CN111257278A - Method for detecting degradation degree of alkaline degradation heparin benzyl ester on line by near infrared - Google Patents
Method for detecting degradation degree of alkaline degradation heparin benzyl ester on line by near infrared Download PDFInfo
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- CN111257278A CN111257278A CN201811500215.4A CN201811500215A CN111257278A CN 111257278 A CN111257278 A CN 111257278A CN 201811500215 A CN201811500215 A CN 201811500215A CN 111257278 A CN111257278 A CN 111257278A
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- near infrared
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- 238000006731 degradation reaction Methods 0.000 title claims abstract description 39
- 230000015556 catabolic process Effects 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 32
- 229960002897 heparin Drugs 0.000 title claims abstract description 18
- 229920000669 heparin Polymers 0.000 title claims abstract description 18
- -1 heparin benzyl ester Chemical class 0.000 title claims abstract description 18
- 238000002329 infrared spectrum Methods 0.000 claims abstract description 23
- 238000001228 spectrum Methods 0.000 claims abstract description 21
- 238000013178 mathematical model Methods 0.000 claims abstract description 20
- 229960005153 enoxaparin sodium Drugs 0.000 claims abstract description 17
- CIJQTPFWFXOSEO-NDMITSJXSA-J tetrasodium;(2r,3r,4s)-2-[(2r,3s,4r,5r,6s)-5-acetamido-6-[(1r,2r,3r,4r)-4-[(2r,3s,4r,5r,6r)-5-acetamido-6-[(4r,5r,6r)-2-carboxylato-4,5-dihydroxy-6-[[(1r,3r,4r,5r)-3-hydroxy-4-(sulfonatoamino)-6,8-dioxabicyclo[3.2.1]octan-2-yl]oxy]oxan-3-yl]oxy-2-(hydroxy Chemical compound [Na+].[Na+].[Na+].[Na+].O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1O)NC(C)=O)O[C@@H]1C(C[C@H]([C@@H]([C@H]1O)O)O[C@@H]1[C@@H](CO)O[C@H](OC2C(O[C@@H](OC3[C@@H]([C@@H](NS([O-])(=O)=O)[C@@H]4OC[C@H]3O4)O)[C@H](O)[C@H]2O)C([O-])=O)[C@H](NC(C)=O)[C@H]1C)C([O-])=O)[C@@H]1OC(C([O-])=O)=C[C@H](O)[C@H]1O CIJQTPFWFXOSEO-NDMITSJXSA-J 0.000 claims abstract description 17
- 238000007781 pre-processing Methods 0.000 claims abstract description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 8
- 238000004458 analytical method Methods 0.000 claims description 7
- 239000013307 optical fiber Substances 0.000 claims description 4
- 230000003595 spectral effect Effects 0.000 claims description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
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- Spectroscopy & Molecular Physics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
Abstract
A method for detecting the degradation degree of alkaline degradation heparin benzyl ester on line by near infrared is characterized by comprising the following steps: (1) collecting the original near infrared spectrum of the solution after the degradation of the heparin ester by using a near infrared spectrum analyzer; (2) correlating the obtained near infrared spectrum with the molecular weight value obtained by the high performance liquid chromatography to establish a mathematical model; (3) comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling, and determining an optimal scheme; (4) and verifying the prediction capability of the mathematical model. The method is simple and easy to implement, is suitable for performing rapid nondestructive pollution-free determination on the molecular weight of the enoxaparin sodium obtained after degradation, so as to detect the degradation degree and provide technical data support for rapid detection for the control of the production process of the enoxaparin sodium.
Description
Technical Field
The invention relates to a method for measuring the degradation degree of alkaline degradation heparin benzyl ester, in particular to a method for rapidly measuring the molecular weight of the alkaline degradation heparin benzyl ester on line by adopting a near infrared spectrum analysis technology.
Background
Near infrared spectrum analysis method, using near infrared spectrum analyzer equipped with optical fiber sensor, on-line collecting original near infrared spectrum of enoxaparin sodium solution, said spectrum mainly reflecting frequency doubling and frequency synthesizing absorption of hydrogen-containing group X-H (X is N, C, O) vibration in enoxaparin sodium. The degraded enoxaparin sodium has 4-alkene pyran uronic acid at the non-reducing end and 1, 6-dehydration structure at the reducing end, and the structural change of hydrogen-containing groups can reflect the degradation degree of heparin ester.
