CN102703922B - Method for separating pantoprazole from tenatoprazole drug raceme - Google Patents
Method for separating pantoprazole from tenatoprazole drug raceme Download PDFInfo
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- CN102703922B CN102703922B CN201210157810.9A CN201210157810A CN102703922B CN 102703922 B CN102703922 B CN 102703922B CN 201210157810 A CN201210157810 A CN 201210157810A CN 102703922 B CN102703922 B CN 102703922B
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Abstract
The invention discloses a method for separating pantoprazole from tenatoprazole drug raceme, and relates to a method for separating pantoprazole drugs. The method takes Cu(II) and L-histidine as chiral selectors and takes disodium hydrogen phosphate as background electrolyte, adopts ligand exchange capillary electrophoresis to ensure that the Cu(II), the L-histidine and pantoprazole drug raceme form ternary complex, then ensures that enantiomer is separated through a capillary electrophoresis apparatus, and adopts the ligand exchange capillary electrophoresis to separate two pantoprazole drug racemes, and the adopted chiral selector comprises the Cu(II) and the L-histidine. The method has high separation efficiency, is simple to operate, and comprises three links of sample processing, instrument preparing and sample handling; the chiral selector is low in cost and easy to obtain, and the amount of sample and reagent is small; and the background electrolyte does not contain organic solvent, is low in cost, and causes little environmental pollution. The method can be applied to in vivo analysis and product optical purity detection of the pantoprazole drugs, and simultaneously provides technical support and guarantee for the research and development of the chiral drugs.
Description
Technical field
The present invention relates to a kind of method of separate drug, particularly relate to a kind of method being separated pantoprazole and Tai Tuola azoles medicine raceme.
Background technology
Pantoprazole and tenatoprazole are class anti-ulcer medicaments, are mainly used in treating the disease relevant to gastric acid secretion such as duodenal ulcer, stomach ulcer, reflux esophagitis.Be that molecular structure is similar by the known pantoprazole of Fig. 1, Fig. 2 and tenatoprazole, take sulphur atom as the chiral drug of chiral centre, there is R, S two enantiomers.Have stereoselective medicine for major part, raceme administration is equivalent to two kinds of medicines administration, in other words drug impurities present 50% simultaneously, and therefore, the research and development of anti-ulcer medicament single enantiomer become focus.Because two enantiomorphs have similar physico-chemical property, conventional method is difficult to be separated.That has reported this type of medicine chiral isolation analysis method at present has Chiral stationary phase liquid chromatography method and Mobile Phase Additives high performance liquid chromatography.Capillary electrophoresis (Capillalry Electrophoresis, CE) is the efficient compartment analysis new technology grown up the eighties in 20th century.It is motivating force with high-voltage electric field, take kapillary as split tunnel, according to the concentration between each component with distribute behavior difference and realize being separated.It is with efficient, quick, easy to be famous, and clastotype is many, sample and reagent consumption is few, environmental pollution is little, cost is low, kind and the concentration of selective agent can be changed when the most important thing is optimized Separation flexibly, be therefore more and more widely used in chiral separation.
Chiral ligand exchange chromatograph method (chiral ligand-exchange chromatography, CLEC), namely in chromatographic system, introduce certain metal ion species and certain chiral ligand, can form two diastereomeric ternary complexes with enantiomorph to be measured, the stereoselectivity realizing optical isomer through chromatographic process is separated.The method neither needs chiral stationary phase also not need pre-column derivatization, and in moving phase, addition is minimum, and chiral selector wide variety, institute in this way convenient, fast, cost is low.At present, chiral ligand exchange capillary electrophoresis is not adopted to be separated the report of this type of chipal compounds both at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of method being separated pantoprazole and Tai Tuola azoles medicine raceme, the method adopts CLEC, with Cu (II), L-Histidine is chiral selector, compartment analysis two anti-ulcer medicament racemies, for In vivo analysis and the optical purity of products detection of this type of antiulcer agent chiral drug, the research and development for this type of chiral drug provide technical support and guarantee.
