CN102798678B - Detection method and content determining method of sodium calcium edetate in pantoprazole sodium for injecting - Google Patents
Detection method and content determining method of sodium calcium edetate in pantoprazole sodium for injecting Download PDFInfo
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- CN102798678B CN102798678B CN201210319454.6A CN201210319454A CN102798678B CN 102798678 B CN102798678 B CN 102798678B CN 201210319454 A CN201210319454 A CN 201210319454A CN 102798678 B CN102798678 B CN 102798678B
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- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 title claims abstract description 89
- 238000001514 detection method Methods 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 42
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 38
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 229950004777 sodium calcium edetate Drugs 0.000 title abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 56
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 18
- 150000002500 ions Chemical class 0.000 claims abstract description 17
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 10
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 78
- 238000012360 testing method Methods 0.000 claims description 60
- 238000002360 preparation method Methods 0.000 claims description 35
- 238000002347 injection Methods 0.000 claims description 34
- 239000007924 injection Substances 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 26
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 26
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 26
- 239000013558 reference substance Substances 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 17
- 238000013016 damping Methods 0.000 claims description 16
- 239000012530 fluid Substances 0.000 claims description 14
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 13
- 238000005374 membrane filtration Methods 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- 238000002474 experimental method Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000012545 processing Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 230000014759 maintenance of location Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 2
- 230000005526 G1 to G0 transition Effects 0.000 abstract 1
- 238000004458 analytical method Methods 0.000 abstract 1
- 239000007853 buffer solution Substances 0.000 abstract 1
- 239000000741 silica gel Substances 0.000 abstract 1
- 229910002027 silica gel Inorganic materials 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 36
- 239000002904 solvent Substances 0.000 description 20
- 239000000523 sample Substances 0.000 description 18
- 238000003556 assay Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- RXPAJWPEYBDXOG-UHFFFAOYSA-N hydron;methyl 4-methoxypyridine-2-carboxylate;chloride Chemical compound Cl.COC(=O)C1=CC(OC)=CC=N1 RXPAJWPEYBDXOG-UHFFFAOYSA-N 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 2
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- ORZHVTYKPFFVMG-UHFFFAOYSA-N xylenol orange Chemical compound OC(=O)CN(CC(O)=O)CC1=C(O)C(C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=C(C)C=2)=C1 ORZHVTYKPFFVMG-UHFFFAOYSA-N 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 1
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- LUOPVTAMVNYAQA-UHFFFAOYSA-N O.O.O.O.O.O.[Na].[Na].[Ca].C(CN(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O Chemical compound O.O.O.O.O.O.[Na].[Na].[Ca].C(CN(CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O LUOPVTAMVNYAQA-UHFFFAOYSA-N 0.000 description 1
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical class [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940087511 calcium disodium versenate Drugs 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000001455 metallic ions Chemical class 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
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- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention belongs to the field of medicament analysis and particularly relates to a detection method and a content determining method for sodium calcium edetate as an accessory in pantoprazole sodium for injecting. The invention aims at solving the technical problem of providing a method with the advantages of simpleness in and convenience for operation, quickness and accuracy for detecting the sodium calcium edetate as the accessory in the pantoprazole sodium for injecting. HPLC (High Performance Liquid Chromatography) detection conditions are as follows: a stationary phase: octadecylsilane bonded silica gel is used as a filling agent; a mobile phase: in terms of volume, an ion pair buffer solution is 85-95 percent, acetonitrile is 5-15 percent and the pH value is adjusted to 2.2-2.6 with phosphoric acid; the flowing speed is 0.8-1.2 ml/min; the column temperature is 30-40DEG C; the detection wavelength is 250-260 nm; and the theoretical plate number is required not to be lower than 2000 calculated in terms of a sodium calcium edetate peak. The detection method has the advantages of simple and convenient operation, accurate and reliable determination result, stronger specificity and shorter detection time; and the retention time of a main peak is about 6 minutes.
