CN106442799B - A kind of Molecular Weight of Low Molecular Weight Heparin and molecular weight distribution detection method - Google Patents
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Abstract
The present invention relates to a kind of Molecular Weight of Low Molecular Weight Heparin and molecular weight distribution detection methods, using high performance liquid chromatography, the method comprises the following steps: step 1, the preparation of low molecular sodium heparin standard solution: step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: step 3, the preparation of test solution: step 4, 0.01% sodium azide solution is prepared: step 5, by above-mentioned 0.01% sodium azide solution, low molecular sodium heparin standard solution, low molecular sodium heparin Molecular weight calibration standard solution and test solution are injected separately into high performance liquid chromatograph, obtain chromatogram, the molecular weight of test sample is calculated according to chromatogram and obtains molecular weight distribution result.
Description
Technical field
The present invention relates to a kind of detection method of drug, in particular to a kind of molecular weight of anticoagulation medicine low molecular weight heparin
And molecular weight distribution detection method.
Background technique
Low molecular weight heparin is the general name for the lower heparin of molecule amount being prepared by unfractionated heparin depolymerization.Average mark
Son amount 4000~6000, according to the difference of molecular weight, last-in-chain(LIC) end structure and compound combination salt, can be divided into different commodity
Preparation, it is colourless or yellowish that is used in Chinese market at present, which mainly has Dalteparin Sodium, Enoxaparin Sodium and nadroparin calcium,
The clear liquid of color.
Low molecular weight heparin has following drug effect
(1) formation of prevention deep vein thrombosis and pulmonary embolism.
(2) established acute deep vein thrombosis is treated.
(3) it when haemodialysis or blood penetrate, prevents from that thrombus or blood clotting occur in extracorporeal circulation system.
(4) unstable angina and non-ST elevation acute myocardial infraction are treated.
There are many methods for the molecular weight determination of low molecular weight heparin (LMWH), such as viscosimetry, high performance liquid chromatography and gradient
Liquor-saturated amine gel electrophoresis of polypropylene etc. also has using using High Performance Gel Permeation Chromatography (HPGPC) measurement low molecular weight heparin point
Son amount and its distribution, chromatographic column are Shodex Asahipak GF-510HQ (7.6mm × 300mm) or TSK G3000SWxl
(7.8mm × 300mm), it is respectively 15 206 and 15 731 that theoretical cam curve is calculated with glucose peaks；35 DEG C of column temperature；Flow velocity
0.5ml.min-1；Differential refraction detector and diode array detector combination, Detection wavelength 234nm.This method has letter
Just, quickly with favorable reproducibility the features such as, be suitable for such drug quality control.
Chinese Pharmacopoeia discloses following methods:
The preparation of mobile phase: weighing anhydrous sodium sulfate 28.4g and be placed in a beaker, and adds purified water about 900ml to dissolve, with dilute sulphur
Acid adjusts pH to 5.0, and purified water constant volume to 1000ml, the membrane filtration through 0.22um can be according to the required proportional preparation of amount, often
Angel's used time must observe the appearance of mobile phase, and the membrane filtration through 0.22um is filtered, and such as find that muddiness should discard, weight
It is new to prepare.
Low molecular sodium heparin standard solution: weighing low molecular sodium heparin standard items about 20mg, and mobile phase is added and is dissolved into
The standard solution of 10mg/ml, disposable 0.22um filter membrane are filled into sample bottle, post mark.Standard solution is sealed
Film sealing, freezen protective.Using preceding taking-up balance to room temperature and mixing reuses.
The preparation of sample solution: weighing sample about 20mg, the sample solution that mobile phase is dissolved into 10mg/ml is added, once
Property 0.22um filter membrane is filled into sample bottle, posts mark.
The preparation of 0.01% sodium azide solution: weighing Sodium azide 10mg and be placed in a beaker, and purified water about 90ml is added to dissolve, and uses
Ultrapure water constant volume uses the preceding membrane filtration with 0.22um to 100ml.
The preparation of Molecular weight calibration standard solution: weighing Molecular Weight of Low Molecular Weight Heparin calibration standard items 10mg, and addition is already expired
The mobile phase of filter is dissolved into the calibration solution of 10mg/ml.Calibration solution is dispensed into several interpolation pipes, every is packed into about
150ul.The solution dispensed is sealed with sealed membrane, freezen protective.Using preceding taking-up balance to room temperature and mixing reuses.