The existing method for determining the molecular weight of enoxaparin sodium is a high performance liquid chromatography, and cannot meet the requirement of on-line rapid analysis. The near-infrared ray spectrum analysis method can monitor the degradation degree of the heparin ester in the degradation process, is efficient and lossless, can quickly judge the degradation endpoint, and can ensure the stability of the molecular weight of the enoxaparin sodium.
Disclosure of Invention
The invention aims to solve the problems that the existing method for determining the degradation degree of heparin benzyl ester by measuring the molecular weight of enoxaparin sodium consumes reagent, has long period, cannot be analyzed on line and the like, and provides a near-infrared online spectrum analysis technology which is green, pollution-free, simple, convenient and feasible, can effectively measure the molecular weight of enoxaparin sodium and judge the degradation degree.
In order to realize the purpose, the invention adopts the technical scheme that:
a method for detecting the degradation degree of alkaline degradation heparin benzyl ester on line by near infrared is characterized by comprising the following steps:
(1) collecting the original near infrared spectrum of the solution after the degradation of the heparin ester by using a near infrared spectrum analyzer;
(2) correlating the obtained near infrared spectrum with the molecular weight value obtained by the high performance liquid chromatography to establish a mathematical model;
(3) comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling, and determining an optimal scheme;
(4) and verifying the prediction capability of the mathematical model.
The method for rapidly determining the degradation degree of the alkaline degradation heparin benzyl ester by adopting the near infrared spectrum analysis technology is characterized by comprising the following steps of:
(1) collecting original near infrared spectrums of the enoxaparin sodium solution with different degradation degrees by adopting a near infrared spectrum analyzer equipped with an optical fiber sensor;
(2) correlating the molecular weight value measured by the high performance liquid chromatography with a spectrogram acquired by a near-infrared analyzer in the 1100-2200nm spectral range by using a Partial Least Squares (PLS) method, establishing a mathematical model, and forming near-infrared analysis mathematical models of different degradation degrees of enoxaparin sodium molecular weight;
(3) then determining the optimal spectrum preprocessing method and the spectrum region by comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling;
(4) and finally, verifying the prediction capability of the mathematical model.
The method is simple and easy to implement, is suitable for performing rapid nondestructive pollution-free determination on the molecular weight of the enoxaparin sodium obtained after degradation, so as to detect the degradation degree and provide technical data support for rapid detection for the control of the production process of the enoxaparin sodium.
Drawings
FIG. 1 is a diagram of a mathematical model of the calibration in the interval of 1253-1779nm obtained by the present invention.
FIG. 2 is a graph of the correlation coefficients of the verification in the 1253-1779nm interval obtained by the present invention.
Detailed Description
The invention relates to a method for detecting the degradation degree of alkaline degraded heparin benzyl ester on line by near infrared, which comprises the following steps:
(1) collecting the original near infrared spectrum of the solution after the degradation of the heparin ester by using a near infrared spectrum analyzer;
(2) correlating the obtained near infrared spectrum with the molecular weight value obtained by the high performance liquid chromatography to establish a mathematical model;
(3) comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling, and determining an optimal scheme;
(4) and verifying the prediction capability of the mathematical model.
Examples
The method comprises the steps of firstly, collecting original near infrared spectrums of enoxaparin sodium solutions with different degradation degrees by using a near infrared spectrum analyzer with an optical fiber sensor, correlating molecular weight values measured by a high performance liquid chromatography with spectrograms collected by the near infrared analyzer in a 1100-2200nm spectral range by using a Partial Least Squares (PLS) method, establishing a mathematical model to form a near infrared analysis mathematical model of the enoxaparin sodium molecular weights with different degradation degrees, then determining an optimal spectrum preprocessing method and a spectrum region by comparing influences of different spectrum preprocessing methods and spectrum region selection on modeling, and finally verifying the prediction capability of the mathematical model.
