CN1185486C - Method for measuring content of N-methylpyrrolidine - Google Patents
Method for measuring content of N-methylpyrrolidine Download PDFInfo
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- CN1185486C CN1185486C CNB031096247A CN03109624A CN1185486C CN 1185486 C CN1185486 C CN 1185486C CN B031096247 A CNB031096247 A CN B031096247A CN 03109624 A CN03109624 A CN 03109624A CN 1185486 C CN1185486 C CN 1185486C
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- crassitude
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- acetonitrile
- solution
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- 238000000034 method Methods 0.000 title claims abstract description 14
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 title abstract 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 title abstract 3
- 230000000694 effects Effects 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000011521 glass Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000002474 experimental method Methods 0.000 claims abstract description 5
- 238000004458 analytical method Methods 0.000 claims abstract description 4
- 239000012488 sample solution Substances 0.000 claims abstract description 4
- 230000035945 sensitivity Effects 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 84
- 239000000523 sample Substances 0.000 claims description 22
- 239000007789 gas Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 13
- 238000012360 testing method Methods 0.000 claims description 11
- 239000013558 reference substance Substances 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 238000012417 linear regression Methods 0.000 claims description 3
- 239000012490 blank solution Substances 0.000 claims description 2
- 239000012159 carrier gas Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 229920000151 polyglycol Polymers 0.000 claims 1
- 239000010695 polyglycol Substances 0.000 claims 1
- 229920002538 Polyethylene Glycol 20000 Polymers 0.000 abstract description 5
- 238000004817 gas chromatography Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000011248 coating agent Substances 0.000 abstract 1
- 238000000576 coating method Methods 0.000 abstract 1
- 238000001514 detection method Methods 0.000 abstract 1
- 239000012088 reference solution Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 6
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 5
- 229960002100 cefepime Drugs 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 229960000927 cefepime hydrochloride Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
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Abstract
The invention relates to a method for measuring the content of N-methylpyrrolidine, which uses a gas chromatograph analysis method and comprises the steps of instruments, reagents, gas chromatography conditions, preparation of a sample solution to be tested and a reference solution, system applicability experiments and the like, wherein the minimum detected quantity of the N-methylpyrrolidine is 16ppm, and a glass chromatographic column (phi 3.2mm multiplied by 3.6mm) formed by coating 5-20% of PEG (20000) on a Chormosorb W (80-100 meshes) support has a good separation effect. The invention has the advantages of high sensitivity, good repeatability and small minimum detection quantity.
Description
Technical field
The present invention relates to the assay method of certain content of chemical substances, specifically relate to N-crassitude Determination on content method.
Background technology
In the building-up process of hydrochloric acid cefepime raw material, can inevitably bring a kind of intermediate of the N-of being called crassitude into, at present, also there is not method to measure this material fast and accurately both at home and abroad, therefore, be badly in need of a kind of method of exploitation, to measure the N-crassitude content in the hydrochloric acid cefepime raw material.
Summary of the invention
The objective of the invention is to remedy the defective that exists in the prior art, and provide a kind of gas chromatography to detect the N-crassitude.
The object of the invention can realize by following measure:
N-crassitude Determination on content method is under certain instrument, reagent and GC conditions, follows these steps to carry out:
(1) preparation of confession test agent solution: get testing sample, weighing adds acetonitrile, dissolving, centrifugal, stand-by;
(2) preparation of contrast solution: precision takes by weighing the N-crassitude, adds acetonitrile, dissolving, stand-by;
(3) system flexibility experiment and result thereof: get the pure product of N-crassitude, the contrast solution that contains the N-crassitude and blank solution acetonitrile respectively, quantitatively, collection of illustrative plates is drawn in the sample introduction analysis;
(4) to record N-crassitude minimum detectable activity be 16PPm in test;
(5) linearity and range: get N-crassitude reference substance in (2), add dilution in acetonitrile and become series concentration, each sample sample introduction is respectively analyzed secondary, carries out linear regression;
(6) N-crassitude Determination on content in the sample, extracting sample solution (1), inject gas chromatograph, record chromatogram; Other gets the reference substance solution of (2), measures with method, by being marked with calculated by peak area outward, promptly get measurement result, wherein chromatographic column is that 5-20%PEG is coated on the Chromosorb W carrier (80-100 order) and is filled on the glass column, is used to separate the N-crassitude, its good separating effect.
The present invention has following advantage compared to existing technology: with gas chromatography determination N-crassitude content, highly sensitive, good reproducibility, N-crassitude minimum detectable activity is 16ppm, N-crassitude contained in the hydrochloric acid cefepime raw material can not only be determined at, and the N-crassitude content in any material can be determined at.
