CN107576735B - Method for measuring high-molecular polymer in ropinan sodium - Google Patents
Method for measuring high-molecular polymer in ropinan sodium Download PDFInfo
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Abstract
The invention discloses a method for detecting a high molecular polymer in a raw material of Ropeinan sodium by gel chromatography, which comprises the following steps of using a chromatographic column of a high performance liquid chromatograph as a chromatographic column with polystyrene gel as a filler, using a mobile phase of 0.1 mol/L and pH =6.8-7.2 buffer solution-methanol, using an ultraviolet detector as the detector, detecting the wavelength of 220-224nm and the flow rate of 0.4-0.6ml/min, absorbing 20 mu l of each of a reference solution, a test solution and a blank solution, injecting the solutions into the high performance liquid chromatograph, recording a chromatogram, calculating the concentration value of the reference solution as X and the corresponding value as Y, and performing linear fitting to obtain a peak area so as to obtain a linear regression equation.
Description
Technical Field
The invention relates to the technical field of analysis, in particular to a method for detecting a high-molecular polymer in ropenem sodium by a determination method.
Background
Faropenem sodium is a penem antibiotic developed by Suntory company in Japan and marketed in 1997, has the characteristics of wide antibacterial spectrum and strong antibacterial activity, is stable to β -lactamase, and has good effects on extended-spectrum β -lactamase-producing bacteria, Citrobacter and enterococcus, and as Faropenem sodium is easy to produce high molecular polymers in the synthesis reaction and the sample storage process, the polymers are shown to be the main reason of penicillin allergy symptoms according to research, the domestic and foreign control of high molecular impurities of β -lactam antibiotics is very important, so that the detection and control of the high molecular polymers by reasonable means have important practical significance.
Disclosure of Invention
The invention aims to establish a detection method for determining a polymer in the ropenem sodium, which can better control the content of the polymer in the ropenem sodium in a raw material medicine of the faropenem sodium and can better control the quality of the raw material medicine of the faropenem sodium.
The technical scheme of the invention is that the method for measuring the faropenem sodium high molecular polymer in the faropenem bulk drug by adopting the gel chromatography comprises the following steps:
preparation of reference substance solution A proper amount of faropenem sodium reference substance is precisely weighed, and 0.1 mol/L pH =7.0 buffer solution is prepared into solution containing 0.01mg of faropenem sodium per 1 ml;
preparation of a test sample solution, sampling about 10mg, precisely weighing, placing into a 10ml measuring flask, adding 0.1 mol/L buffer solution with pH =7.0, diluting to scale, and shaking up;
a blank solution was prepared with 0.1 mol/L pH =7.0 buffer;
the chromatographic column is as follows: polystyrene gel TSKgel G2000SWxl chromatography column;
the chromatographic conditions are as follows: column temperature 40 ℃, detector: the detection wavelength of the ultraviolet detector is 222 nm; flow rate: 0.5 ml/min.
Mobile phase 0.1 mol/L pH =7.0, buffer solution methanol =95: 5;
sample introduction: sampling 20 μ l of each of the control solution, the sample solution and the blank solution, and recording chromatogram;
calculating a linear regression equation of the concentration value of the standard substance solution and the corresponding peak area value, wherein the correlation coefficient is not less than 0.99; precisely sucking 20 mu l of test solution to be injected into a liquid chromatograph, wherein in the chromatogram of the test solution, the content of the faropenem sodium polymer is not more than 0.15 percent, and the separation degree between the faropenem sodium polymer and an adjacent chromatographic peak is more than 1.5.
Description of the drawings: FIG. 1 is a chromatogram of the separation of Faropenem sodium from polymer under different mobile phase systems.
The present invention will be described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. Such alterations and modifications are intended to be included herein by the scope of this disclosure, and such modifications are intended to be within the meaning of those skilled in the art.
EXAMPLE 1 selection of chromatography columns
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate and phosphoric acid
Chromatographic conditions
Chromatographic column G-1010.0 mm × 300mm sephadex chromatographic column
The detection wavelength is 222nm, the flow rate is 1.2ml/min, the column temperature is 35 ℃, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution
Preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection.
And (4) conclusion: the chromatographic peak tailing of the separation using the filler is serious, and the faropenem sodium cannot be separated from the polymer.
EXAMPLE 2 selection of chromatography columns
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate and phosphoric acid
Chromatographic conditions
Chromatographic column G-1014.0 mm × 400mm sephadex chromatographic column
The detection wavelength is 222nm, the flow rate is 1.2ml/min, the column temperature is 35 ℃, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution;
preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection.
