetil bulk pharmaceutical chemicals product to be tested about 80mg and sets in 10ml measuring bottle, adds 4ml acetonitrile
After ultrasonic dissolution, then plus aqueous sulfuric acid to scale, shake up, filter, subsequent filtrate is taken, as test solution.
Reference substance stock solution: it takes sodium azide reference substance about 30mg to set in 250ml measuring bottle, diluent is added to dissolve and dilute
To scale, shake up；Precision measures 1.0ml and sets in 100ml measuring bottle, adds diluent to scale, shakes up, as reference substance deposit
Liquid.
Reference substance solution: precision measures reference substance stock solution 1.0ml and sets in 10ml measuring bottle, adds diluent to scale, shakes
It is even, it (is equivalent in every 1ml containing about azide ion N as reference substance solution3-For 0.08 μ g).
System suitability solution: precision weighs test sample about 80mg and sets in 10ml measuring bottle, adds 4ml acetonitrile ultrasonic dissolution,
Precision measures reference substance stock solution 1.0ml into the measuring bottle, adds aqueous sulfuric acid to scale, shakes up, filter, take subsequent filtrate, make
For system suitability solution.
Precision measures above-mentioned reference substance solution, system suitability solution and each 50 μ l of test solution and injects liquid chromatogram
Instrument records preceding 16 minutes chromatograms (being elution principal component after 16 minutes, can not acquire), for investigating the letter at azido compound peak
It makes an uproar ratio；The separating degree at azide peak and adjacent peak；If retaining in chromatogram obtained by test solution if any with azide peak
The impurity peaks of time consistency calculate azide content by external standard method.
Embodiment 2: the determination of Detection wavelength
Instrument: ultraviolet-visible spectrophotometer
Detection wavelength: 200-400nm full wavelength scanner
Precision weighs sodium azide reference substance about 30mg and sets in 250ml measuring bottle, adds diluent to dissolve and is diluted to scale, shakes
It is even, as reference substance mother liquor.Precision measures reference substance mother liquor 5.0ml and sets in 10ml measuring bottle, and diluent is added to shake up to scale,
As wavelength detecting reference substance solution.
It takes sodium azide wavelength detecting reference substance solution appropriate, is measured by " UV-VIS spectrophotometry operating instruction ",
Spectra re-recorded scanning curve figure, the results are shown in attached figure 1 for UV scanning.
Referring to attached drawing 1, can be obtained by UV scanning figure result: sodium azide about has larger absorption in wavelength 205nm, because
This chooses best detection wavelength of the 205nm as detector.
Embodiment 3: system suitability and specificity test
The system suitability of instrument when the system suitability of the present embodiment has investigated continuous sample introduction simultaneously.
Blank solution: diluent；
Reference substance solution, system suitability solution: preparation method is the same as embodiment 1；
By the chromatographic condition in embodiment 1 successively into 1 needle of blank solution, 6 needle of reference substance solution, 1 needle of system suitability solution, meter
The relative standard deviation for calculating retention time and peak area, the results are shown in Table 2.
2 system suitability result of table
Conclusion: referring to attached drawing 2, blank solution is noiseless.Referring to attached drawing 3, in chromatogram obtained by reference substance solution, azide peak
Signal-to-noise ratio 100 or more, much higher than the 20 ~ 30 of general limit signal-to-noise ratio, retention time RSD less than 1.0%, and down to
0.007%, peak area RSD is less than 5%；
Referring to attached drawing 4, azide peak retention time is Azide in 6.114, with reference substance solution in system suitability solution
Object peak retention time is consistent, and the separating degree of azide peak and adjacent peak is 3.5, is already greater than the 1.5 of standard requirements.Illustrate this
Analysis method system suitability and specificity are good.
Embodiment 4: detection limit and quantitative limit
Respective concentration or the amount of note people's instrument when signal-to-noise ratio method is generally 3:1 or 2:1 with signal-to-noise ratio, which are limited, according to detection determines detection
Limit, respective concentration or the amount of injection instrument determine quantitative limit when quantitative limit signal-to-noise ratio method is generally 10:1 with signal-to-noise ratio.