The object of the invention is to be achieved through the following technical solutions:
A kind of method being separated pantoprazole and Tai Tuola azoles medicine raceme, the method is with Cu(II) and L-Histidine make chiral selector, Sodium phosphate dibasic is background electrolyte, use ligand exchange capillary electrophoresis, make Cu(II), L-Histidine and draw azoles medicine formed ternary complex, then raceme is made to realize being separated by capillary electrophoresis apparatus, it uses ligand exchange capillary electrophoresis to be separated two and draws azole drug raceme, and chiral selector used is Cu(II) and L-Histidine;
Its concrete separating step is as follows:
A. the configuration of sample and running buffer: the configuration of sample stock solution, precision takes pantoprazole and tenatoprazole sample powder 10 mg respectively, puts in the brown volumetric flask of 10 mL, scale is settled to dissolve with methanol, shake up, obtain the storing solution that each sample concentration is 1 mg/mL ,-20
oc Refrigerator store; The preparation of sample test solution, precision measures in the brown volumetric flask of each sample storing solution 1 mL respectively to 10 mL, with methanol constant volume to scale, shakes up, and obtains 100 μ g/mL test liquids, 4
oc Refrigerator store; The preparation of running buffer 1, take SODIUM PHOSPHATE, MONOBASIC, neutralized verdigris and L-Histidine 0.0195 g successively, 0.040 g, 0.0620 g be placed in 50 mL beakers, add 25 mL second distillation water dissolution, pH 5.0 is adjusted to 0.1 mol/L sodium hydroxide solution and 10% phosphoric acid, obtain running buffer, for subsequent use after 0.45 μm of filtering with microporous membrane; The preparation of running buffer 2, take SODIUM PHOSPHATE, MONOBASIC, neutralized verdigris and L-Histidine 0.0195 g successively, 0.060 g, 0.0932 g be placed in 50 mL beakers, add 25 mL second distillation water dissolution, pH 5.0 is adjusted to 0.1 mol/L sodium hydroxide solution and 10% phosphoric acid, obtain running buffer, for subsequent use after 0.45 μm of filtering with microporous membrane.
B. instrument prepares: sepn process is carried out in quartz capillary, choose the kapillary of internal diameter 50 μm, intercept segment length 53 cm, detection window is being obtained apart from the polyimide layer of port 8 cm place removing kapillary, new kapillary needs to rinse and activation before use, during continuous analysis, successively with 0.1 mol/LNaOH, redistilled water and running buffer respectively rinse 10 min successively before each analysis;
C. separation condition is set: pantoprazole: separation voltage 10 kV, determined wavelength 290 nm; Tenatoprazole: separation voltage 10 kV, determined wavelength 306 nm;
D. sample introduction: sample introduction height 10 cm, sample injection time 10 s, positive pole sample introduction negative pole detects, and rushes post 5 min, then carry out sample introduction next time between sample introduction with running buffer.
A kind of described method being separated pantoprazole and Tai Tuola azoles medicine raceme, the sample operation of drawing azole drug raceme is separated: running buffer and sample are all through 0.45 μm of filtering with microporous membrane described in it, and ultrasonic degas, sample dissolve with methanol, 4 DEG C of Refrigerator stores are for subsequent use.
A kind of described method being separated pantoprazole and Tai Tuola azoles medicine raceme, the electrophoretic separation condition pantoprazole raceme drawing azole drug raceme is separated: running buffer: 5 mmol/L SODIUM PHOSPHATE, MONOBASIC, containing 18 mmol/L L-Histidines, 6 mmol/L neutralized verdigriss, are adjusted to pH 5.0 described in it; Separation voltage: 10 kV; Ultraviolet detection wavelength: 290 nm; Electrophoretic separation condition tenatoprazole raceme: running buffer 5 mmol/L SODIUM PHOSPHATE, MONOBASIC, containing 24 mmol/L L-Histidines, 12 mmol/L neutralized verdigriss, is adjusted to pH 5.0; Separation voltage: 15 kV; Ultraviolet detection wavelength: 306 nm.
A kind of described method being separated pantoprazole and Tai Tuola azoles medicine raceme, is separated described in it and draws the ligating atom selected by azole drug raceme to be Cu(II), chiral ligand is L-Histidine, and their coordination ratio are 1:2.
A kind of described method being separated pantoprazole and Tai Tuola azoles medicine raceme, is separated described in it and draws the instrument of azole drug raceme to prepare: kapillary overall length 53 cm, useful length 45 cm, internal diameter: 50 mm; New kapillary needs to rinse and activation before use, when analyzing continuously, respectively rinses 10 min successively before each analysis with 0.1mol/LNaOH, redistilled water and running buffer; Rush post 5 min with running buffer between sample introduction, then carry out sample introduction next time.
Advantage of the present invention and effect are:
1. the present invention adopts CLEC separation efficiency high, simple to operate, and back-ground electolyte is not containing organic solvent, and chiral selector kind and concentration flexibly changing, analysis cost are low, environmentally friendly, and chiral selector consumption is few and cheap and easy to get.