Description
Technical field
The invention belongs to Pharmaceutical Analysis field, be specifically related to detection method and the content assaying method of auxiliary material mosatil in injection Pantoprazole Sodium.
Background technology
Injection Pantoprazole Sodium is mainly used in the acute hemorrhage of upper gastrointestinal tract due to duodenal ulcer, gastric ulcer, AGML, compositeness gastric ulcer etc., the affinity of this product and liver cytochrome P 450 is lower, and have the approach of II phase metabolism, thereby interact few compared with Omeprazole and Lansoprazole with the other drug by cytochrome P 450 Enzyme metabolism.In addition, Pantoprazole Sodium is subject to the catalyzing hydrolysis of metallic ion, affects the stability in product preparation and instillation process, therefore needs to add complexing of metal ion agent, all adds natrium adetate in commercially available sample.But natrium adetate can become soluble complex compound with calcium binding, cause the minimizing of calcium, in intravenous formulations, use natrium adetate can cause blood calcium to decline.And mosatil does not conform to chelating calcium ion, can not produce low calcium phenomenon, therefore, consider to select mosatil to replace natrium adetate.In order to control better product quality, the method for measuring Ca-EDTA sodium content in injection Pantoprazole Sodium has been drafted in invention.
Mosatil quality standard is recorded in two 469 pages of Chinese Pharmacopoeia versions in 2010, and chemical name is: the hexahydrate of Calcium Disodium Versenate, molecular formula: C
10h
12caN
2na
2o
86H
2o, molecular weight: 482.38, structural formula is as follows:
The method that mosatil quality standard has been recorded its assay is: get the about 50mg of injection Pantoprazole Sodium, accurately weighed, put in conical flask, the 100ml that adds water makes to dissolve, add 3 of xylenol orange indicator solutions, be titrated to solution with bismuth nitrate vs (0.01mol/L) and become redness from yellow.Every 1ml bismuth nitrate vs (0.01mol/L) is equivalent to the C of 3.743mg
10h
12caN
2na
2o
8.While adopting above-mentioned titration method to measure the content of complying with ground this calcium sodium in injection Pantoprazole Sodium, main composition Pantoprazole Sodium has interference to measurement result, and this law specificity is not strong.
In order more fast, accurately to detect the impurity in parenteral solution, inventor provides the assay of a kind of new detection method for injection Pantoprazole Sodium auxiliary material mosatil, the object of easy to realize, quick, precisely control product quality.
Summary of the invention
Technical matters solved by the invention is to provide a kind of easy and simple to handle, and rapid, accurate detection method, for detection of the auxiliary material mosatil in injection Pantoprazole Sodium.Mosatil of the present invention is ethylene dinitrilotetra-acetic acid calcium disodium hexahydrate, and molecular formula is C
10h
12caN
2na
2o
86H
2o.
The detection method of mosatil of the present invention adopts liquid chromatographic detection, and HPLC testing conditions is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: volume ratio is: ion pair damping fluid 85%-95%: acetonitrile 5%-15%, with phosphoric acid tune pH to 2.2～2.6;
Wherein ion pair damping fluid compound method is: take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration;
Preferred: ion pair damping fluid (take ammonium dihydrogen phosphate (ADP) 2.3g, be dissolved in water to 2000ml, add 16ml TBAH, with 0.45 μ m membrane filtration): acetonitrile volume ratio is 90%:10%, with phosphoric acid tune pH to 2.42;
Flow velocity: 0.8-1.2ml/min; Preferably 1.0ml/min;
Column temperature: 30-40 ℃; Preferably 35 ℃;
Detect wavelength: 250-260nm; Preferably 257nm;
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak.
The processing of experiment material:
(1) preparation of need testing solution: get injection Pantoprazole Sodium, solubilizer (water that pH value is 2.2～2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and mix with the liquor ferri trichloridi (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation) of same volume, place, as need testing solution;
(2) preparation of reference substance solution:
Take mosatil reference substance solution, solubilizer (water that pH value is 2.2～2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and mix with the liquor ferri trichloridi (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation) of same volume, place product solution in contrast.
