CN101685083A - Super fast liquid phase chromatography-tandem mass spectrometric method for determining hydroxypropyl-beta-cyclodextrin - Google Patents
Super fast liquid phase chromatography-tandem mass spectrometric method for determining hydroxypropyl-beta-cyclodextrin Download PDFInfo
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Abstract
The invention relates to a super fast liquid phase chromatography-tandem mass spectrometric method for determining hydroxypropyl-beta-cyclodextrin. The method comprises the following steps: (1) preparing hydroxypropyl-beta-cyclodextrin standard curve solution; (2) preparing hydroxypropyl-beta-cyclodextrin quality control solution; (3) treating a sample; and (4) performing liquid phase chromatography-tandem mass spectrometric analysis on the standard curve solution and the quality control solution respectively, and establishing a method for determining the hydroxypropyl-beta-cyclodextrin in thesample solution. The method has simple operation and good reproducibility, and can quantitatively analyze HP-beta-CD.
Description
Technical field
The present invention relates to the measuring method of mass spectrum in the analytical approach applied research field, relate in particular to a kind of supper-fast liquid chromatography-tandem mass spectrometry method (UFLC-MS/MS) that is used to measure HP-.
Background technology
HP-(Hydroxypropyl-beta-cyclodextrin; HP-β-CD) is a kind of hydroxyalkylation derivant of cycloheptaamylose, is one of more thorough β-CDYan Shengwu of relevant in recent years preparation method, toxicological test, range of application research.HP-β-CD not only can equally with β-CD have good envelope effect to chemical compound lot, can improve by the envelope Stability of Substance, and it also has water-soluble height and improves in vivo by the release rate of envelope medicine and bioavilability, therefore, HP-β-CD makes range of application wider because of some special good characteristics that it had, now in pharmaceutically widespread use.Since HP-β-CD water-soluble greater than 50%, good fluidity, hemolytic activity be low, non-stimulated to muscle, and can increase stability of drug, therefore many medicines prepare injection and obtain satisfied effect with HP-β-CD.
Though at present HP-β-CD is prepared the existing research of injection, concentrates on to its distribution research in vivo.This research is main by oral behind the radio-labeled
14Behind C-HP-β-CD, research is in tissue (mainly being liver and kidney)
14The C level because HP-β-CD sample is impure and do not have more effective method of quality control, is used
14When C-HP-β-CD studies the real internal metabolism of HP-β-CD is studied lack of evidence, simultaneously
14The C radio-labeled is harmful to the human research.
For controlling its quality and clinical application, be that the accumulative total eliminating amount in Study on pharmacokinetics and the urine is calculated simultaneously, mensuration HP-β-CD method of setting up science is very urgent, and method for quantitatively determining is set up and is had great significance accurately.Characteristic about HP-β-CD reaches many at the report of application facet at present, as the patent No. in the 1984-2009 Chinese patent database is ZL02116766.4 " organic drug and betadex derivative complex and preparation method thereof ", application number is 02149146.1 " anticarcinogen taxol self-emulsifying solid nano grain---the preparation method of injection taxol ", the patent No. be ZL03825141.8's " with the capsule that contains the water-based filled compositions of the cyclodextrin stabilization of deriving " etc., but it is carried out the chromatogram of quantitative examination, mass spectrometry method is learned and is not but seen bibliographical information.
Summary of the invention
The supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-that technical matters to be solved by this invention provides a kind of simple to operate, favorable reproducibility, can carry out quantitative test.
For addressing the above problem, a kind of supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-of the present invention may further comprise the steps:
(1) preparation of HP-typical curve solution: the HP-standard items are settled to 10 μ g/ml with moving phase, get standard solution, then this standard solution being diluted to concentration with moving phase successively is 50,100,250,500,1000,2000,2500ng/ml promptly gets typical curve solution;
(2) preparation of HP-quality control solution: it is 50,100,800 that 10 μ g/ml standard solution in the described step (1) are diluted to concentration successively with moving phase, and 2000ng/ml promptly gets quality control solution;
(3) sample preparation: wherein said sample is freeze-dried type docetaxel injecta or the urine that contains HP-;
(4) respectively typical curve solution, quality control solution are carried out the liquid chromatography-tandem mass spectrometry analysis, set up the method for HP-in the working sample solution.
