CN107219317B - Method for rapidly determining molecular weight, distribution and impurity content of polyethylene glycol derivative - Google Patents
Method for rapidly determining molecular weight, distribution and impurity content of polyethylene glycol derivative Download PDFInfo
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Abstract
The invention discloses a method for rapidly determining the molecular weight, the distribution and the impurity content of a polyethylene glycol derivative. The invention adopts an ACQUITY APC XT series ultra-efficient gel column, takes methanol as a mobile phase, and measures the molecular weight and the distribution of the polyethylene glycol derivative by differential refraction to obtain the molecular weight of the polyethylene glycol derivative; meanwhile, the relative contents of the main component and the impurities of the polyethylene glycol derivative are obtained by an area normalization method. The method has the advantages of high resolution and high analysis speed, can quickly determine the molecular weight and the distribution of the polyethylene glycol derivative within 5.3min at the shortest time, and can effectively separate impurities in the polyethylene glycol derivative to obtain the purity of the main component and the content of the impurities. The invention provides a new determination method for process research and development, quality control and the like, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of analysis and test, and particularly relates to a Gel Permeation Chromatography (GPC) determination method for polymer molecular weight.
Background
Polyethylene glycol (PEG) derivatives are widely applied in the industries of cosmetics, pharmacy, chemical industry, food processing and the like, and the molecular weight and purity of the derivatives have great influence on the performance of products. For example, the polyethylene glycol derivative can be used as a modifier of protein drugs, can modify the protein drugs, overcomes the defects of easy enzymatic hydrolysis, short circulation half-life, high immunogenicity, low solubility and the like of the protein drugs, can be used for modifying other drugs to improve the performance (increase water solubility, prolong half-life and the like) of the drugs, and has great influence on the efficacy of the modified drugs due to the molecular weight, the distribution and the impurity content of the molecular weight. Therefore, it is important to establish a method for rapidly and effectively determining the molecular weight, the distribution thereof and the content of impurities.
The method for measuring the molecular weight of the polymer mainly comprises a viscosity method, an infrared spectroscopy method, a Gel Permeation Chromatography (GPC) method, a matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) method, a fast atom bombardment mass spectrometry (FAB-MS) method, a nuclear magnetic resonance method and the like. Wherein, the viscosity method, the infrared spectrum and the nuclear magnetic resonance method can not obtain the molecular weight distribution and the polymer purity; MALDI-TOF MS and FAB-MS mass spectrometry instruments are expensive and cannot be popularized. GPC can not only determine the relative molecular weight of a polymer but also obtain a molecular weight distribution, and can determine the relative content of impurities from the peak area size of GPC chromatography, and is the preferred method for determining the molecular weight of a high molecular polymer.
At present, methods for measuring the molecular weight of the PEG derivative are few, and a method for measuring the molecular weight of the PEG derivative quickly, efficiently and accurately needs to be developed.
Disclosure of Invention
The invention aims to: the method solves the problem that the method for measuring the molecular weight of the PEG derivative in the prior art is less, and provides a novel method for measuring the molecular weight, the distribution and the impurity content of the PEG derivative.
In order to realize the aim, the invention provides a method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, which adopts an ACQUITY APC XT series ultra-efficient gel column, takes methanol as a mobile phase, and determines the molecular weight and the distribution of the polyethylene glycol derivative by differential refraction to obtain the molecular weight of the polyethylene glycol derivative; meanwhile, the relative contents of the main component and the impurities of the polyethylene glycol derivative are obtained by an area normalization method.
Specifically, the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative comprises the following steps:
(1) preparation of standard solution: adding methanol and water in a volume ratio of 80: 20-100: 0 into a polyethylene glycol standard substance, standing at room temperature for 24 hours, and standing until the polyethylene glycol standard substance is completely dissolved for later use;
(2) preparation of sample solution: weighing 50mg of a polyethylene glycol derivative sample, placing the polyethylene glycol derivative sample in a 10mL volumetric flask, adding methanol and water with the volume ratio of 80: 20-100: 0 to dissolve to a constant volume for later use;
(3) injecting the standard solution obtained in the step (1) into an ultra-high efficiency polymer system for determination, and taking methanol as a mobile phase to obtain an ultra-high efficiency gel chromatogram of the standard solution; taking the logarithm of the peak position molecular weight of the standard substance as a vertical coordinate and the elution volume as a horizontal coordinate to obtain a standard correction curve;
(4) injecting the sample solution obtained in the step (2) into an ultra-high efficiency polymer system for determination, and taking methanol as a mobile phase to obtain an ultra-high efficiency gel chromatogram of the sample solution; calculating the number average molecular weight, the weight average molecular weight and the molecular weight distribution coefficient of the polyethylene glycol derivative sample by using gel chromatography software according to the standard calibration curve obtained in the step (3);
(5) and (4) obtaining the relative contents of the main components and the impurities in the polyethylene glycol derivative sample through peak area integration and area normalization calculation of the ultra-high performance gel chromatogram of the sample solution obtained in the step (4).