Quantitative limit (LOQ) solution: precision measures reference substance solution 5.0ml and sets in 20ml measuring bottle, adds diluent to scale, shakes
It is even, as quantitative limit (LOQ) solution.It is parallel to prepare 6 parts.
Detection limit (LOD) solution: precision measures quantitative limit solution 3.0ml and sets in 10ml measuring bottle, adds diluent to scale, shakes
It is even, (LOD) solution is limited as detection.
By each 1 needle of 6 parts of quantitative limit solution of chromatographic condition sample introduction of embodiment 1, detection limit 3 needle of solution the results are shown in Table 3.
3 azide quantitative limit of table and detection limit result
Conclusion: the signal-to-noise ratio at azide peak guarantees in sample between 10~13 in chromatogram obtained by 6 parts of LOQ solution
The azide of 2.38ppm or more can be with quantitative detection；The signal-to-noise ratio at azide peak is equal in chromatogram obtained by 3 needle LOD solution
It is 3, guarantees that the azide of 0.71ppm or more in sample can be detected, it was demonstrated that sensitivity of the invention is good.
Embodiment 5: linear and range
Instrument and reagent are the same as embodiment 1.
Take concentration (with N3Meter) be 0.0190 μ g/ml, 0.0380 μ g/ml, 0.0609 μ g/ml, 0.0761 μ g/ml,
The azide reference substance of 0.1141 μ g/ml, 0.1521 μ g/ml are limited respectively as LOQ, 50%, 80%, 100%, 150%, 200%
The reference substance solution of degree；It is measured respectively by 1 chromatographic condition of embodiment, using peak area as ordinate, concentration is that abscissa is made linearly
Regression figure the results are shown in Table 4, attached drawing 5:
4 azide linearity and range result of table
Conclusion: azide meets at least in 0.0190-0.1521 μ g/mL concentration range in LOQ value to 200% limit model
Interior standard is enclosed, and related coefficient is that 0.9994, Y y-intercept accounts for the 7% of 100% response, illustrates that the analysis method detects nitrine
Compound has good linear relationship in 0.0190-0.1521 μ g/mL concentration range.
Embodiment 6: repetitive test
By the degree of closeness that is repeatedly measured by sampling between acquired results come the precision of judgment method.
Reference substance solution: preparation method is the same as embodiment 1.
Repeated solution: preparation method is the same as the system suitability solution in embodiment 1.It is parallel to prepare 6 parts.
By 1 chromatographic condition sample introduction reference substance solution of embodiment, 2 needle, 6 parts of each 1 needles of repeated solution calculate azide and contain
Amount, acquires relative standard deviation, the results are shown in Table 5.
The repeated result of table 5
Conclusion: the RSD of azide content is 5% in 6 parts of repeated solution, illustrates that analysis method repeatability is good.
Embodiment 7: recovery test
The rate of recovery between theoretical addition amount and actually detected amount by measuring azide is come the accuracy of method of assuring.
Candesartan Cilexetil is weighed respectively is placed in suitable volumetric flask the concentration 8mg/ml for making candesartan Cilexetil in right amount, point
It is 3 groups, every group 3 parts.Being separately added into suitable azide reference substance makes its 3 groups concentration (with N3Meter) it is respectively 0.0192 μ
G/ml, 0.0767 μ g/ml, 0.1150 μ g/ml, are equivalent to the sample recovery rate solution of LOQ, 100%, 150%, upper by what is prepared
It states solution to measure by 1 chromatographic condition of embodiment, the rate of recovery is calculated as follows, the results are shown in Table 6.
Since azide being not detected in test solution, therefore the amount of having is 0ng/ml.
The rate of recovery of the azide in sample recovery rate solution under the different limit concentration of table 6
Conclusion: in test sample be added the limit concentration of LOQ ~ 150% azide, the rate of recovery 83.83% ~ 105.62% it
Between, and RSD shows that the accuracy of the method is good less than 10%.
Embodiment 8: serviceability test
When durability refers to that determination condition has small variation, the impregnable Bearing degree of measurement result.Allusion quotation in liquid chromatogram
The variable of type has: column temperature, flow velocity, chromatographic column etc..The flow velocity of this research is 0.6ml/min, 0.7ml/min and 0.8ml/
min；Column temperature is 28 DEG C, 30 DEG C and 32 DEG C；Two chromatographic columns of chromatographic column 1 and chromatographic column 2(be same model, different lot numbers, specifically
7) information is shown in Table, other chromatographic conditions in addition to flow velocity, column temperature and chromatographic column are the same as embodiment 1.