Described moving phase is any one in methanol-water, methyl alcohol-ammonium acetate, acetonitrile-water, the acetonitrile-water-acetate.
The volume ratio of described methanol-water is 1: 1～9: 1; The volume ratio of methyl alcohol-ammonium acetate is 2: 1～4: 1; The volume ratio of acetonitrile-water is 4: 6～9: 1; The volume ratio of acetonitrile-water-acetate is 40: 59: 1～60: 39: 1; Wherein the concentration of ammonium acetate is 1～10mM.
The disposal route of the freeze-dried type docetaxel injecta that contains HP-in the described step (3) is meant that sample is settled to 100 μ g/ml with the moving phase dilution gets the sample storing solution, in the sample storing solution, add moving phase vortex mixing then, after centrifugal, get the method for supernatant as sample solution; Wherein the volume ratio of sample storing solution and moving phase is 1: 90～1: 110.
Urine process method in the described step (3) is meant 1: 1～1: 2 ethylenediamine tetraacetic acid adding sample volume in sample successively and 1: 50～1: 55 ammoniacal liquor, the vortex mixing gets mixed liquor, in mixed liquor, add moving phase then, after centrifugal, get the method for supernatant as sample solution; Wherein the volume ratio of mixed liquor and moving phase is 1: 6～1: 7.
It is that the flow velocity with 0.1～10ml/min detects in 20～40 ℃ the chromatographic column that stratographic analysis in the described step (4) is meant at column temperature.
Mass spectrophotometry in the described step (4) is meant by electro-spray ionization, adopts many reaction detection mode to carry out positive ion and detects; Wherein ion gun is ESI; The detection ion pair is m/z1215.7 → 1215.7, m/z1273.4 → 1273.4, m/z 1331.6 → 1331.6, m/z 1389.8 → 1389.8, m/z 1447.5 → 1447.5, m/z 1506.7 → 1506.7, m/z 1563.5 → 1563.5, m/z 1622.4 → 1622.4.
The present invention compared with prior art has the following advantages:
1, the present invention adopts supper-fast liquid chromatography (UFLC)-tandem mass spectrum (MS/MS) method to measure HP-β-CD, after its mass spectrum condition is carried out system optimization, and, investigated stability of the present invention by measuring the HP-β-CD content in the freeze-dried type injection docetaxel.
A, specificity: the present invention to blank solution (referring among Fig. 2 a), standard solution (referring to the b among Fig. 2) solution of 1 μ g/ml HP-β-CD analyzes, other composition does not disturb the mensuration of HP-β-CD in the sample as can be known.
B, matrix effect: with the freeze-dried type docetaxel is research object, adds HP-β-CD standard solution and be made into that to contain HP-β-CD be that the solution of 1 μ g/ml is investigated matrix effect to measuring the influence of HP-β-CD in the docetaxel standard solution.Adopt UFLC-MS/MS that institute's obtain solution is analyzed, get peak area A, retention time is 0.89min; Adopt UFLC-MS/MS that 1 μ g/ml HP-β-CD standard solution is analyzed, obtain corresponding peak area B, with the matrix effect of A/B investigation method, A/B ≈ 1, the result shows that this method do not have matrix effect (referring to Fig. 3).
C, typical curve and detection limit: be 50 to HP-β-CD concentration respectively, 100,250,500,1000,2000, the typical curve solution of 2500ng/ml carries out UFLC-MS/MS to be analyzed, and is horizontal ordinate with concentration, and peak area is that ordinate is handled, the result shows that linear dependence is good in 50～2500ng/mL scope, y=5.6x-158 (r
2=0.9991), weight is 1/x
2, the lowest detection line is 50ng/mL (referring to table 1).