2. the invention provides the ligand exchange capillary electrophoresis that azole drug is drawn in separation two, with Cu(II) and L-Histidine make chiral selector, under suitable pH condition, make Cu(II), L-Histidine respectively and draw left-handed, the dextrorotation of azoles medicine to form ternary complex, then realize medicine raceme by capillary electrophoresis apparatus to be separated, can be used for this type of In vivo analysis drawing azoles medicine and optical purity of products to detect, simultaneously also for researching and developing this similar drug and single enantiomer administration provides technical support and guarantee.
Accompanying drawing explanation
Fig. 1 is pantoprazole structural formula;
Fig. 2 is Tai Tuola azoles structural formula
;
Fig. 3 is that CLEC of the present invention is separated pantoprazole raceme color atlas;
Fig. 4 is that CLEC of the present invention is separated tenatoprazole raceme color atlas.
Embodiment
The present invention is described in detail with reference to the accompanying drawings.
Fig. 3 is that CLEC is separated pantoprazole raceme color atlas, and two enantiomorph analysis times, resolution was greater than 1.5 in 25 min.
Fig. 4 is that CLEC is separated tenatoprazole raceme color atlas, and two enantiomorph analysis times, resolution was greater than 1.5 in 25 min.
Embodiment one:
1. precision takes pantoprazole raceme 10 mg, put in the brown volumetric flask of 10 mL, is settled to scale, shakes up with dissolve with methanol.Obtain the storing solution that sample concentration is 1 mg/mL ,-20
oc Refrigerator store.Precision measures in the brown volumetric flask of stock sample solution 1 mL respectively to 10 mL, with methanol constant volume to scale, shakes up, and obtains 100 μ g/mL test liquids, for subsequent use after 0.45 μm of filtering with microporous membrane.
2. prepare 5 mmol/LNaH
2pO
4make background electrolyte containing 8 mmol/L neutralized verdigriss and 16 mmol/LL-Histidines, use H
3pO
4be adjusted to pH 5.0 with NaOH, through 0.45 μm of filtering with microporous membrane, and ultrasonic degas is for subsequent use.Capillary column walks baseline after respectively rinsing 10 min with 0.1 mol/LNaOH, redistilled water and above-mentioned running buffer successively, after baseline is steady, (about 2 min) adopt siphon sample introduction, sample introduction height 10 cm, sample injection time 10 s, positive pole sample introduction negative pole detects, record electrophorogram.Respectively rush post 5 min with redistilled water and running buffer successively between sample introduction, walk baseline 2 about min, then enter next sample.Separation voltage: 10 kV, ultraviolet detection wavelength: 290 nm.Separation electrophoresis figure is as Fig. 3, and pantoprazole raceme reaches baseline separation, and resolution is greater than 1.5.
Embodiment two:
1. precision takes tenatoprazole raceme 10 mg, in the brown volumetric flask of 10 mL, is settled to scale, shakes up with dissolve with methanol.Obtain the storing solution that sample concentration is 1 mg/mL ,-20
oc Refrigerator store.Precision measures in the brown volumetric flask of stock sample solution 1 mL to 10 mL, with methanol constant volume to scale, shakes up, and obtains 100 μ g/mL test liquids, for subsequent use after 0.45 μm of filtering with microporous membrane.
2. prepare 5 mmol/LNaH
2pO
4make running buffer containing 12 mmol/L neutralized verdigriss and 24 mmol/LL-Histidines, use H
3pO
4be adjusted to pH 5.0 with NaOH, through 0.45 μm of filtering with microporous membrane, and ultrasonic degas is for subsequent use.Capillary column walks baseline after respectively rinsing 10 min with 0.1 mol/LNaOH, redistilled water and above-mentioned running buffer successively, after baseline is steady, (about 2 min) adopt siphon sample introduction, sample introduction height 10 cm, sample injection time 10 s, positive pole sample introduction negative pole detects, record electrophorogram.Respectively rush post 5 min with redistilled water and running buffer successively between sample introduction, walk baseline 2 about min, then enter next sample.Separation voltage: 15 kV, ultraviolet detection wavelength: 306 nm.Separation electrophoresis figure is as Fig. 4, and tenatoprazole raceme reaches baseline separation, and resolution is for 1.5.