7 chromatographic column information table of table
Blank solution, system suitability solution are taken respectively, are measured in different flow velocitys, column temperature, chromatography column condition, peak knot
Fruit such as the following table 8:
8 durability testing result of table
Note: " " expression does not change compared with specified value.
Testing result: to the flow rate of mobile phase and column temperature progress minor alteration or replacement same type in chromatographic parameter condition
When different lot number chromatographic columns, blank is noiseless, and the separating degree of azide and adjacent peak is all larger than in system suitability solution
1.5, it was demonstrated that this method has good durability.
Claims (8)
1. the detection method of azido compound in a kind of candesartan Cilexetil, which is characterized in that the method includes taking Candesartan
Ester bulk pharmaceutical chemicals product to be tested is diluted after acetonitrile ultrasonic dissolution is added using aqueous sulfuric acid；The volume ratio of the acetonitrile and sulfuric acid water
For 40:60 ~ 60:40；It is filtered after shake well, takes filtrate stand-by as test solution；Chromatographic column is with octadecylsilane key
Conjunction silica gel is stationary phase, uses acetonitrile-aqueous sulfuric acid for mobile phase A, and acetonitrile-water is that Mobile phase B carries out gradient elution, is carried out
HPLC detection, records map.
2. detection method according to claim 1, which is characterized in that acetonitrile and aqueous sulfuric acid in the mobile phase A
The ratio between volume is 40:60.
3. detection method according to claim 1, which is characterized in that the ratio between acetonitrile and the volume of water in the Mobile phase B
For 90:10.
4. described in any item detection methods according to claim 1 ~ 3, which is characterized in that the aqueous sulfuric acid is
0.0009mol/L sulfuric acid solution.
5. described in any item detection methods according to claim 1 ~ 3, which is characterized in that the temperature of the stationary phase is 28~32
DEG C, the flow velocity of the mobile phase is 0.6~0.8 mL/min.
6. described in any item detection methods according to claim 1 ~ 3, which is characterized in that the Detection wavelength of HPLC detection is
205nm。
7. described in any item detection methods according to claim 1 ~ 3, which is characterized in that the sample volume of the HPLC detection is 50
μl。
8. described in any item detection methods according to claim 1 ~ 3, which is characterized in that, in the gradient elution, mobile phase A
With Mobile phase B with volume percent, elution program are as follows:
0-15min, mobile phase A and Mobile phase B volume ratio are 100:0, carry out isocratic elution；
15-16min, mobile phase A and Mobile phase B volume ratio are 10:90 by linear gradient, carry out linear gradient elution；
16-30min, mobile phase A and Mobile phase B volume ratio are 10:90, carry out isocratic elution；
30-31min, mobile phase A and Mobile phase B volume ratio are 100:10 by linear gradient, carry out linear gradient elution；
31-40min, mobile phase A and Mobile phase B volume ratio are 100:0, carry out isocratic elution.
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| CN112129853A (en) * | 2020-09-07 | 2020-12-25 | 天地恒一制药股份有限公司 | Method for detecting nitrosamine impurities in candesartan cilexetil |
| 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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Cited By (3)
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| CN112129853A (en) * | 2020-09-07 | 2020-12-25 | 天地恒一制药股份有限公司 | Method for detecting nitrosamine impurities in candesartan cilexetil |
| CN113866300A (en) * | 2021-09-26 | 2021-12-31 | 山东建筑大学 | Method for detecting sodium azide in medicine or intermediate thereof |
| CN115372523A (en) * | 2021-09-26 | 2022-11-22 | 山东建筑大学 | Method for detecting sodium azide in medicine or intermediate thereof |
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Denomination of invention: A detection method for azide compounds in candesartan ester Granted publication date: 20220520 Pledgee: Bank of Changsha Limited by Share Ltd. Liuyang branch Pledgor: TIANDI HENGYI PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980011973 |