Table 1: the accuracy of typical curve and precision
| Concentration (ng/ml) | Mean value ± standard deviation (n=6) | Accuracy (%) | Precision (%) |
| ??50 | ??50.15±0.43 | ??0.87 | ??100.30 |
| ??100 | ??99.93±0.62 | ??0.62 | ??99.94 |
| ??250 | ??251.00±2.71 | ??1.08 | ??100.00 |
| ??500 | ??487.33±6.07 | ??1.25 | ??97.53 |
| ??1000 | ??949.67±12.63 | ??1.33 | ??95.07 |
| ??2000 | ??2026.67±20.55 | ??1.01 | ??101.32 |
| ??2500 | ??2638.33±38.91 | ??1.47 | ??105.67 |
D, accuracy and precision: quality control sample (QC sample) is analyzed, and METHOD FOR CONTINUOUS DETERMINATION 3 days repeats 6 every day, asks and calculates accuracy of the present invention and precision, and data show that the present invention meets the analysis requirement.(referring to table 2)
Table 2: in a few days reach the day to day precision measurement result
E, recovery of standard addition: get 2 μ g/ml docetaxel standard solution, 950,900,800 μ L respectively, add 10 μ g/ml HP-β-CD standard solution 50,100,200 μ L successively, carry out mark-on behind the mixing and reclaim experiment, the recovery sees Table 3.
Table 3: recovery of standard addition result
| HP-β-CD standard solution (μ L) | Concentration (ng/ml) | The recovery (%) | Accuracy (%) |
| ??50 | ??500 | ??100.67 | ??0.87 |
| ??100 | ??1000 | ??108.50 | ??1.16 |
| ??200 | ??2000 | ??107.25 | ??2.95 |
F, stability: QC sample low, high concentration is analyzed, investigated 0h, place 6h in the sample cell, room temperature is placed 7h, 24h, 5d, 3 freezing repeatedly-room temperatures, and 4 ℃ of stability of preserving down under the 5d condition, the result shows that measured object is stable under these conditions.(referring to table 4)
Table 4: stable measurement result
2, since the present invention have specificity height, favorable reproducibility, highly sensitive, analysis speed is fast, characteristics such as simple to operate, therefore applicable to the metabolism research of HP-β-CD in the control of HP-β-CD quality in the preparation and the body, for HP-β-CD pharmacokinetic is laid a good foundation.
Description of drawings
Below in conjunction with accompanying drawing the specific embodiment of the present invention is described in further detail.
Fig. 1 is a full ion scan mass spectrogram of the present invention.
Fig. 2 is a specificity experiment chromatic graph spectrum of the present invention; Wherein a is a zero standard solution, and b is the standard solution of 1 μ g/mlHP-β-CD.
Fig. 3 is that matrix of the present invention suppresses experiment chromatic graph spectrum; Wherein A is 1 μ g/ml HP-β-CD standard solution, and B is the sample solution of 1 μ g/ml HP-β-CD.
Fig. 4 is mensuration HP-β of the present invention-CD standard items chromatic graph spectrum.
Fig. 5 is HP-β in mensuration docetaxel of the present invention (freeze-dried type) preparation-CD chromatic graph spectrum.
Fig. 6 is HP-β in the mensuration urine of the present invention-CD chromatic graph spectrum.
Embodiment
The supper-fast liquid chromatography of embodiment 1 usefulness (UFLC)-tandem mass spectrum (MS/MS) method is measured the content of HP-β-CD in the preparation, may further comprise the steps:
(1) preparation of HP-β-CD typical curve solution: precision takes by weighing the HP-β-CD standard items 0.0050g of NIHON SHOKUHIN company production in the 10ml volumetric flask, with volume ratio is 1: 1～9: 1 methanol-water moving phase constant volume, shake up 500 μ g/ml HP-β-CD standard solution as storing solution; Draw storing solution 200 μ l in another 10ml volumetric flask, the moving phase constant volume, shake up 10 μ g/ml HP-β-CD standard solution.