Chromatographic condition:
| Conditional content | Title/index |
| Liquid chromatograph | Waters2695 |
| Detector | UV detector and Composition distribution |
| Ultraviolet detection wavelength | 234nm |
| 2414 detectors | Internal temperature: 37 DEG C；Sensitivity:4 |
| Gel chromatographic columns | TSKG2000SWXL, 7.8mm × 300mm × 5 μm |
| Flow velocity | 0.5ml/min |
| Sample volume | 25μl |
| Acquisition time | 30min |
| GPC special-purpose software | EMPOWER work station |
The above method is complicated for operation, and the period is long, low efficiency, and resolution ratio is low while accuracy and sensitivity are to be improved.
Summary of the invention
The present invention provides a kind of Molecular Weight of Low Molecular Weight Heparin and molecular weight distribution detection method, using high performance liquid chromatography
Method, the method comprises the following steps:
Step 1, the preparation of low molecular sodium heparin standard solution:
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution:
Step 3, the preparation of test solution:
Step 4,0.01% sodium azide solution is prepared:
Step 5, by above-mentioned 0.01% sodium azide solution, low molecular sodium heparin standard solution, low molecular weight heparin sodium molecule
Amount calibration standard solution and test solution are injected separately into high performance liquid chromatograph, obtain chromatogram, are calculated according to chromatogram
The molecular weight of test sample and obtain molecular weight distribution result.
Preferably, detection method of the present invention, steps are as follows:
Step 1, the preparation of low molecular sodium heparin standard solution: low molecular sodium heparin standard items about 18-22mg is weighed, is added
Enter the standard solution for flowing phased soln into 8-12mg/ml, disposable 0.2-0.24um filter membrane is filled into sample bottle, posts mark
Know, standard solution is sealed with sealed membrane, freezen protective, using preceding taking-up balance to room temperature and mixing reuses,
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: low molecular sodium heparin Molecular weight calibration is weighed
The calibration solution that filtered mobile phase is dissolved into 8-12mg/ml is added in standard items 8-12mg, calibration solution is dispensed into several
In a interpolation pipe, every loading 145-155ul is sealed the solution dispensed with sealed membrane, freezen protective, is put down using preceding take out
Weighing apparatus is to room temperature and mixing reuses,
Step 3, the preparation of test solution: weighing sample 18-22mg, and the sample that mobile phase is dissolved into 8-12mg/ml is added
Product solution, disposable 0.2-0.24um filter membrane are filled into sample bottle, post mark,
Step 4,0.008-0.012% sodium azide solution is prepared: weighing Sodium azide 48-52mg in 480-520mL volumetric flask
In, add flowing phased soln constant volume, shake up to obtain the final product,
Step 5, by above-mentioned 0.008-0.012% sodium azide solution, low molecular sodium heparin standard solution, low molecular weight heparin
Sodium molecule amount calibration standard solution and test solution are injected separately into high performance liquid chromatograph, obtain chromatogram, according to chromatography
Figure calculate test sample molecular weight and obtain molecular weight distribution as a result,
Wherein the chromatographic condition of the high performance liquid chromatography is as follows:
Mobile phase: 25~75mM ammonium acetate solution
Type of elution: isocratic elution.
Most preferably, detection method of the present invention, steps are as follows:
Step 1, the preparation of low molecular sodium heparin standard solution: weighing low molecular sodium heparin standard items about 20mg, is added
Mobile phase is dissolved into the standard solution of 10mg/ml, and disposable 0.22um filter membrane is filled into sample bottle, posts mark, will mark
Quasi- solution is sealed with sealed membrane, freezen protective, and using preceding taking-up balance to room temperature and mixing reuses,
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: low molecular sodium heparin Molecular weight calibration is weighed
The calibration solution that filtered mobile phase is dissolved into 10mg/ml is added in standard items 10mg, and calibration solution is dispensed into several
In intubation, every loading about 150ul is sealed the solution dispensed with sealed membrane, freezen protective, uses preceding taking-up balance to room
Warm and mixing reuses,
Step 3, the preparation of test solution: weighing sample about 20mg, and the sample that addition mobile phase is dissolved into 10mg/ml is molten
Liquid, disposable 0.22um filter membrane are filled into sample bottle, post mark,
Step 4,0.01% sodium azide solution is prepared: being weighed Sodium azide 50mg in 500mL volumetric flask, is added flowing phased soln
Constant volume shakes up to obtain the final product,
Step 5, by above-mentioned 0.01% sodium azide solution, low molecular sodium heparin standard solution, low molecular weight heparin sodium molecule
Amount calibration standard solution and test solution are injected separately into high performance liquid chromatograph, obtain chromatogram, are calculated according to chromatogram
The molecular weight of test sample and obtain molecular weight distribution as a result,
Wherein the chromatographic condition of the high performance liquid chromatography is as follows:
Mobile phase: 25~75mM ammonium acetate solution
Type of elution: isocratic elution.