As a preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, in the step (1) and the step (2), the volume ratio of methanol to water is 95: 5.
As a preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, in the step (2), the concentration of a polyethylene glycol derivative sample in the sample solution is 4-6 mg/mL.
As a more preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, the concentration of a polyethylene glycol derivative sample in the sample solution is 5 mg/mL.
As a preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, in the step (3), the standard substance is polyethylene glycol, and the peak molecular weight is 200-500000 Da.
As a preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, in the step (3) and the step (4), a chromatographic column of the ultra-high performance polymer system is an ACQUITY APCXT series ultra-high performance gel column, and the molecular weight range is 200-500000 Da.
As a preferred technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, two or three ultra-efficient gel columns of the ACQUITY APC XT series are connected in series.
As a preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, water is further added as an improver in the steps (3) and (4), and the volume ratio of methanol to water is 90: 10-98: 2.
As a more preferable technical scheme of the method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative, in the step (3) and the step (4), the volume ratio of the methanol to the water is 95: 5.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) compared with the prior art, the method has the advantage of high resolution, and can effectively separate the main components and impurities of the polyethylene glycol derivatives to obtain the purity and the relative content of the impurities;
(2) compared with the existing method, the method has the advantage of high analysis speed, and the relative molecular weight and the distribution condition of a polyethylene glycol derivative sample can be detected only within 5.3min (two ultra-high performance gel chromatographic columns are connected in series) or 8.5min (three ultra-high performance gel chromatographic columns are connected in series);
(3) the traditional Gel Permeation Chromatography (GPC) method is divided into fat solubility and water solubility, the used mobile phase is usually fixed and invariable, and the two can not be interchanged or mixed absolutely; the most commonly used mobile phase for the fat-soluble GPC method is tetrahydrofuran (a moderately polar organic solvent) or toluene (a non-polar organic solvent); the most commonly used mobile phase for water-soluble GPC methods is an aqueous solution. Since the PEG derivatives are easily soluble in water and more polar organic solvents, but the column efficiency is rapidly reduced due to the interaction of the chromatographic column filler of water-soluble GPC with the PEG derivatives, it is preferable to use more polar organic solvents as the mobile phase and the solvent for dissolving the sample, and the above-mentioned liposoluble mobile phase is not suitable. The method adopts a novel ACQUITY APC XT series ultra-efficient gel column, and the filler is rigid ethylene bridge hybrid polyethoxy silane particles, thus being applicable to an organic solvent system; according to the solubility of the polyethylene glycol derivative, a strong polar organic solvent methanol is selected as a solvent for dissolving a sample and a chromatographic mobile phase, a small amount of water is added as an improver, the volume ratio of the methanol to the water in the sample solvent is finally determined to be 80: 20-100: 0, and the volume ratio of the methanol to the water in the mobile phase is 90: 10-98: 2, so that a satisfactory effect can be achieved.
Drawings
FIG. 1 is a graph of APC calibration curves for polyethylene glycol standards.
FIG. 2 is an APC analysis chromatogram of a polyethylene glycol derivative.
FIG. 3 is an APC chromatogram of polyethylene glycol derivatives at different concentrations (mg/mL).
FIG. 4 is an APC analysis chromatogram of monomethoxypolyethylene glycol propionaldehyde (mPEG _ pALD).
FIG. 5 is an APC analysis chromatogram of Y-shape PEGylated amine (Y-shape PEG-NH 2).
Detailed Description
In order to make the objects, technical solutions and advantageous technical effects of the present invention clearer, the present invention is further described in detail with reference to the following embodiments. It should be understood that the embodiments described in this specification are only for the purpose of illustrating the invention and are not to be construed as limiting the invention, and the parameters, proportions and the like of the embodiments may be suitably selected without materially affecting the results.