HP-β-CD standard solution of getting 500 μ L, 10 μ g/ml is put into vortex vortex mixer (Jin Cheng of Jintan City Educational Instrument Factory) eddy current mixing after adding moving phase 1500 μ L in the 3ml centrifuge tube, 2500ng/ml solution; Get 800 μ L, 2500ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 200 μ L, put into vortex vortex mixer eddy current mixing, get 2000ng/ml solution; Get 500 μ L, 2000ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 500 μ L, put into vortex vortex mixer eddy current mixing, get 1000ng/ml solution; Get 500 μ L, 1000ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 500 μ L, put into vortex vortex mixer eddy current mixing, get 500ng/ml solution; Get 500 μ L, 500ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 500 μ L, put into vortex vortex mixer eddy current mixing, get 250ng/ml solution; Get 400 μ L, 250ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 600 μ L, put into vortex vortex mixer eddy current mixing, get 100ng/ml solution; Get 500 μ L, 100ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 500 μ L, put into vortex vortex mixer eddy current mixing, get 50ng/ml solution.Above-mentioned 50,100,250,500,1000,2000 and 2500ng/ml solution be typical curve solution.
(2) preparation of HP-β-CD QC solution: HP-β-CD standard solution of getting 200 μ L, 10 μ g/ml behind the adding moving phase 800 μ L, is put into vortex vortex mixer eddy current mixing in the 1.5ml centrifuge tube, get 2000ng/ml solution; Get 400 μ L, 2000ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 600 μ L, put into vortex vortex mixer eddy current mixing, get 800ng/ml QC solution; Get 125 μ L, 800ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 875 μ L, put into vortex vortex mixer eddy current mixing, get 100ng/ml solution; Get 500 μ L, 100ng/ml solution in the 1.5ml centrifuge tube, behind the adding moving phase 500 μ L, put into vortex vortex mixer eddy current mixing, get 50ng/ml solution.Above-mentioned 50,100,800,2000ng/ml solution is QC solution.
(3) sample adopts freeze-dried type docetaxel injecta (Shandong Qilu Pharmaceutical Co., Ltd.), its disposal route is: precision takes by weighing freeze-dried type docetaxel 0.0010g in the 10ml volumetric flask, it with volume ratio 1: 1～9: 1 methanol-water moving phase dissolving, and be diluted to scale and be settled to 10ml, shake up 100 μ g/ml sample storing solutions; Accurate then absorption sample storing solution adds the moving phase mixing in the 5ml centrifuge tube, get 1 μ g/ml sample solution; After this 1 μ g/ml sample solution put into vortex vortex mixer mesoscale eddies mixing 1min, put into supercentrifuge (Anting Scientific Instrument Factory, Shanghai) with the centrifugal 5min of the speed of 5000r/min after, drawing supernatant with liquid-transfering gun, to put into the sample introduction bottle as sample solution standby.Wherein the volume ratio of sample storing solution and moving phase is 1: 90～1: 110.
(4) adopt supper-fast high performance liquid chromatograph (day island proper Tianjin)-triple quadrupole bar tandem mass spectrometer (American AB company) to carry out the liquid chromatography-tandem mass spectrometry analysis, obtain full scan ion figure (referring to Fig. 1) and chromatogram 4 to typical curve solution, quality control solution respectively.
Set up the method for HP-in the working sample solution, the chromatographiccondition of this method is as follows: chromatographic column: Shim-pack XR-ODS post (diameter 3.0mm, length 75mm) (day island proper Tianjin company), flow velocity: 0.1～10ml/min, column temperature: 25 ℃, sample size: 10 μ l, whole analysis process time spent 3min; The mass spectrophotometry condition is as follows: by electro-spray ionization, adopt many reaction detection mode to carry out the positive ion check and analysis, ion gun is ESI
+And ESI
-The detection ion pair is m/z1215.7 → 1215.7, m/z 1273.4 → 1273.4, m/z 1331.6 → 1331.6, m/z1389.8 → 1389.8, m/z1447.5 → 1447.5, m/z 1506.7 → 1506.7, m/z 1563.5 → 1563.5, m/z 1622.4 → 1622.4.Simultaneously relevant parameters DP, EP, TEM, CE etc. are optimized---DP:70; EP:5; CE:100; CXP:9; CUR:10, CAD:1, IS:5500; TEM:260; GS1:50; GS2:60.
HP-β-CD content in institute's working sample is 19.8mg/ml.
The content that the supper-fast liquid chromatographies of embodiment 2 usefulness (UFLC)-tandem mass spectrum (MS/MS) method is measured the HP-β-CD in the urine is 4.5mg/ml, and obtains chromatogram 6.