Method of the invention is obtained by screening, and screening process is as follows:
Chromatographic column selection: Waters Acquity uplc BEH 125SEC, 4.6*150mm a 1.7um color is used only
Spectrum column runs this method, sample middle-molecular-weihydroxyethyl smaller portions is separated can well, and analysis time shortens, but calibration curve
Correlation is not high, and testing result and official method difference are larger.If a Waters Acquity uplc APC200 is used only,
4.6*150mm 2.5um chromatographic column runs this method, sample middle-molecular-weihydroxyethyl major part is separated can well, analysis time
Shorten, but the correlation of same calibration curve is not high, testing result and official method difference are larger.Finally use two root chromatogram columns
Associated with mode, preferable separating effect can be obtained, while testing result is also accurate.
It flows the selection of phase concentration: in method development process, having investigated the influence of flowing phase concentration other side method, made respectively
25mM ammonium acetate solution, 50mM ammonium acetate solution, 75mM ammonium acetate solution are used as leacheate and carries out Molecular Weight of Low Molecular Weight Heparin
And the detection of molecular weight distribution method.It was found that testing result does not have significant difference, but the separating degree of chromatographic peak increases with concentration
Added with the trend to improve.
Methodology validation:
The specificity of method: reservation of the blank solution in Molecular weight calibration standard items and low molecular sodium heparin standard solution
Occur in time without chromatographic peak.
Accuracy: the low molecular weight heparin standard items weight average molecular weight detected using this method and sign value or pharmacopeia side
The absolute difference of method detected value≤150Da.
Repeatability: the weight average molecular weight maximum for the 6 needle low molecular weight heparin that single inspector does and the smallest difference≤
150Da, RSD≤2% of weight percentages of components of the molecular weight greater than 8000 (> M8000), molecular weight is less than 2000 (<
M2000 RSD≤2% of weight percentages of components), composition weight of the molecular weight between 8000 to 2000 (M8000~2000)
Percentage RSD≤2%.
Intermediate precision: the weight average molecular weight maximums of two 12 needle low molecular weight heparin of inspector and the smallest difference≤
150Da, RSD≤2% of weight percentages of components of the molecular weight greater than 8000 (> M8000), molecular weight is less than 2000 (<
M2000 RSD≤2% of weight percentages of components), composition weight of the molecular weight between 8000 to 2000 (M8000~2000)
Percentage RSD≤2%.
Verifying conclusion: this method can accurate, stable, efficiently detect the weight average molecular weight and molecule of low molecular weight heparin
Amount distribution.
Beneficial effects of the present invention
The present invention is measured using high performance liquid chromatography, and efficiently quickly, stability is good, high sensitivity.
It is of the invention compared with the prior art compared with advantage is:
| Method of the invention | Art methods |
| Flow velocity is low, saves mobile phase | Flow velocity is high, expends mobile phase |
| Sample volume is small, saves sample | Sample volume is big, wastes sample |
| Short 30min of equilibration time or so | Equilibration time is grown 5 hours or balance is stayed overnight |
| Baseline stability | Baseline is easy drift |
| Analysis time short 10~20min | Analysis time grows 30~60min |
| High resolution | Resolution ratio is low |
| High sensitivity | Sensitivity is low |
Detailed description of the invention
The chromatogram that Fig. 1 official method obtains
The chromatogram that Fig. 2 the method for the present invention obtains
Specific embodiment
The present invention is further illustrated by the following examples.
Embodiment 1
Step 1, the preparation of low molecular sodium heparin standard solution: weighing low molecular sodium heparin standard items about 20mg, is added
Mobile phase is dissolved into the standard solution of 10mg/ml, and disposable 0.22um filter membrane is filled into sample bottle, posts mark.It will mark
Quasi- solution is sealed with sealed membrane, freezen protective.Using preceding taking-up balance to room temperature and mixing reuses.
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: low molecular sodium heparin Molecular weight calibration is weighed
The calibration solution that filtered mobile phase is dissolved into 10mg/ml is added in standard items 10mg.Calibration solution is dispensed into several
In intubation, every loading about 150ul.The solution dispensed is sealed with sealed membrane, freezen protective.Use preceding taking-up balance to room
Warm and mixing reuses.
Step 3, the preparation of test solution: weighing sample about 20mg, and the sample that addition mobile phase is dissolved into 10mg/ml is molten
Liquid, disposable 0.22um filter membrane are filled into sample bottle, post mark.