Wherein, 0.01%～0.02% liquor ferri trichloridi used should fresh preparation before mensuration.
Before detection, according to HPLC testing conditions, precision measures contrast solution 20 μ l injection liquid chromatographies, regulates detection sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale.
The advantage of this detection method is: easy and simple to handle; Measurement result accurately and reliably; Specificity is stronger; Main peak retention time is about 6 minutes, and detection time is shorter.
On the basis of above-mentioned detection method, the present invention also provides a kind of content assaying method, can be quick, easy, determine accurately the content of auxiliary material mosatil in injection Pantoprazole Sodium, realize the object of controlling injection Pantoprazole Sodium quality.
(1) preparation of need testing solution: get injection Pantoprazole Sodium, solubilizer (water that pH value is 2.2～2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and mix with the liquor ferri trichloridi (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation) of same volume, place, as need testing solution;
(2) preparation of reference substance solution:
Take mosatil reference substance solution, solubilizer (water that pH value is 2.2～2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and with the liquor ferri trichloridi of same volume (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation, fresh preparation before each test) mix, place product solution in contrast.
The HPLC testing conditions of mosatil content assaying method is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: ion pair damping fluid (take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration): acetonitrile volume ratio is 85%-95%:5%-15%, with phosphoric acid tune pH to 2.2～2.6;
Preferred: ion pair damping fluid (take ammonium dihydrogen phosphate (ADP) 2.3g, be dissolved in water to 2000ml, add 16ml TBAH, with 0.45 μ m membrane filtration): acetonitrile volume ratio is 90%:10%, with phosphoric acid tune pH to 2.42;
Flow velocity: 0.8-1.2ml/min; Preferably 1.0ml/min;
Column temperature: 30-40 ℃; Preferably 35 ℃;
Detect wavelength: 250-260nm; Preferably 257nm;
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak.
Adopt content assaying method of the present invention can be quick, easy, determine accurately the content of auxiliary material mosatil in injection Pantoprazole Sodium, realize the object of controlling injection Pantoprazole Sodium quality.
Accompanying drawing explanation
The linear graph of Fig. 1 mosatil.
Embodiment
Illustrate but do not limit the present invention by specific description of embodiments of the present invention below.
At present, the correlation technique that detects auxiliary material mosatil in injection Pantoprazole Sodium has the Pharmacopoeia of the People's Republic of China (hereinafter to be referred as " Chinese Pharmacopoeia ") to adopt the method for titration measuring Ca-EDTA sodium content, and condition determination provides as follows:
Get the about 50mg of injection Pantoprazole Sodium, accurately weighed, put in conical flask, the 100ml that adds water makes to dissolve, and adds 3 of xylenol orange indicator solutions, is titrated to solution becomes redness from yellow with bismuth nitrate vs (0.01mol/L).Every 1ml bismuth nitrate vs (0.01mol/L) is equivalent to the C of 3.743mg
10h
12caN
2na
2o
8.But the method exists major component Pantoprazole Sodium to have interference to measurement result, the defect that specificity is not strong.
The detection method of mosatil of the present invention adopts liquid chromatographic detection, and HPLC testing conditions is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent; Mobile phase: ion pair damping fluid (take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration): acetonitrile volume ratio is 85%-95%:5%-15%, with phosphoric acid tune pH to 2.2～2.6; Flow velocity: 0.8-1.2ml/min; Column temperature: 30-40 ℃; Detect wavelength: 250nm-260nm; Number of theoretical plate: calculate and should be not less than 2000 by mosatil peak;
The processing of experiment material:
(1) preparation of need testing solution: get this product, solubilizer (water that pH value is 2.2-2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and with the liquor ferri trichloridi of same volume (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation, fresh preparation before each test) mix, place, as need testing solution;
(2) preparation of reference substance solution:
Take mosatil reference substance solution, solubilizer (water that pH value is 2.2-2.6) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and with the liquor ferri trichloridi of same volume (with 0.01%～0.02% liquor ferri trichloridi of solvent preparation, fresh preparation before each test) mix, place product solution in contrast.