Wherein the preparation of HP-β-CD typical curve solution, HP-β-CD QC solution and liquid chromatography-tandem mass spectrometry analysis are all with embodiment 1.
Sample adopts urine, its disposal route is: with the accurate experimenter's urine of drawing of liquid-transfering gun, after adding 1: 1～1: 2 ethylenediamine tetraacetic acid (EDTA) of volume of urine, put into 1: 50～1: 55 the ammoniacal liquor that adds volume of urine behind the vortex vortex mixer mesoscale eddies mixing, the vortex mixing gets mixed liquor, in mixed liquor, add volume ratio then and be 1: 1～9: 1 methanol-water moving phase, vortex mixing 2min, put into again supercentrifuge with the centrifugal 5min of the speed of 5000r/min after, drawing supernatant with liquid-transfering gun, to put into the sample introduction bottle as sample solution standby.Wherein the volume ratio of mixed liquor and moving phase is 1: 6～1: 7.
Embodiment 3 is used to measure the supper-fast liquid chromatography-tandem mass spectrometry method of HP-β-CD, and wherein the preparation of HP-β-CD typical curve solution, HP-β-CD QC solution and liquid chromatography-tandem mass spectrometry analysis are all with embodiment 1.
The processing of sample is with embodiment 1 or embodiment 2.
Moving phase is that volume ratio is methyl alcohol-ammonium acetate of 2: 1～4: 1; Wherein the concentration of ammonium acetate is 1～10mM.
Embodiment 4 is used to measure the supper-fast liquid chromatography-tandem mass spectrometry method of HP-β-CD, and wherein the preparation of HP-β-CD typical curve solution, HP-β-CD QC solution and liquid chromatography-tandem mass spectrometry analysis are all with embodiment 1.
The processing of sample is with embodiment 1 or embodiment 2.
Moving phase is the acetonitrile-water of volume ratio 4: 6～9: 1.
Embodiment 5 is used to measure the supper-fast liquid chromatography-tandem mass spectrometry method of HP-β-CD, and wherein the preparation of HP-β-CD typical curve solution, HP-β-CD QC solution and liquid chromatography-tandem mass spectrometry analysis are all with embodiment 1.
The processing of sample is with embodiment 1 or embodiment 2.
Moving phase is the acetonitrile-water-acetate of volume ratio 40: 59: 1～60: 39: 1.
Methyl alcohol in the foregoing description, ammonium acetate, acetonitrile, acetate are the chromatographically pure that Merck KGaA company produces; The sterilized water for injection that hydromining is produced with Jingxi district, Xi'an company limited of Double-Crane Pharmaceutical Co., Ltd.
Claims (7)
1, a kind of supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-may further comprise the steps:
(1) preparation of HP-typical curve solution: the HP-standard items are settled to 10 μ g/ml with moving phase, get standard solution, then this standard solution being diluted to concentration with moving phase successively is 50,100,250,500,1000,2000,2500ng/ml promptly gets typical curve solution;
(2) preparation of HP-quality control solution: it is 50,100,800 that 10 μ g/ml standard solution in the described step (1) are diluted to concentration successively with moving phase, and 2000ng/ml promptly gets quality control solution;
(3) sample preparation: wherein said sample is freeze-dried type docetaxel injecta or the urine that contains HP-;
(4) respectively typical curve solution, quality control solution are carried out the liquid chromatography-tandem mass spectrometry analysis, set up the method for HP-in the working sample solution.
2, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 1, it is characterized in that: described moving phase is any one in methanol-water, methyl alcohol-ammonium acetate, acetonitrile-water, the acetonitrile-water-acetate.
3, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 2, it is characterized in that: the volume ratio of described methanol-water is 1: 1～9: 1; The volume ratio of methyl alcohol-ammonium acetate is 2: 1～4: 1; The volume ratio of acetonitrile-water is 4: 6～9: 1; The volume ratio of acetonitrile-water-acetate is 40: 59: 1～60: 39: 1; Wherein the concentration of ammonium acetate is 1～10mM.
4, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 1, it is characterized in that: the disposal route of the freeze-dried type docetaxel injecta that contains HP-in the described step (3) is meant that sample is settled to 100 μ g/ml with the moving phase dilution gets the sample storing solution, in the sample storing solution, add moving phase vortex mixing then, after centrifugal, get the method for supernatant as sample solution; Wherein the volume ratio of sample storing solution and moving phase is 1: 90～1: 110.
5, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 1, it is characterized in that: the urine process method in the described step (3) is meant 1: 1～1: 2 ethylenediamine tetraacetic acid adding sample volume in sample successively and 1: 50～1: 55 ammoniacal liquor, the vortex mixing gets mixed liquor, in mixed liquor, add moving phase then, after centrifugal, get the method for supernatant as sample solution; Wherein the volume ratio of mixed liquor and moving phase is 1: 6～1: 7.
6, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 1 is characterized in that: it is that the flow velocity with 0.1～10ml/min detects in 20～40 ℃ the chromatographic column that the stratographic analysis in the described step (4) is meant at column temperature.
7, the supper-fast liquid chromatography-tandem mass spectrometry method that is used to measure HP-as claimed in claim 1, it is characterized in that: the mass spectrophotometry in the described step (4) is meant by electro-spray ionization, adopts many reaction detection mode to carry out positive ion and detects; Wherein ion gun is ESI; The detection ion pair is m/z1215.7 → 1215.7, m/z 1273.4 → 1273.4, m/z 1331.6 → 1331.6, m/z 1389.8 → 1389.8, m/z 1447.5 → 1447.5, m/z 1506.7 → 1506.7, m/z 1563.5 → 1563.5, m/z1622.4 → 1622.4.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104458879A (en) * | 2014-09-26 | 2015-03-25 | 浙江工商大学 | Concentration detection device and method for beta-cyclodextrin solution |
| CN104459171A (en) * | 2014-09-26 | 2015-03-25 | 浙江工商大学 | Concentration detection device and method for beta-cyclodextrin solution |
| CN111089915A (en) * | 2019-11-15 | 2020-05-01 | 沈阳和合医学检验所有限公司 | Method for measuring concentration of docetaxel drug in human plasma |
| CN112834599A (en) * | 2020-07-21 | 2021-05-25 | 宁波大学 | Position isomerism analysis reagent and method for position isomerism aminobiphenyl molecules |
| WO2022017547A1 (en) * | 2020-07-21 | 2022-01-27 | 宁波大学 | Beta cyclodextrin-based, aminobenzene sulfonic acid positional isomer analysis reagent and method |
| CN114324659A (en) * | 2021-12-29 | 2022-04-12 | 江苏海悦康医药科技有限公司 | Method for detecting organic impurities in gamma cyclodextrin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| MX2007006432A (en) * | 2004-12-06 | 2007-07-19 | Biogen Idec Inc | Detection and quantitation of cyclodextrins. |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104458879A (en) * | 2014-09-26 | 2015-03-25 | 浙江工商大学 | Concentration detection device and method for beta-cyclodextrin solution |
| CN104459171A (en) * | 2014-09-26 | 2015-03-25 | 浙江工商大学 | Concentration detection device and method for beta-cyclodextrin solution |
| CN111089915A (en) * | 2019-11-15 | 2020-05-01 | 沈阳和合医学检验所有限公司 | Method for measuring concentration of docetaxel drug in human plasma |
| CN112834599A (en) * | 2020-07-21 | 2021-05-25 | 宁波大学 | Position isomerism analysis reagent and method for position isomerism aminobiphenyl molecules |
| WO2022017547A1 (en) * | 2020-07-21 | 2022-01-27 | 宁波大学 | Beta cyclodextrin-based, aminobenzene sulfonic acid positional isomer analysis reagent and method |
| CN112834599B (en) * | 2020-07-21 | 2024-04-05 | 宁波大学 | Position isomerism analysis reagent and method for position isomerism amino biphenyl molecule |
| CN114324659A (en) * | 2021-12-29 | 2022-04-12 | 江苏海悦康医药科技有限公司 | Method for detecting organic impurities in gamma cyclodextrin |
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