And (4) conclusion: the chromatographic peak tailing of the separation using the filler is serious, and the separation degree of faropenem sodium and polymer is 1.2, so that the experimental requirement cannot be met.
EXAMPLE 3 selection of chromatography columns
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate and phosphoric acid
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 222nm, the flow rate is 1.2ml/min, the column temperature is 35 ℃, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution;
preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection.
And (4) conclusion: the faropenem sodium peak shape of the chromatographic column using the filler is symmetrical.
Example 4 selection and optimization of chromatographic conditions
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate, phosphoric acid, ammonium acetate
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 222nm, the flow rate is 0.5ml/min, the column temperature is 35 ℃, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution methanol =95: 5;
preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection.
The four mobile phases in table 1 are analyzed respectively, the chromatogram is shown in fig. 1, and the separation degree of faropenem sodium main component and the detected high molecular polymer and the total analysis time are used as the investigation indexes.
Table 1 different mobile phase compositions for optimizing chromatographic separations
| Numbering | Mobile phase composition | Degree of separation | Analysis time (min) |
| a | 0.1 mol/L pH =7.0 buffer solution-methanol (95: 5) | 1.74 | 30 |
| b | 0.1 mol/L pH =7.0 buffer solution-methanol (90: 10) | 1.56 | 30 |
| c | 0.1 mol/L pH =7.0 buffer solution-methanol-acetonitrile (90: 5: 5) | 1.68 | 30 |
| d | 0.1 mol/L pH =7.0 buffer solution-acetonitrile (95: 5) | 1.68 | 30 |
| e | 0.1 mol/L pH =7.0 buffer solution-acetonitrile (90: 10) | 1.44 | 30 |
In the above five chromatographic systems, 0.1 mol/L pH =7.0 buffer solution-methanol (95: 5) was found to be the most suitable index when used as mobile phase.
EXAMPLE 5 Effect of flow Rate
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate, phosphoric acid, ammonium acetate
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 220nm, the column temperature is 40 ℃, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution methanol =95: 5;
preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection. The flow rates were respectively: 0.5ml/min, 1ml/min
And (4) conclusion: the results showed that the high molecular polymer was not effectively separated from the main component faropenem sodium peak at a flow rate of 1.0ml/min, and that the separation of the peaks was good when the flow rate was reduced to 0.5 ml/min.
EXAMPLE 6 Effect of column temperature
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump
Reagent: water, potassium dihydrogen phosphate, phosphoric acid, ammonium acetate
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 220nm, the flow rate is 0.5ml/min, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution methanol =95: 5;
preparation of test solutions: an appropriate amount of faropenem sodium was diluted to a 1mg/ml solution with a pH =7.0 buffer solution, and placed at 25 ℃ for 48 hours for injection. The column temperatures were respectively: the results at 25 ℃ and 35 ℃ and 50 ℃ are shown in Table 2.
TABLE 2 Effect of different column temperatures on the degree of separation of high molecular weight polymers
| Column temperature | Retention time of polymer | Main peak retention time | Main peak tailing factor | Degree of separation |
| 25℃ | 21.98 | 24.82 | 1.35 | 2.03 |
| 35℃ | 21.68 | 24.36 | 1.29 | 2.12 |
| 50℃ | 21.36 | 23.52 | 1.54 | 1.96 |
And (4) conclusion: as a result, the separation effect and symmetry of the main component and the impurity front are optimized at 35 ℃.
Example 7 specificity
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump, water bath, and light box
Reagent: water, potassium dihydrogen phosphate, phosphoric acid, ammonium acetate, hydrochloric acid, and sodium hydroxide
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 220nm, the column temperature is 35 ℃, the flow rate is 0.5ml/min, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution methanol =95: 5;
taking a proper amount of Faropenem sodium raw material, respectively carrying out strong acid (0.1 mol/L HCl) water bath and strong base (0.1 mol/L NaOH) water bath, heating for destruction, illuminating, neutralizing, and respectively diluting with a mobile phase to obtain a test solution containing 0.2mg of Faropenem sodium in each 1ml, and taking 1 to separate the solution.
And (4) conclusion: the results show that under the chromatographic system, various destructive tests can enlarge polymer peaks, the basic destruction and the acid destruction are most obvious, and the separation degree of each peak is good. The solvent does not interfere with the determination of faropenem sodium and its high molecular impurities. The specificity of the method is good.