Step 4, by above-mentioned low molecular sodium heparin standard solution, low molecular sodium heparin Molecular weight calibration standard solution and
Test solution is injected separately into high performance liquid chromatograph, obtains chromatogram, calculates the molecular weight of test sample according to chromatogram and obtains
Molecular weight distribution result out.
The result is that:
Claims (2)
1. a kind of Molecular Weight of Low Molecular Weight Heparin and molecular weight distribution detection method, using high performance liquid chromatography, the method step
It is rapid as follows:
Step 1, the preparation of low molecular sodium heparin standard solution: weighing low molecular sodium heparin standard items 18-22mg, and flowing is added
At the standard solution of 8-12mg/ml, disposable 0.2-0.24 μm of filter membrane be filled into sample bottle phased soln, posts mark, will
Standard solution is sealed with sealed membrane, freezen protective, and using preceding taking-up balance to room temperature and mixing reuses,
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: low molecular sodium heparin Molecular weight calibration standard is weighed
The calibration solution that filtered mobile phase is dissolved into 8-12mg/ml is added in product 8-12mg, and calibration solution is dispensed into several
In intubation, every loading 145-155 μ l is sealed the solution dispensed with sealed membrane, freezen protective, extremely using preceding taking-up balance
Room temperature and mix reuse,
Step 3, the preparation of test solution: weighing sample 18-22mg, and the sample that addition mobile phase is dissolved into 8-12mg/ml is molten
Liquid, disposable 0.2-0.24 μm of filter membrane are filled into sample bottle, post mark,
Step 4,0.008-0.012% sodium azide solution is prepared: being weighed Sodium azide 48-52mg in 480-520mL volumetric flask, is added
Phased soln constant volume is flowed, is shaken up to obtain the final product,
Step 5, by above-mentioned 0.008-0.012% sodium azide solution, low molecular sodium heparin standard solution, low molecular sodium heparin point
Son amount calibration standard solution and test solution are injected separately into high performance liquid chromatograph, chromatogram are obtained, according to chromatogram meter
Calculate test sample molecular weight and obtain molecular weight distribution as a result,
Wherein the chromatographic condition of the high performance liquid chromatography is as follows:
Mobile phase: 25~75mM ammonium acetate solution
Type of elution: isocratic elution.
2. detection method according to claim 1, the method comprises the following steps:
Step 1, the preparation of low molecular sodium heparin standard solution: weighing low molecular sodium heparin standard items about 20mg, and flowing is added
At the standard solution of 10mg/ml, disposable 0.22 μm of filter membrane is filled into sample bottle phased soln, posts mark, and standard is molten
Liquid is sealed with sealed membrane, freezen protective, and using preceding taking-up balance to room temperature and mixing reuses,
Step 2, the preparation of low molecular sodium heparin Molecular weight calibration standard solution: low molecular sodium heparin Molecular weight calibration standard is weighed
The calibration solution that filtered mobile phase is dissolved into 10mg/ml is added in product 10mg, and calibration solution is dispensed into several interpolation pipes
In, every about 150 μ l of loading seal the solution dispensed with sealed membrane, freezen protective, are balanced to room temperature simultaneously using preceding taking-up
Mixing reuses,
Step 3, the preparation of test solution: weighing sample about 20mg, and the sample solution that mobile phase is dissolved into 10mg/ml is added,
Disposable 0.22 μm of filter membrane is filled into sample bottle, posts mark,
Step 4,0.01% sodium azide solution is prepared: being weighed Sodium azide 50mg in 500mL volumetric flask, is added flowing phased soln fixed
Hold, shake up to obtain the final product,
Step 5, by above-mentioned 0.01% sodium azide solution, low molecular sodium heparin standard solution, low molecular sodium heparin molecular weight school
Quasi- standard solution and test solution are injected separately into high performance liquid chromatograph, obtain chromatogram, are calculated according to chromatogram for examination
The molecular weight of product and obtain molecular weight distribution as a result,
Wherein the chromatographic condition of the high performance liquid chromatography is as follows:
Mobile phase: 25~75mM ammonium acetate solution
Type of elution: isocratic elution.
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| CN109459503B (en) * | 2017-09-06 | 2023-04-07 | 上海绿谷制药有限公司 | Method for measuring weight average molecular weight and content of heparin drugs |
| CN112154325B (en) * | 2018-07-26 | 2023-02-14 | 深圳市海普瑞药业集团股份有限公司 | Method for analyzing sugar chain distribution of low-molecular heparin and application thereof |
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