CN114965844A - Method for detecting content of acetate in low-molecular-weight heparin - Google Patents
Method for detecting content of acetate in low-molecular-weight heparin Download PDFInfo
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000003055 low molecular weight heparin Substances 0.000 title claims abstract description 16
- 229940127215 low-molecular weight heparin Drugs 0.000 title claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 21
- 238000010828 elution Methods 0.000 claims abstract description 12
- 239000000523 sample Substances 0.000 claims abstract description 12
- 239000012488 sample solution Substances 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims abstract description 10
- 238000004255 ion exchange chromatography Methods 0.000 claims abstract description 9
- 239000012088 reference solution Substances 0.000 claims abstract description 9
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010812 external standard method Methods 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims abstract description 4
- 239000007924 injection Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 17
- 239000001632 sodium acetate Substances 0.000 claims description 17
- 235000017281 sodium acetate Nutrition 0.000 claims description 17
- 238000005303 weighing Methods 0.000 claims description 12
- 239000011550 stock solution Substances 0.000 claims description 10
- 238000007865 diluting Methods 0.000 claims description 9
- 239000013558 reference substance Substances 0.000 claims description 9
- 239000012490 blank solution Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 229960005153 enoxaparin sodium Drugs 0.000 abstract description 12
- 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 abstract description 12
- 229950003543 nadroparin calcium Drugs 0.000 abstract description 7
- 229940018872 dalteparin sodium Drugs 0.000 abstract description 6
- 238000004445 quantitative analysis Methods 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 102000005393 Sodium-Potassium-Exchanging ATPase Human genes 0.000 description 1
- 108010006431 Sodium-Potassium-Exchanging ATPase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012795 verification Methods 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
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/96—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation using ion-exchange
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- 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)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention provides a method for detecting the content of acetate in low-molecular heparin (nadroparin calcium, dalteparin sodium and enoxaparin sodium) by adopting an ion chromatography, which comprises the following specific steps: s1, preparing a reference solution; s2: preparing a sample solution; wherein the chromatographic conditions are as follows: dionex IonPac AS11-HC (4X 250 mm) column; dionex IonPac AG11-HC (4X 50 mm) guard column; a conductance detector; ASRS _4mm suppressors; the suppressor current was 75 mA; the flow rate is 0.9-1.1 ml/min; the column temperature is 28-32 ℃; the sample injection volume is 25 mu l; a potassium hydroxide generator; and (3) an elution mode: gradient elution. The method adopts an external standard method for quantitative analysis, has the advantages of good repeatability, high accuracy and sensitivity and the like, and can realize direct detection of the sample.
Description
Technical Field
The invention relates to the technical field of chemical drug analysis, in particular to a method for detecting the content of acetate in low-molecular heparin by adopting an ion chromatography.
Background
The low molecular heparin is a series of products produced by taking heparin as a raw material and adopting different degradation processes, has a better antithrombotic effect than heparin, has the advantages of good subcutaneous injection absorption, high bioavailability, long in vivo half-life period, small bleeding tendency and the like, and is widely applied to clinic at present.
The low molecular weight heparin (nadroparin calcium, dalteparin sodium, enoxaparin sodium) is produced by adding glacial acetic acid to adjust pH, and partial acetate residue can be removed in the grading step. According to the requirement of the determination method of the residual solvent of general rule <0861> of Chinese pharmacopoeia 2020, acetic acid is a third type solvent, and the limit requirement is 0.5%.
Disclosure of Invention
The invention aims to provide a method for detecting the acetate content in low-molecular heparin (nadroparin calcium, dalteparin sodium and enoxaparin sodium) by adopting an ion chromatography, and the method adopts an external standard method for quantitative analysis, has the advantages of good repeatability, high accuracy and sensitivity and the like, and can realize direct detection of a sample. The content of acetate in low molecular weight heparin (nadroparin calcium, dalteparin sodium and enoxaparin sodium) can be rapidly and accurately detected by ion chromatography, and the limit of quantitation can reach 0.001%.
The method is simple, feasible, accurate and reliable, and comprises the following specific steps:
s1, preparing an acetate reference solution: precisely weighing 139mg of sodium acetate, placing the sodium acetate in a 100ml measuring flask, adding water to dissolve the sodium acetate, diluting the sodium acetate to a scale, and shaking up; precisely measuring 1ml of the solution, placing the solution in a 10ml measuring flask, adding water to dilute the solution to a scale, and shaking the solution uniformly to obtain an acetate reference substance stock solution; precisely measuring 0.5ml of acetate reference stock solution, placing into a 10ml measuring flask, adding water to dilute to scale, and shaking.
S2, preparing a sample solution: precisely weighing low molecular weight heparin (nadroparin calcium, dalteparin sodium, enoxaparin sodium) about 30mg, placing into 10ml measuring flask, adding appropriate amount of water to dissolve and dilute to scale, shaking, and filtering.