Example 8 sample introduction precision detection
Instruments and reagents
The instrument comprises the following steps: waters2998 detector, Waters2695 solution delivery pump,
Reagent: water, potassium dihydrogen phosphate and phosphoric acid
Chromatographic conditions
A chromatographic column: g2000SWxl (300 mm) polystyrene gel chromatographic column
The detection wavelength is 220nm, the column temperature is 35 ℃, the flow rate is 0.5ml/min, the mobile phase is 0.1 mol/L phosphate buffer solution with the pH value of 7.0, and the sample injection amount is 20 mu l
Mobile phase 0.1 mol/L pH =7.0 buffer solution methanol =95: 5;
taking 1mg/ml of reference substance solution, taking continuous sample introduction for 6 times, and measuring peak area, wherein the relative standard deviation RSD is 0.32%.
And (4) conclusion: the method has good injection precision.
Example 9 linear relationship examination:
the chromatographic conditions are the same as example 8, a proper amount of faropenem sodium reference substance is precisely weighed, diluted by 0.1 mol/L pH =7.0 buffer solution to prepare reference substance solutions containing 0.0005, 0.001, 0.002, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1 and 1.5mg of faropenem sodium in each 1ml, and the concentration (C) of faropenem sodium is linearly regressed by the peak area (A) of faropenem sodium, and the result of linear equation A =65099008.3C-100055.5 shows that faropenem sodium has a good linear relation with the peak area within the concentration range of 0.0002 mg/ml-1.5 mg/ml, and r =1.0000
Example 10 detection and quantitation limits
The chromatographic conditions are the same as example 8, a proper amount of Faropenem sodium reference substance is precisely measured, dissolved in a buffer solution with the pH =7.0 of 0.1 mol/L, diluted step by step and injected with 10ul of sample, a chromatogram is recorded with the S/N =3 as the detection limit, the minimum detection concentration is about 0.2ug/ml, and the sensitivity is good.
EXAMPLE 11 sample determination
The chromatography conditions were exactly the same as example 8, and the appropriate amount of faropenem sodium sample powder was precisely weighed, diluted with 0.1 mol/L buffer pH =7.0 and made into a solution containing about 1mg per 1ml, and the results of 3 batches of samples were determined as shown in table 3.
TABLE 3 results of sample measurement
| Batch number | Peak area of control | Peak area of impurity | Impurities% |
| 160816 | 600657 | 9307 | 0.01 |
| 160817 | 596926 | 9293 | 0.01 |
| 160818 | 598834 | 8753 | 0.01 |
EXAMPLE 12 durability detector wavelength variation
The chromatographic conditions were the same as in example 8, with the detector wavelength being varied as: detector wavelength variation 1: 220nm, detector wavelength variation 2: 224nm, original detector wavelength: 222nm, the test results are shown in Table 4.
Table 4 comparative table of wavelength change test results of detector
| Wavelength of detector | 222nm | 220nm | 224nm |
| Degree of separation | 2.12 | 2.18 | 2.10 |
And (4) conclusion: the required separation effect can be achieved by measuring under the chromatographic condition, and the change of the detection wavelength within the allowable range of 220 nm-224 nm has no influence on the separation of the faropenem sodium high molecular polymer.
EXAMPLE 13 durable flow Rate variation
The chromatographic conditions were as in example 8, with the flow rate being varied as: flow rate variation 1: 0.4ml/min, flow rate variation 2: 0.6ml/min, original flow rate: 0.5ml/min, and the test results are shown in Table 5.
Table 5 flow rate variation test results comparison table
| Flow rate of flow | 0.4ml/min | 0.6ml/min | 0.5ml/min |
| Degree of separation | 2.31 | 1.98 | 2.12 |
And (4) conclusion: the required separation effect can be achieved by measuring under the chromatographic condition, and the change of the flow rate within the allowable range of 0.4 ml/min-0.6 ml/min has no influence on the separation of the faropenem sodium high molecular polymer.
EXAMPLE 14 durability column temperature Change
The chromatographic conditions were as in example 8, with the column temperature being varied as: column temperature change 1: 35 ℃ and column temperature variation of 2: 45 ℃ and original column temperature: the test results are shown in Table 6 at 40 ℃.
Table 6 comparative table of column temperature change test results
| Column temperature | 35℃ | 45℃ | 40℃ |
| Degree of separation | 2.12 | 2.10 | 2.12 |
And (4) conclusion: the required separation effect can be achieved by measuring under the chromatographic conditions, and the change of the column temperature within the allowable range of 55-45 ℃ has no influence on the separation of the faropenem sodium high molecular polymer.