Before detection, according to HPLC testing conditions, precision measures contrast solution 20 μ l injection liquid chromatographies, regulates detection sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale.
The advantage of this detection method is: easy and simple to handle, rapidly, accurately.
The preparation of the chromatographic condition in the content assaying method of mosatil and need testing solution, reference substance solution also can be with reference to detection method condition and the preparation method of mosatil.
One, be below the testing conditions screening experiment of injection Pantoprazole Sodium method for detecting impurities of the present invention and content assaying method.
1, determine and detect wavelength
In two mosatil quality standards of " Chinese Pharmacopoeia " version in 2010, adopt with its content of volumetric determination, in research process, find that major component Pantoprazole Sodium has interference to the mensuration of mosatil, in order effectively to control the content of mosatil, maximum absorption wavelength to mosatil is studied, and needs to determine more suitable detection wavelength.
Determine the detection wavelength of detection method of the present invention:
It is appropriate that precision takes mosatil, solubilizer (water that pH value is 2.42) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and (taking 0.012g ferric trichloride, to be dissolved in pH value be in 2.42 water with the liquor ferri trichloridi of same volume, and be settled to 100ml, fresh preparation before each test) mix, place product solution in contrast.
Get above-mentioned reference substance solution and scan within the scope of 200-400nm, its result is as follows:
| No. | Spike long (nm) | Peak value | Paddy wavelength | Valley |
| 1 | 398.00 | 0.7717 | 282.00 | 0.3203 |
| 2 | 255.00 | 2.4198 | 233.00 | 1.3795 |
| 3 | 223.00 | 1.7265 | 202.00 | 0.1675 |
Result: mosatil has absorption maximum at 255 ± 2nm place, the detection wavelength of finally selecting mosatil is 257nm.
2, determine mobile phase
2.1 chromatographic condition
Mobile phase: set different mobile phase conditions, investigate the impact of mobile phase on detection method; Fixing phase: take octadecylsilane chemically bonded silica as filling agent; Detect wavelength: mosatil detects wavelength 257nm; Flow velocity: 1.0ml/min; Column temperature: 35 ℃; Number of theoretical plate calculates and should be not less than 2000 by mosatil peak.
The preparation of design sample:
(1) preparation of need testing solution: get this product, solubilizer (water that pH value is 2.42) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and with the liquor ferri trichloridi of same volume (with 0.012% liquor ferri trichloridi of solvent preparation, fresh preparation before each test) mix, place, as need testing solution;
(2) preparation of reference substance solution:
Take mosatil reference substance solution, solubilizer (water that pH value is 2.42) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and with the liquor ferri trichloridi of same volume (with 0.012% liquor ferri trichloridi of solvent preparation, fresh preparation before each test) mix, place product solution in contrast.
2.2 screen mobile phase condition on the basis of 2.1 chromatographic conditions.Mobile phase screening group is in table 1, and testing result is in table 2.
Table 1 mobile phase screening Groups List
In table 1:
In mobile phase 1-3, adopt phosphorus acid for adjusting pH value to 2.60.
In mobile phase 4-6: adopt phosphorus acid for adjusting pH value to 2.20.
In mobile phase 7-9: adopt phosphorus acid for adjusting pH value to 2.42.
In mobile phase 10-12: adopt phosphorus acid for adjusting pH value to 2.42.