FIG. 1 is a diagram of a mathematical model of the calibration in the interval of 1253-1779nm obtained by the present invention. FIG. 2 is a graph of correlation coefficients for the verification in the 1253-1779nm interval obtained by the present invention.
Table 1: model parameters obtained for the present invention
Table 2: the stability test result obtained by 10 times of prediction on a certain sample by the method of the invention
As a result: processing the near infrared spectrogram by using a first derivative method, selecting a spectrogram in a 1253-1779nm interval, and establishing a mathematical model by using a partial least square method, wherein Rc is 0.9265, and RMSECV is 3.63; verifying the prediction ability, wherein Rp is 0.9048, and RMSEP is 3.86; the model can be used for rapidly detecting the degradation degree of the alkaline degradation heparin benzyl ester on line.
Claims (2)
1. A method for detecting the degradation degree of alkaline degradation heparin benzyl ester on line by near infrared is characterized by comprising the following steps:
(1) collecting the original near infrared spectrum of the solution after the degradation of the heparin ester by using a near infrared spectrum analyzer;
(2) correlating the obtained near infrared spectrum with the molecular weight value obtained by the high performance liquid chromatography to establish a mathematical model;
(3) comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling, and determining an optimal scheme;
(4) and verifying the prediction capability of the mathematical model.
2. The method of claim 1, wherein the degradation degree of the alkaline-degraded heparin benzyl ester is determined by the following steps:
(1) collecting original near infrared spectrums of the enoxaparin sodium solution with different degradation degrees by adopting a near infrared spectrum analyzer equipped with an optical fiber sensor;
(2) correlating the molecular weight value measured by the high performance liquid chromatography with a spectrogram acquired by a near-infrared analyzer in the 1100-2200nm spectral range by using a Partial Least Squares (PLS) method, establishing a mathematical model, and forming near-infrared analysis mathematical models of different degradation degrees of enoxaparin sodium molecular weight;
(3) then determining the optimal spectrum preprocessing method and the spectrum region by comparing the influence of different spectrum preprocessing methods and spectrum region selection on modeling;
(4) and finally, verifying the prediction capability of the mathematical model.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811500215.4A CN111257278A (en) | 2018-11-30 | 2018-11-30 | Method for detecting degradation degree of alkaline degradation heparin benzyl ester on line by near infrared |
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|---|---|---|---|
| CN201811500215.4A CN111257278A (en) | 2018-11-30 | 2018-11-30 | Method for detecting degradation degree of alkaline degradation heparin benzyl ester on line by near infrared |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1792621A1 (en) * | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Orally administrable heparin derivatives |
| CN101597343A (en) * | 2009-05-07 | 2009-12-09 | 张丽萍 | A kind of method for base group modification of Low molecular heparin |
| CN101799409A (en) * | 2010-01-13 | 2010-08-11 | 枣庄赛诺康生化有限公司 | Method for quickly measuring potency of crude heparin sodium by using near infrared spectral analysis technology |
| CN105891343A (en) * | 2014-12-06 | 2016-08-24 | 烟台东诚药业集团股份有限公司 | Analysis and detection method for fine structures of components of sulodexide |
-
2018
- 2018-11-30 CN CN201811500215.4A patent/CN111257278A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1792621A1 (en) * | 2005-11-30 | 2007-06-06 | Debiopharm S.A. | Orally administrable heparin derivatives |
| CN101597343A (en) * | 2009-05-07 | 2009-12-09 | 张丽萍 | A kind of method for base group modification of Low molecular heparin |
| CN101799409A (en) * | 2010-01-13 | 2010-08-11 | 枣庄赛诺康生化有限公司 | Method for quickly measuring potency of crude heparin sodium by using near infrared spectral analysis technology |
| CN105891343A (en) * | 2014-12-06 | 2016-08-24 | 烟台东诚药业集团股份有限公司 | Analysis and detection method for fine structures of components of sulodexide |
Non-Patent Citations (1)
| Title |
|---|
| 祝贺等: "不同1，6酐衍生物依诺肝素钠结构及其抗凝血活性比较", 《药学学报》 * |
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Application publication date: 20200609 |