Description of drawings
Fig. 1: the gas chromatogram of N-crassitude
Fig. 2: the gas chromatogram of N-crassitude reference substance test solution
Fig. 3: the gas chromatogram of blank reagent acetonitrile
Fig. 4: the gas chromatogram of N-crassitude minimum detectable activity
Fig. 5: linear concentration is the gas chromatogram of 63.8 μ g/ml
Fig. 6: linear concentration is the gas chromatogram of 159.6 μ g/ml
Fig. 7: linear concentration is the gas chromatogram of 255.4 μ g/ml
Fig. 8: linear concentration is the gas chromatogram of 319.2 μ g/ml
Fig. 9: linear concentration is the gas chromatogram of 478.8 μ g/ml
Figure 10: linear concentration is the gas chromatogram of 638.4 μ g/ml
Figure 11: the gas chromatogram of 1 batch sample N-crassitude assay
Figure 12: the gas chromatogram of 2 batch sample N-crassitude assays
Figure 13: the gas chromatogram of 3 batch sample N-crassitude assays
Embodiment
Enumerate an embodiment below, the present invention is further specified.
Embodiment 1:
Measure N-crassitude contained in the cefepime Hydrochloride as follows.
1.1 instrument and equipment and reagent
Day island proper Tianjin GC-9A gas chromatograph; The F1D detecting device; The TL9900 chromatographic work station.
Acetonitrile (chromatographically pure, Tedia Company, LOT809011);
N-crassitude (pearl Guangdong, Zhuhai light drug development company limited provides)
1.2 GC conditions
Chromatographic column: fill glass column (the φ 3.2mm * 3.6m) that 8%PEG (20000) is coated in Chromosorb w (Chromosorb) (80-100 order) carrier
Column temperature: 100 ℃ keep rising to 150 ℃ with 20 ℃/minute in 8 minutes and kept 10 fens;
Injector temperature: 180 ℃;
Detector temperature: 180 ℃;
Sensitivity: 10
2Decay 2 °;
Carrier gas: high purity nitrogen 50ml/min;
Sample size: 2 μ l.
1.3 it is an amount of to get sample to be determined for the preparation of test agent solution, precision takes by weighing and places the 10ml volumetric flask, and the accurate acetonitrile that adds is to scale, the ultrasound wave dissolving, in hydro-extractor with 3000r/min from 10min, stand-by.
1.4 the preparation precision of contrast solution takes by weighing N-crassitude 0.5g, places the 100ml volumetric flask, adds acetonitrile to scale, dissolving shakes up.Precision is measured above-mentioned solution 1ml, places the 10ml container bottle to add acetonitrile to scale, and dissolving shakes up, and is stand-by.
1.5 system suitability experiment and result thereof: it is a certain amount of to get the pure product of N-crassitude, contrast solution (containing the N-crassitude), blank solvent acetonitrile respectively, sample introduction is analyzed, under above-mentioned GC conditions, the gas chromatogram of N-crassitude and reference substance test solution is seen Fig. 1,2, from figure as can be known, the retention time of N-crassitude is respectively 3.067min, the retention time of blank solvent acetonitrile is 6.400min, see Fig. 3, to the not influence of the assay of N-crassitude, and degree of separation and tailing factor meet the requirement of Chinese Pharmacopoeia.
1.6 the N-crassitude minimum detectable activity 16ppm that test records sees Fig. 4.
1.7 linearity and range: get N-crassitude reference substance, add dilution in acetonitrile and make the series concentration that every ml contains 63.8,159.6,255.4,319.2,478.8,638.4 μ g/ml, each sample feeding is analyzed secondary (seeing Fig. 5～10), linear regression again, the N-crassitude is good in the scope internal linear relation of 63.8～638.4 μ g/ml as a result, linear equation is y=1796.8x-62199, r=0.9989.X is a concentration, and r is a related coefficient, and y is a peak area.
1.8 N-crassitude Determination on content extracting sample solution 2 μ l inject gas chromatographs in the sample, the record chromatogram.Other gets above-mentioned reference substance solution, measures with method, by being marked with calculated by peak area outward, promptly.The measurement result of N-crassitude sees the following form 1 in the three batches of test samples, and the measurement result gas chromatogram of test sample is seen Figure 11～13.
The measurement result of table 1, test sample residual quantity (%)
| Lot number | The N-crassitude |
| 1 | 0.145 |
| 2 | 0.155 |
| 3 | 0.160 |
1.9 illustrate: the groping in the process of this experimental technique, we have prepared 5%, 8%, 10%, 15%, 20% PEG (20000) respectively and have been coated in respectively on Chromosorb w (80-100 order) carrier as filler and insert glass column (φ 3.2mm * 3.6m).By investigation to this serial chromatographic column, chromatographic column is that 8%PEG (20000) is coated in glass column on Chromosorb w (80-100 order) carrier (separating effect of φ 3.2mm * 3.6m) is best as a result, other chromatographic columns also in various degree the N-crassitude is had certain separating effect, be applied on the suitable carrier as filler so use the PEG (20000) of different proportion, the method that the chromatographic column of filling is measured the N-crassitude has specificity.
The integral and calculating of all collection of illustrative plates the results are shown in Table 2.