Table 2 mobile phase screening group testing result
| Mobile phase | Retention time | Main peak degree of separation | Main peak tailing factor | Content (%) |
| 1 | 11.342min | 6.282 | 1.085 | 108.2% |
| 2 | 6.521min | 3.891 | 1.082 | 99.8% |
| 3 | 4.208min | 1.584 | 1.024 | 89.7% |
| 4 | 35.212min | 9.122 | 1.455 | 110.7% |
| 5 | 20.341min | 8.889 | 1.356 | 105.3% |
| 6 | 14.112min | 6.521 | 1.117 | 98.2% |
| 7 | 11.215min | 9.124 | 1.069 | 105.3% |
| 8 | 6.518min | 4.226 | 1.028 | 100.2% |
| 9 | 4.876min | 1.598 | 1.011 | 91.3% |
| 10 | 34.875min | 10.022 | 1.487 | 107.2% |
| 11 | 19.835min | 7.771 | 1.365 | 102.7% |
| 12 | 13.928min | 7.255 | 1.168 | 96.2% |
Table 2 result shows: according to the situation of content, retention time, main peak degree of separation, tailing factor, and to mosatil, inspection has a certain impact in conjunction with the pH of mobile phase; But impact is little within the scope of 2.3-2.5, organic phase adopts retention time and the experimental result impact on major component of methyl alcohol and acetonitrile very large, as seen from the above table, be 2.42 when selecting pH, ion pair damping fluid: when acetonitrile=90:10, main peak tailing factor value the best, symmetry is best, and retention time is the most suitable.
Table 3 mobile phase screening Groups List
Table 3 mobile phase 1-6, with phosphorus acid for adjusting pH to 2.42.
Table 4 mobile phase screening group testing result
| Mobile phase | Retention time | Main peak degree of separation | Main peak tailing factor | Content (%) |
| 1 | 6.752min | 4.280 | 1.052 | 108.2% |
| 2 | 6.581min | 3.892 | 1.042 | 99.8% |
| 3 | 6.668min | 3.987 | 1.038 | 89.7% |
| 4 | 6.498min | 4.228 | 1.058 | 110.7% |
| 5 | 6.553min | 3.992 | 1.038 | 105.3% |
| 6 | 6.662min | 5.012 | 1.027 | 98.2% |
The result of table 4 shows, changes the consumption of ammonium dihydrogen phosphate (ADP) in mobile phase, changes the addition of ion-pairing agent TBAH simultaneously, and main peak retention time, degree of separation, tailing factor are all comparatively suitable.Therefore finally select to take ammonium dihydrogen phosphate (ADP) 2.30g, be dissolved in water to 2000ml, get 1800ml and add 16ml TBAH, with adding acetonitrile 200ml after 0.45 μ m membrane filtration, adjust pH to 2.42 system as mobile phase with phosphoric acid.
3, determine flow velocity and column temperature
3.1 chromatographic condition
Mobile phase: take ammonium dihydrogen phosphate (ADP) 2.30g, be dissolved in water to 2000ml, get 1800ml and add 16ml TBAH, with adding acetonitrile 200ml after 0.45 μ m membrane filtration, with phosphoric acid tune pH to 2.42.
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Detect wavelength: 257nm;
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak.
3.2 investigate column temperature and flow velocity
Investigate column temperature at 30-40 ℃, flow velocity is in the impact of 0.8-1.2ml/min, and other chromatographic conditions are shown in 3.1, and need testing solution and reference substance solution preparation method are shown in detection method optimal selection of the present invention.The impact of column temperature and flow velocity the results are shown in Table 5.
Table 5 column temperature and flow velocity are investigated result table
| Condition | Detect wavelength | Retention time (min) | Content (%) |
| 30 ℃ of column temperatures; Flow velocity 0.8ml/min | 257nm | 6.532 | 98.7 |
| 35 ℃ of column temperatures; Flow velocity 1.0ml/min | 257nm | 5.521 | 99.2 |
| 40 ℃ of column temperatures; Flow velocity 1.2ml/min | 257nm | 4.678 | 99.6 |
Column temperature is at 30-40 ℃, flow velocity in 0.8-1.2ml/min scope on its assay without impact.
The selection result of comprehensive 1-3, determine that the chromatographic condition in detection method of the present invention and content assaying method is:
The HPLC testing conditions of mosatil is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: ion pair damping fluid (take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration): acetonitrile (85%-95%:5%-15%), with phosphoric acid tune pH to 2.2～2.6;
Preferred flow phase: take ammonium dihydrogen phosphate (ADP) 2.30g, be dissolved in water to 2000ml, get 1800ml and add 16ml TBAH, with adding acetonitrile 200ml after 0.45 μ m membrane filtration, with phosphoric acid tune pH to 2.42.