Claims (2)
1. one kind is separated the method for pantoprazole medicine raceme, it is characterized in that, the method is with Cu(II) and L-Histidine make chiral selector, SODIUM PHOSPHATE, MONOBASIC is background electrolyte, use ligand exchange capillary electrophoresis, make Cu(II), L-Histidine and draw azoles medicine raceme formed ternary complex, then raceme is made to realize being separated by capillary electrophoresis apparatus, it uses ligand exchange capillary electrophoresis to be separated pantoprazole medicine raceme, and chiral selector used is Cu(II) and L-Histidine;
Its concrete separating step is as follows:
1) precision takes pantoprazole raceme 10 mg, put in the brown volumetric flask of 10 mL, is settled to scale, shakes up, obtain the storing solution that sample concentration is 1 mg/mL ,-20 DEG C of Refrigerator stores with dissolve with methanol; Precision measures in the brown volumetric flask of stock sample solution 1 mL respectively to 10 mL, with methanol constant volume to scale, shakes up, and obtains 100 μ g/mL test liquids, for subsequent use after 0.45 μm of filtering with microporous membrane;
2) 5 mmol/L NaH are prepared
2pO
4make background electrolyte containing 8 mmol/L neutralized verdigriss and 16 mmol/L L-Histidines, use H
3pO
4be adjusted to pH 5.0 with NaOH, through 0.45 μm of filtering with microporous membrane, and ultrasonic degas is for subsequent use; Capillary column walks baseline after respectively rinsing 10 min with 0.1 mol/LNaOH, redistilled water and above-mentioned running buffer successively, after baseline is steady, adopt siphon sample introduction, sample introduction height 10 cm, sample injection time 10s, and positive pole sample introduction negative pole detects, record electrophorogram; Respectively rush post 5 min with redistilled water and running buffer successively between sample introduction, walk baseline 2 min, then enter next sample; Separation voltage: 10 kV, ultraviolet detection wavelength: 290 nm.
2. one kind is separated the method for tenatoprazole medicine raceme, it is characterized in that, the method is with Cu(II) and L-Histidine make chiral selector, SODIUM PHOSPHATE, MONOBASIC is background electrolyte, use ligand exchange capillary electrophoresis, make Cu(II), L-Histidine and draw azoles medicine raceme formed ternary complex, then raceme is made to realize being separated by capillary electrophoresis apparatus, it uses ligand exchange capillary electrophoresis to be separated tenatoprazole medicine raceme, and chiral selector used is Cu(II) and L-Histidine;
Its concrete separating step is as follows:
1) precision takes tenatoprazole raceme 10 mg, in the brown volumetric flask of 10 mL, is settled to scale, shakes up, obtain the storing solution that sample concentration is 1 mg/mL ,-20 DEG C of Refrigerator stores with dissolve with methanol; Precision measures in the brown volumetric flask of stock sample solution 1 mL to 10 mL, with methanol constant volume to scale, shakes up, and obtains 100 μ g/mL test liquids, for subsequent use after 0.45 μm of filtering with microporous membrane;
2) 5 mmol/LNaH are prepared
2pO
4make running buffer containing 12 mmol/L neutralized verdigriss and 24 mmol/LL-Histidines, use H
3pO
4be adjusted to pH 5.0 with NaOH, through 0.45 μm of filtering with microporous membrane, and ultrasonic degas is for subsequent use; Capillary column walks baseline after respectively rinsing 10 min with 0.1 mol/LNaOH, redistilled water and above-mentioned running buffer successively, after baseline is steady, adopt siphon sample introduction, sample introduction height 10 cm, sample injection time 10s, and positive pole sample introduction negative pole detects, record electrophorogram; Respectively rush post 5 min with redistilled water and running buffer successively between sample introduction, walk baseline 2 min, then enter next sample; Separation voltage: 15 kV, ultraviolet detection wavelength: 306 nm.
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| CN103063756B (en) * | 2012-11-29 | 2014-07-30 | 沈阳化工大学 | Method for separating antiulcer medicament by double-chiral selector capillary electrophoresis method |
| CN110508135B (en) * | 2019-07-16 | 2021-12-21 | 沈阳化工大学 | Capillary electrochromatography method for separating pantoprazole racemate |
| CN114486444B (en) * | 2022-02-07 | 2024-02-20 | 洛阳师范学院 | Capillary electrophoresis separation method of atenolol non-racemate mixture |
| CN115518415A (en) * | 2022-10-08 | 2022-12-27 | 沈阳化工大学 | Capillary electrochromatography method for separating pantoprazole racemate |
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