Example 15 flow phase Change
The chromatographic conditions were the same as in example 8, the mobile phase was 1: prepared from 0.1 mol/L sodium dihydrogen phosphate, pH =7.0 buffer, the mobile phase was 2: prepared from 0.1 mol/L potassium dihydrogen phosphate, pH =7.0 buffer, the mobile phase was 3: prepared from 0.1 mol/L pH =7.0 buffer, and the test results are shown in Table 7
Table 7 comparative table of flowing phase change test results
| Mobile phase | 0.1 mol/L sodium dihydrogen phosphate | 0.1 mol/L Potassium dihydrogen phosphate | 0.1mol ammonium acetate |
| Degree of separation | 2.12 | 2.15 | 2.11 |
And (4) conclusion: therefore, the change of the buffer solution has no influence on the separation of the faropenem sodium high molecular polymer.
Example 16 solution stability
The chromatographic conditions are the same as example 8, a sample is precisely weighed to 50mg to 50ml in a volumetric flask, 0.1 mol/L pH =7.0 buffer solution is added for dissolution, the solution is diluted to a scale, the solution is shaken up, the solution is placed at room temperature, 10ul samples are respectively injected in 0, 1, 2, 5, 8, 12 and 24 hours, the peak area is measured, the peak area of the faropenem sodium high molecular polymer is gradually increased along with the increase of time within 24 hours, the area is 42 times of 0 hour after the solution is placed at room temperature for 24 hours, and the peak area of the main component basically has no obvious change
In conclusion, faropenem sodium is unstable in a buffer solution with 0.1 mol/L pH =7.0, and easily generates high molecular impurities, so that a test article needs to be newly prepared.
Claims (4)
1. The method for detecting the faropenem sodium high molecular polymer in the raw material of the faropenem sodium by the polystyrene gel chromatography method is characterized by comprising the following steps:
preparing a control solution by precisely weighing an appropriate amount of faropenem sodium control, and preparing a solution containing 0.01mg of faropenem sodium per 1ml by using 0.1 mol/L buffer with pH = 7.0;
preparing a test solution, namely taking a sample containing faropenem sodium about 10mg, precisely weighing, putting the sample into a 10ml measuring flask, adding 0.1 mol/L buffer solution with pH =7.0, diluting to scale, and shaking up;
a blank solution was prepared with 0.1 mol/L pH =7.0 buffer;
the chromatographic column is a polystyrene gel TSKgel G2000SWxl 7.8 × 300mm 5 μm chromatographic column;
the chromatographic conditions comprise that the column temperature is 35-45 ℃, a detector is an ultraviolet detector, the detection wavelength is 220-224nm, the flow rate is 0.4-0.6ml/min, the mobile phase is 0.1 mol/L, the pH is =6.8-7.2, phosphate buffer solution is methanol =97-93, and the flow rate is 3-7;
under the chromatographic conditions, precisely sucking 20 μ l of reference solution, 20 μ l of test solution and 20 μ l of blank solution, injecting into a liquid chromatograph, recording chromatogram, and calculating linear regression equation of the concentration of the reference solution and corresponding peak area value, wherein the correlation coefficient should be not less than 0.99; precisely sucking 20 mu l of test solution to be injected into a liquid chromatograph, wherein in the chromatogram of the test solution, the content of the faropenem sodium polymer is not more than 0.15 percent, and the separation degree between the faropenem sodium polymer and an adjacent chromatographic peak is more than 1.5.
2. The method for detecting the faropenem sodium high molecular polymer in the faropenem sodium raw material according to claim 1, wherein the column temperature is 35 ℃, the detection wavelength is 220nm, the flow rate is 0.4ml/min, and the mobile phase is 0.1 mol/L, pH =6.8 phosphate buffer solution, methanol =97: 3.
3. The method for detecting the faropenem sodium high molecular polymer in the raw material of the faropenem sodium according to claim 1, wherein the column temperature is 45 ℃, the detection wavelength is 224nm, the flow rate is 0.6ml/min, and the mobile phase is 0.1 mol/L, pH =7.2 phosphate buffer solution, methanol =93: 7.
4. The method for detecting the faropenem sodium high molecular polymer in the faropenem sodium raw material according to claim 1, wherein the column temperature is 40 ℃, the detection wavelength is 222nm, the flow rate is 0.5ml/min, and the mobile phase is 0.1 mol/L pH =7.0 phosphate buffer solution methanol =95: 5.
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