Flow velocity: the preferred 0.8ml/min of 0.8-1.2ml/min(flow velocity);
Column temperature: 30-40 ℃ (preferably 35 ℃ of column temperatures);
Detect the preferred 257nm of wavelength: 250nm-260nm();
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak.
Two,, below for after the chromatographic condition of detection method of the present invention and content assaying method determines, verify that it measures the experiment of effect.
1, with existing method contrast
Detection method of the present invention and " Chinese Pharmacopoeia " 2010 two 469 pages Ca-EDTA assays of version (volumetric method) are contrasted to detection, the results are shown in following table 6.
Table 6 content balance detects
| Assay method | Sample lot number | Content (%) |
| Detection method of the present invention | 101001-40mg | 99.8% |
| " Chinese Pharmacopoeia " method | 101001-40mg | 81.2% |
The mosatil content assaying method that " Chinese Pharmacopoeia " two of versions in 2010 are recorded records Lower result, and this explanation Pantoprazole Sodium has interference to its mensuration, and this method specificity is bad; And the measurement result of detection method of the present invention meets the requirements substantially.
2, the specificity research of detection method of the present invention
Prepare negative sample in prescription ratio, and by above-mentioned method preparation negative sample solution, the reference substance solution of drafting.Precision measures above-mentioned each solution 20 μ l injection liquid chromatographies, records chromatogram.As seen from the figure, negative sample solution, under this chromatographic condition, does not disturb the assay of this product.
3, linear test and scope
It is appropriate that precision takes mosatil reference substance, and solubilizer dissolves and dilute the reference substance solution of making a series of concentration.According to the above-mentioned assay chromatographic condition of drafting, get respectively the each 20 μ l sample introductions of variable concentrations contrast solution and measure, record chromatogram, the results are shown in Table 7.
Table 7 mosatil linear relationship test findings table
| Concentration (μ g/ml) | 1.979 | 3.959 | 5.938 | 7.917 | 11.876 | 19.793 | 31.669 |
| Peak area | 78116 | 154313 | 256797 | 394528 | 538536 | 868451 | 1563653 |
Take Ca-EDTA na concn x(μ g/ml) as horizontal ordinate, peak area y is ordinate, carries out linear regression, obtain regression equation to be: y=49164x-33245, r=0.998.
Test findings shows, the concentration of mosatil is within the scope of 1.979 μ g/ml～31.669 μ g/ml, and the concentration of its peak area and mensuration is good linear relationship, when this product assay, the concentration of reference substance solution and need testing solution all, in 7.5 μ g/ml left and right, belongs within the scope of linear relationship.
4, sample introduction precision
According to above-mentioned chromatographic condition, get respectively mosatil reference substance solution continuous sample introduction and measure 5 times, record chromatogram, to investigate sample introduction precision, it the results are shown in Table 8.
Table 8 sample introduction Precision test result table
| Numbering | 1 | 2 | 3 | 4 | 5 |
| Peak area | 334178 | 334165 | 330518 | 314542 | 332972 |
Above result shows, the sample introduction precision RSD of mosatil is: 2.54%.This law sample introduction precision is good, substantially meets the demands.
5, need testing solution stability test
Get middle test agent (101001,40mg) and prepare mosatil assay need testing solution, the accurate 20 μ l that draw, according to above-mentioned chromatographic condition, in 0,2,6,8 hour sample introduction, investigate the stability of solution, the results are shown in Table 9.
Table 9 mosatil need testing solution stability test result table
| Time (h) | 0 | 2 | 6 | 8 | RSD |
| Peak area (101001) | 323506 | 328178 | 338620 | 335721 | 2.09% |
Conclusion: need testing solution is more stable in 8 hours.