Table 2, the tabulation of Fig. 1-13 collection of illustrative plates integral result
| Sequence number | Retention time | Peak width | Peak area | Analysis result % | The peak ownership |
| 1 | 3.067 | 0.426 | 701836 | 100.0000 | The N-crassitude |
| 2 | 3.425 | 0.359 | 375163 | 0.0438 | The N- |
| 3 | 6.625 | 0.784 | 857012441 | 99.9562 | Acetonitrile |
| 4 | 6.400 | 0.747 | 602714932 | 100.0000 | Acetonitrile |
| 5 | 3.231 | 0.355 | 2646 | 0.0004 | The N- |
| 6 | 6.218 | 0.704 | 680997862 | 99.9996 | Acetonitrile |
| 7 | 3.133 | 0.669 | 65092 | 0.0056 | The N-crassitude |
| 8 | 5.933 | 0.846 | 1154065962 | 99.9944 | Acetonitrile |
| 9 | 3.083 | 0.466 | 216554 | 0.0321 | The N- |
| 10 | 5.833 | 0.822 | 675062739 | 99.9679 | Acetonitrile |
| 11 | 3.083 | 0.433 | 380651 | 0.0471 | The N- |
| 12 | 5.917 | 0.840 | 808047141 | 99.9529 | Acetonitrile |
| 13 | 3.083 | 0.403 | 515112 | 0.0590 | The N-crassitude |
| 14 | 5.917 | 0.843 | 871990729 | 99.9410 | Acetonitrile |
| 15 | 3.167 | 0.452 | 811571 | 0.0752 | The N-crassitude |
| 16 | 6.617 | 0.908 | 1077939560 | 99.9248 | Acetonitrile |
| 17 | 3.167 | 0.388 | 1084979 | 0.1218 | The N- |
| 18 | 6.067 | 0.858 | 889494964 | 99.8782 | Acetonitrile |
| 19 | 3.667 | 0.988 | 16629 | 0.0026 | N-methyl pyrrole is alkane slightly |
| 20 | 7.083 | 0.743 | 641662588 | 99.9974 | Acetonitrile |
| 21 | 3.433 | 0.738 | 19620 | 0.0029 | The N-crassitude |
| 22 | 6.567 | 0.751 | 687477139 | 99.9971 | Acetonitrile |
| 23 | 3.633 | 0.339 | 20552 | 0.0033 | The N- |
| 24 | 6.833 | 0.757 | 632274345 | 99.9967 | Acetonitrile |
Listed sequence number 1-24 in the table 2 is illustrated among Fig. 1-13, as can be seen from Table 2 the concentration of the size of peak area and sample relation in direct ratio.
Assay method of the present invention not only is used for the N-crassitude that hydrochloric acid cefepime raw material contains, and can be used for the contained N-crassitude of any material.
Claims (1)
1, N-crassitude Determination on content method is characterized in that it being to comprise following instrument, reagent, GC conditions:
Column temperature: 100 ℃ keep rising to 150 ℃ with 20 ℃/minute in 8 minutes and kept 10 minutes;
Injector temperature: 180 ℃
Detector temperature: 180 ℃
Sensitivity: 10
2Decay 2 °
Carrier gas: high purity nitrogen 50ml/min;
Sample size: 2 μ l;
Follow these steps to carry out:
(1) preparation of confession test agent solution: get testing sample, weighing adds acetonitrile, dissolving, centrifugal, stand-by;
(2) preparation of contrast solution: precision takes by weighing the N-crassitude, adds acetonitrile, dissolving, stand-by;
(3) system flexibility experiment and result thereof: divide the pure product of another name N-crassitude, the contrast solution that contains the N-crassitude and blank solution acetonitrile, quantitatively, collection of illustrative plates is drawn in the sample introduction analysis;
(4) to record N-crassitude minimum detectable activity be 16PPm in test;
(5) linearity and range: get N-crassitude reference substance in (2), add dilution in acetonitrile and become series concentration, each sample sample introduction is respectively analyzed secondary, carries out linear regression;
(6) N-crassitude Determination on content in the sample, extracting sample solution (1), inject gas chromatograph, record chromatogram; Other gets the reference substance solution of (2), measures with method, and by being marked with calculated by peak area outward, wherein chromatographic column is analyzed for the 5-20% polyglycol is coated in the glass column of filling on the Chromosorb carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031096247A CN1185486C (en) | 2003-04-09 | 2003-04-09 | Method for measuring content of N-methylpyrrolidine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031096247A CN1185486C (en) | 2003-04-09 | 2003-04-09 | Method for measuring content of N-methylpyrrolidine |
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| Publication Number | Publication Date |
|---|---|
| CN1442692A CN1442692A (en) | 2003-09-17 |
| CN1185486C true CN1185486C (en) | 2005-01-19 |
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| CNB031096247A Expired - Fee Related CN1185486C (en) | 2003-04-09 | 2003-04-09 | Method for measuring content of N-methylpyrrolidine |
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| Country | Link |
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