S3, ion chromatography determination: performing chromatographic analysis on the blank solution (water), the acetate reference solution and the sample solution by adopting ion chromatography, recording the peak area of acetate in each solution, and calculating the content of acetate in the sample according to the external standard method shown in the following formula.
Content (%)
In the formula, A T The area of the peak of acetate in the sample solution is shown; a. the 0 The area of the peak of acetate in the blank solution is shown; a. the S The peak area of acetate in the reference solution; m T Is the sample weighing (mg); m S Weighing sodium acetate (mg) as a reference solution; 0.720 is a conversion coefficient between sodium acetate and acetate ions.
The chromatographic detection conditions of S3 are as follows: dionex IonPac AS11-HC (4X 250 mm) column; dionex IonPac AG11-HC (4X 50 mm) guard column; a conductance detector; ASRS _4mm suppressors; the suppressor current was 75 mA; the flow rate is 0.9-1.1 ml/min; the column temperature is 28-32 ℃; the sample injection volume is 25 mu l; a potassium hydroxide generator; and (3) an elution mode: gradient elution, elution procedure was as follows:
| time (min) | 0 | 15 | 15.1 | 25 | 25.1 | 35 |
| Concentration of Potassium hydroxide (mmol/L) | 1.0 | 1.0 | 30 | 30 | 1.0 | 1.0 |
Preferably, the flow rate is 0.9-1.1 ml/min, and more preferably 1.0 ml/min.
Preferably, the column temperature is 28-32 ℃, and more preferably 30 ℃.
The invention has the beneficial effects that:
the ion chromatography detection method for the acetate content in the low molecular heparin (nadroparin calcium, dalteparin sodium and enoxaparin sodium) is easy to operate, short in operation time, and greatly improves the analysis efficiency, and the method is good in repeatability, high in accuracy, good in specificity and durability, capable of accurately detecting trace acetate (the limit of quantification is 0.001%) in a sample, suitable for quality control of the low molecular heparin, and capable of meeting detection requirements.
Drawings
FIG. 1 is a detection spectrum of a control solution in example 2
FIG. 2 is a detection spectrum of a sample solution in example 2
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. Unless otherwise indicated, the reagents used in the following examples are conventional commercially available reagents and the methods and equipment used are those conventionally used in the art.
The instruments and reagents used in the embodiments of the present invention:
the instrument comprises the following steps: an ICS-6000 ion chromatograph (Thermo) equipped with an autosampler, pump, potassium hydroxide generator, conductivity detector and Chromeleon 7.2 chromatographic workstation; electronic balance (mettler-toledo).
Reagent: sodium acetate (ACS Reagent, Honeywell ≥ 99.0%)
Example 1 verification of the detection method
1.1 solution preparation
Acetate control solution: precisely weighing about 139mg of sodium acetate, placing the sodium acetate into a 100ml measuring flask, adding water to dissolve the sodium acetate, diluting the sodium acetate to a scale, and shaking up; precisely measuring 1ml of the solution, placing the solution in a 10ml measuring flask, adding water to dilute the solution to a scale, and shaking the solution uniformly to obtain an acetate reference substance stock solution; precisely measuring 0.5ml of acetate reference stock solution, placing into a 10ml measuring flask, adding water to dilute to scale, and shaking.
Sample solution: precisely weighing about 30mg of enoxaparin sodium, placing into a 10ml measuring flask, adding appropriate amount of water to dissolve and dilute to scale, shaking, and filtering.
1.2 chromatographic conditions
Dionex IonPac AS11-HC (4X 250 mm) column; dionex IonPac AG11-HC (4X 50 mm) guard column; a conductance detector; ASRS — 4mm suppressor; the suppressor current was 75 mA; the flow rate is 1.0 ml/min; the column temperature is 30 ℃; the sample injection volume is 25 mu l; a potassium hydroxide generator; and (3) an elution mode: gradient elution, elution procedure was as follows:
| time (min) | 0 | 15 | 15.1 | 25 | 25.1 | 35 |
| Concentration of Potassium hydroxide (mmol/L) | 1.0 | 1.0 | 30 | 30 | 1.0 | 1.0 |
1.3 results and analysis
1.3.1 precision
Precisely weighing about 30mg of enoxaparin sodium, placing into a 10ml measuring flask, adding water to dissolve, precisely adding 0.5ml of acetate reference stock solution, diluting with water to scale, shaking, and filtering to obtain a sample solution. The measurement was repeated 6 times by two different analysts on different days, respectively, and the acetate content and RSD value of nadroparin calcium were calculated (see table 1). The result shows that the RSD value of 12 detection results of two persons is 1.8%, and the precision of the method is high.