6, replica test
Get middle test agent (101001,40mg), 6 parts of need testing solutions of parallel preparation respectively, prepare reference substance solution according to said method, and accurate test sample and the reference substance solution 20 μ l sample introductions mensuration drawn, record chromatogram, the content of mosatil in calculation sample.The results are shown in Table 10.
Table 10 replica test result table
| 101001 | 1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Content (bottle) | 1.38mg | 1.37mg | 1.38mg | 1.39mg | 1.38mg | 1.37mg | 0.51 |
From above result, this law is for the assay of mosatil, and repeatability is good.
7, recovery test
Get the negative sample solution 1ml preparing in prescription ratio, put in 100ml measuring bottle, add respectively mosatil reference substance stock solution (concentration: 0.7511mg/ml) 1.5ml, 2ml, 2.5ml solubilizer to be diluted to scale, shake up, as need testing solution, and mix with the liquor ferri trichloridi of same volume, each concentration is prepared 3 parts.And prepare reference substance solution according to the above-mentioned method of drafting, and accurate test sample and the reference substance solution 20 μ l sample introductions mensuration drawn, record chromatogram, and calculate the amount of recording and the recovery of mosatil, and it the results are shown in Table 11.
Table 11 mosatil recovery test result table
Above test findings shows, measures mosatil by this law, and its method recovery is good, and relative standard deviation is less, substantially meets the requirements.
8, mosatil assay
Learn research by said method, the content assaying method of drafting this product mosatil is:
Chromatographic condition octadecylsilane chemically bonded silica is filling agent; Mobile phase: take ammonium dihydrogen phosphate (ADP) 2.30g, be dissolved in water to 2000ml, get 1800ml and add 16ml TBAH, with adding acetonitrile 200ml after 0.45 μ m membrane filtration, with phosphoric acid tune pH to 2.42.Detection wavelength is 257nm; Flow velocity: 0.8ml/min.
Get this product, solubilizer (water that pH value is 2.42) dissolves and is also quantitatively diluted to the solution that approximately contains mosatil 15ug/ml in every 1ml, and (taking 0.012g ferric trichloride, to be dissolved in pH value be in 2.42 water with the liquor ferri trichloridi of same volume, and be settled to 100ml, fresh preparation before each test) mix, to place, precision measures 20ul, injection liquid chromatography, records chromatogram; Separately get mosatil reference substance appropriate, accurately weighed, be measured in the same method.Press external standard method with calculated by peak area.
According to the method described above, pilot scale three batch sample mosatils are carried out to assay, it the results are shown in following table 12:
Test agent mosatil assay result table in table 12
| Lot number | Specification | Content (mg/ props up) |
| 101001 | 40mg | 1.38mg |
| 101101 | 40mg | 1.42mg |
| 101102 | 40mg | 1.42mg |
| 101001 | 80mg | 2.84mg |
| 101101 | 80mg | 2.78mg |
| 101102 | 80mg | 2.84mg |
To sum up, detection method of the present invention adopts HPLC method to measure the content of auxiliary material mosatil in injection Pantoprazole Sodium, measurement result more accurately and reliably, specificity is stronger, main peak retention time is about 6 minutes, and detection time is shorter, adopts acetonitrile as mobile phase, methanol as mobile phase relatively, result is more reliable.
Claims (10)
1. the detection method of mosatil in injection Pantoprazole Sodium, is characterized in that: adopt high performance liquid chromatography to detect, HPLC testing conditions is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: ion pair damping fluid and acetonitrile volume are: ion pair damping fluid 85%-95%, acetonitrile 5%-15%, with phosphoric acid tune pH to 2.2～2.6;
Wherein ion pair damping fluid compound method is: take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration;
Flow velocity: 0.8-1.2ml/min;
Column temperature: 30-40 ℃;
Detect wavelength: 250nm～260nm;
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak;
The processing of experiment material:
(1) preparation of need testing solution:
Get pH value and be 2.2～2.6 water, be mixed with 0.01%～0.02% liquor ferri trichloridi; Get injection Pantoprazole Sodium, add pH value and be 2.2～2.6 water-soluble solution and be quantitatively diluted to the solution containing mosatil 15 μ g/ml in every 1ml, mix with 0.01%～0.02% liquor ferri trichloridi of same volume, place, as need testing solution;
(2) preparation of reference substance solution:
Get pH value and be 2.2～2.6 water, be mixed with 0.01%～0.02% liquor ferri trichloridi; Take mosatil reference substance solution, add pH value and be 2.2～2.6 water-soluble solution and be quantitatively diluted to the solution containing mosatil 15 μ g/ml in every 1ml, mix with 0.01%～0.02% liquor ferri trichloridi of same volume, place product solution in contrast.