Example 1
The determination of the molecular weight, the distribution and the impurity content of monomethoxypolyethylene glycol propionaldehyde (mPEG _ pALD) comprises the following steps:
1.1 solution preparation
Preparation of standard solution: respectively collecting polyethylene glycol (PEG) standard 2.0mg, and peak molecular weight (M)p) Adding 1.5mL of methanol and water with the volume ratio of 95:5 into the mixture respectively of 2010Da, 3120Da, 6240Da, 8600Da, 12000Da, 23000Da, 40000Da, 230000Da and 478000Da, standing at room temperature for 24h, and waiting for determination after the standard substance is completely dissolved.
Preparation of sample solution: 50mg of mPEG _ pALD sample is weighed and placed in a 10mL volumetric flask, methanol and water with the volume ratio of 95:5 are added for dissolving to a constant volume, and the volume is to be detected.
1.2 Experimental conditions
Chromatographic conditions are as follows: a chromatographic column: ACQUITY APC XT 450 (4.6X 150mm, 2.5 μm), molecular weight Range: 20000Da to 400000 Da; ACQUITY APC XT 200 (4.6X 150mm, 2.5 μm), molecular weight Range: 3000Da to 70000 Da; ACQUITY APC XT 45 (4.6X 150mm, 1.7 μm), molecular weight Range: 200Da to 5000 Da; three chromatographic columns are connected in series. Column temperature: 40 ℃; mobile phase: methanol and water in a volume ratio of 95: 5; flow rate: 0.5 mL/min; refractive index detector: 40 ℃; sample introduction amount: 10 μ L (FIGS. 1 to 3).
1.3 creation of Standard Curve
Under the above chromatographic conditions, the peak molecular weight (M) of the polyethylene glycol standard sample was measured using a standard solutionp) The logarithm of (d) is the ordinate (log w) and the elution volume is the abscissa (V), and a third order equation is used to fit the standard curve.
1.4 sample measurements and results
Injecting the sample solution into an ultra-efficient polymer system for determination to obtain an ultra-efficient gel chromatogram of the sample solution (figure 4); the number average molecular weight (M) of the sample was calculated from the standard curven) Weight average molecular weight (M)w) And the molecular weight distribution coefficient (D), see Table 1.
Table 1 test results for different PEG derivative samples
The relative content of impurities can be obtained by area normalization, and the results are shown in table 2. As shown in Table 2, the content of the main component mPEG _ pALD determined by the method is 98.60%, and the RSD is 0.0059%; the content of impurity 1 is 1.32%, and RSD is 0.44%; the content of the impurity 2 is 0.073%, and the RSD is 7.87%, which shows that the repeatability of the method for measuring the main component and the impurity content of mPEG _ pALD is good.
TABLE 2 APC System determination of mPEG _ pALD Main Components and impurity content determination results
Example 2
The molecular weight and the distribution of the Y-shape polyethylene glycol amine (Y-shape PEG-NH2) and the determination of the impurity content comprise the following steps:
2.1 preparation of the solution
Preparation of standard solution: respectively collecting polyethylene glycol (PEG) standard 2.0mg, and peak molecular weight (M)p) Respectively 600Da, 1500Da, 2010Da, 3120Da, 6240Da, 8600Da, 12000Da, 23000Da and 40000Da, adding 1.5mL of methanol and water with the volume ratio of 90: 10%, standing at room temperature for 24h, and waiting for determination after the standard substance is completely dissolved.
Preparation of sample solution: weighing 40mg of a Y-type polyethylene glycol amine sample, placing the sample in a 10mL volumetric flask, adding methanol and water with the volume ratio of 90:10 to dissolve to a constant volume, and measuring.
2.2 Experimental conditions
Chromatographic conditions are as follows: a chromatographic column: ACQUITY APC XT 200 (4.6X 150mm, 2.5 μm), molecular weight Range: 3000Da to 70000 Da; ACQUITY APC XT 45 (4.6X 150mm, 1.7 μm), molecular weight Range: 200Da to 5000 Da; the two chromatographic columns are connected in series. Column temperature: 40 ℃; mobile phase: methanol and water in a volume ratio of 90: 10; flow rate: 0.5 mL/min; refractive index detector: 40 ℃; sample introduction amount: 10 μ L.
2.3 creation of Standard Curve
Under the above chromatographic conditions, the peak molecular weight (M) of the polyethylene glycol standard sample was measured using a standard solutionp) The logarithm of (d) is the ordinate (log w) and the elution volume is the abscissa (V), and a third order equation is used to fit the standard curve.