TABLE 1 precision test results
1.3.2 accuracy
Precisely weighing about 30mg of enoxaparin sodium, putting into a 10ml measuring flask, and preparing 12 parts in parallel, wherein the serial numbers are 1-12; dissolving the measuring flask with the number of 1-3 with water and diluting to a scale; adding 0.25ml of acetate reference substance stock solution into a measuring flask with the number of 4-6, and diluting the measuring flask with water to a scale; adding 0.5ml of acetate reference substance stock solution into a measuring flask with the number of 7-9, and diluting the measuring flask with water to a scale; adding 0.6ml of acetate reference substance stock solution into a measuring flask with the number of 10-12, and diluting the measuring flask with water to a scale; the standard sample solutions with the standard adding amounts of 0%, 50%, 100% and 120% are obtained, and the content of acetate at each concentration point and the standard adding recovery rate are calculated (see table 2). The result shows that the average recovery rate of each standard sample is 98.8-110%, and the method is high in accuracy.
TABLE 2 accuracy test results
EXAMPLE 2 actual sample testing
The reference substance and the sample solution are prepared as described in the above 1.1, and different batches of enoxaparin sodium are respectively detected under the chromatographic conditions of 1.2, and the results are shown in table 3 and attached figures 1-2. As can be seen from Table 3, the acetate content of enoxaparin sodium was less than 0.002% for each batch, and the results were very low.
TABLE 3 examination results of acetate content in enoxaparin sodium
Claims (4)
1. A method for detecting the content of acetate in low-molecular heparin is characterized by comprising the following steps:
s1, preparing an acetate reference solution: precisely weighing 139mg of sodium acetate, placing the sodium acetate in a 100ml measuring flask, adding water to dissolve the sodium acetate, diluting the sodium acetate to a scale, and shaking up; precisely measuring 1ml of the solution, placing the solution in a 10ml measuring flask, adding water to dilute the solution to a scale, and shaking the solution uniformly to obtain an acetate reference substance stock solution; precisely measuring 0.5mL of acetate reference substance stock solution, placing into a 10mL measuring flask, adding water to dilute to scale, shaking to obtain the acetate reference substance solution with concentration of 5 μ g/mL,
s2, preparing a sample solution: precisely weighing low molecular weight heparin about 30mg, placing into a 10ml measuring flask, adding appropriate amount of water, dissolving and diluting to scale, shaking, filtering to obtain,
s3, ion chromatography determination: performing chromatographic analysis on the blank solution (water), the acetate reference solution and the sample solution by adopting ion chromatography, recording the peak area of acetate in each solution, calculating the content of acetate in the sample according to the external standard method of the following formula,
content (%)
In the formula, A T The area of the peak of acetate in the sample solution is shown; a. the 0 The area of the peak of acetate in the blank solution is shown; a. the S The peak area of acetate in the reference solution; m T Is the sample weighing (mg); m S Weighing sodium acetate (mg) as a reference solution; 0.720 is a conversion coefficient between sodium acetate and acetate ions.
2. The method for detecting the acetate content in the low molecular heparin according to claim 1, wherein the chromatographic detection conditions of S3 are as follows: dionex IonPac AS11-HC (4X 250 mm) column; dionex IonPac AG11-HC (4X 50 mm) guard column; a conductance detector; ASRS _4mm suppressors; the suppressor current was 75 mA; the flow rate is 0.9-1.1 ml/min; the column temperature is 28-32 ℃; the injection volume is 25 mul; potassium hydroxide generator, gradient elution.
3. The method for detecting the content of acetate in low molecular heparin according to claim 1, wherein the elution mode in the chromatographic condition is gradient elution, and the elution procedure is as follows.
4. The method for detecting the content of acetate in low molecular weight heparin according to claim 1, wherein the limit of quantitation of acetate is 0.001%.
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| CN102128885A (en) * | 2010-12-08 | 2011-07-20 | 广东中烟工业有限责任公司 | Method for quickly and simultaneously detecting 16 inorganic anions and organic acids in tobacco |
| CN103344711A (en) * | 2013-06-07 | 2013-10-09 | 上海和臣医药工程有限公司 | Content detecting method for creatine phosphate disodium salt and impurities anions thereof |
| CN106841440A (en) * | 2017-01-20 | 2017-06-13 | 山东省分析测试中心 | The detection method of organic acid in a kind of environment |
| CN113109496A (en) * | 2021-04-20 | 2021-07-13 | 陕西中烟工业有限责任公司 | Ion chromatography determination method for 8 anions and acid radical ions in cigarette paper |
-
2022
- 2022-06-02 CN CN202210620426.1A patent/CN114965844A/en active Pending
Patent Citations (4)
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| CN102128885A (en) * | 2010-12-08 | 2011-07-20 | 广东中烟工业有限责任公司 | Method for quickly and simultaneously detecting 16 inorganic anions and organic acids in tobacco |
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| CN106841440A (en) * | 2017-01-20 | 2017-06-13 | 山东省分析测试中心 | The detection method of organic acid in a kind of environment |
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| Title |
|---|
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