2. the detection method of mosatil in injection Pantoprazole Sodium according to claim 1, is characterized in that: mobile phase ion pair damping fluid-acetonitrile percent by volume in HPLC testing conditions: 90% ︰ 10%.
3. the detection method of mosatil in injection Pantoprazole Sodium according to claim 1, is characterized in that: in HPLC testing conditions, the pH value of mobile phase is 2.42.
4. the detection method of mosatil in injection Pantoprazole Sodium according to claim 1, is characterized in that: the flow velocity described in HPLC testing conditions is 0.8ml/min; Column temperature is 35 ℃.
5. according to the detection method of mosatil in the injection Pantoprazole Sodium described in claim 1-4 any one, it is characterized in that: detect wavelength 257nm.
6. the content assaying method of mosatil in injection Pantoprazole Sodium, is characterized in that: adopt liquid chromatographic detection, HPLC testing conditions is as follows:
Fixing phase: take octadecylsilane chemically bonded silica as filling agent;
Mobile phase: ion pair damping fluid and acetonitrile volume are: ion pair damping fluid 85%-95%, acetonitrile 5%-15%, with phosphoric acid tune pH to 2.2～2.6;
Wherein ion pair damping fluid compound method is: take ammonium dihydrogen phosphate (ADP) 2.0～3.0g, be dissolved in water to 2000ml, add 15-20ml TBAH, with 0.45 μ m membrane filtration;
Flow velocity: 0.8-1.2ml/min;
Column temperature: 30-40 ℃;
Detect wavelength: 250nm-260nm;
Number of theoretical plate calculates and should be not less than 2000 by mosatil peak;
The processing of experiment material:
(1) preparation of need testing solution:
Get pH value and be 2.2～2.6 water, be mixed with 0.01%～0.02% liquor ferri trichloridi; Get injection Pantoprazole Sodium, add pH value and be 2.2～2.6 water-soluble solution and be quantitatively diluted to the solution containing mosatil 15 μ g/ml in every 1ml, mix with 0.01%～0.02% liquor ferri trichloridi of same volume, place, as need testing solution;
(2) preparation of reference substance solution:
Get pH value and be 2.2～2.6 water, be mixed with 0.01%～0.02% liquor ferri trichloridi; Take mosatil reference substance solution, add pH value and be 2.2～2.6 water-soluble solution and be quantitatively diluted to the solution containing mosatil 15 μ g/ml in every 1ml, mix with 0.01%～0.02% liquor ferri trichloridi of same volume, place product solution in contrast.
7. the content assaying method of mosatil in injection Pantoprazole Sodium according to claim 6, is characterized in that: mobile phase ion pair damping fluid-acetonitrile percent by volume in HPLC testing conditions: 90% ︰ 10%.
8. the content assaying method of mosatil in injection Pantoprazole Sodium according to claim 6, is characterized in that: in HPLC testing conditions, the pH value of mobile phase is 2.42.
9. the content assaying method of mosatil in injection Pantoprazole Sodium according to claim 6, is characterized in that: the flow velocity described in HPLC testing conditions is 0.8ml/min; Column temperature is 35 ℃.
10. according to the content assaying method of mosatil in the injection Pantoprazole Sodium described in claim 6-9 any one, it is characterized in that: detect wavelength 257nm.
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