2.4 sample measurements and results
Injecting the sample solution into an ultra-efficient polymer system for determination to obtain an ultra-efficient gel chromatogram of the sample solution (figure 5); calculating the number average molecular weight, weight average molecular weight and molecular weight distribution coefficient of the sample by a standard curve (see table 1); and then the relative contents of the polymer and the impurities in the sample are obtained through peak area normalization calculation, and the result shows that the content of the main component of the Y-type polyethylene glycol amine is 99.51 percent, and the content of the impurity 1 is 0.49 percent.
Appropriate changes and modifications to the embodiments described above will become apparent to those skilled in the art from the disclosure and teachings of the foregoing description. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and variations of the present invention should fall within the scope of the claims of the present invention. Furthermore, although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
Claims (6)
1. A method for rapidly determining the molecular weight, the distribution and the impurity content of a polyethylene glycol derivative is characterized in that an ACQUITY APC XT series ultra-efficient gel column is adopted, methanol is used as a mobile phase, and the molecular weight and the distribution of the polyethylene glycol derivative are determined by differential refraction to obtain the molecular weight of the polyethylene glycol derivative; meanwhile, the relative contents of the main component and the impurities of the polyethylene glycol derivative are obtained by an area normalization method;
the method comprises the following steps:
(1) preparation of standard solution: adding methanol and water in a volume ratio of 80: 20-100: 0 into a polyethylene glycol standard substance, standing at room temperature for 24 hours, and standing until the polyethylene glycol standard substance is completely dissolved for later use;
(2) preparation of sample solution: weighing 50mg of a polyethylene glycol derivative sample, placing the polyethylene glycol derivative sample in a 10mL volumetric flask, adding methanol and water with the volume ratio of 80: 20-100: 0 to dissolve to a constant volume for later use;
(3) injecting the standard solution obtained in the step (1) into an ultra-high efficiency polymer system for determination, and taking methanol as a mobile phase to obtain an ultra-high efficiency gel chromatogram of the standard solution; taking the logarithm of the peak position molecular weight of the standard substance as a vertical coordinate and the elution volume as a horizontal coordinate to obtain a standard correction curve;
(4) injecting the sample solution obtained in the step (2) into an ultra-high efficiency polymer system for determination, and taking methanol as a mobile phase to obtain an ultra-high efficiency gel chromatogram of the sample solution; calculating the number average molecular weight, the weight average molecular weight and the molecular weight distribution coefficient of the polyethylene glycol derivative sample by using gel chromatography software according to the standard calibration curve obtained in the step (3);
(5) obtaining the relative contents of main components and impurities in the polyethylene glycol derivative sample through peak area integration and area normalization calculation of the ultra-high performance gel chromatogram of the sample solution obtained in the step (4);
in the step (1) and the step (2), the volume ratio of the methanol to the water is 95: 5;
in the step (3) and the step (4), the mobile phase is formed by adding water as an improver into methanol, and the volume ratio of the methanol to the water is 95: 5.
2. The method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative according to claim 1, wherein in the step (2), the concentration of the polyethylene glycol derivative sample in the sample solution is 4-6 mg/mL.
3. The method for rapidly determining the molecular weight and the distribution of the molecular weight and the impurity content of the polyethylene glycol derivative according to claim 2, wherein in the step (2), the concentration of the polyethylene glycol derivative sample in the sample solution is 5 mg/mL.
4. The method for rapidly determining the molecular weight, the distribution and the impurity content of the polyethylene glycol derivative according to claim 1, wherein in the step (3), the standard substance is polyethylene glycol, and the peak molecular weight is 200-500000 Da.
5. The method for rapidly determining the molecular weight, the distribution thereof and the impurity content of the polyethylene glycol derivative according to claim 1, wherein in the steps (3) and (4), the chromatographic column of the ultra-high performance polymer system is an ACQUITY APC XT series ultra-high performance gel column, and the molecular weight range is 200-500000 Da.
6. The method for rapidly determining the molecular weight, the distribution thereof and the impurity content of the polyethylene glycol derivative according to claim 5, wherein the ACQUITY APC XT series ultra-efficient gel column is two or three in series.
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Address after: 510070 Guangzhou City, Guangzhou, Guangdong, No. 34 Patentee after: Institute of testing and analysis, Guangdong Academy of Sciences (Guangzhou analysis and testing center, China) Address before: 510070 Guangzhou City, Guangzhou, Guangdong, No. 34 Patentee before: GUANGDONG INSTITUTE OF ANALYSIS (CHINA NATIONAL ANALYTICAL CENTER, GUANGZHOU) |