CN111458436A - Method for measuring photodegradation impurities in levofloxacin raw material and preparation - Google Patents
Method for measuring photodegradation impurities in levofloxacin raw material and preparation Download PDFInfo
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- CN111458436A CN111458436A CN202010308173.5A CN202010308173A CN111458436A CN 111458436 A CN111458436 A CN 111458436A CN 202010308173 A CN202010308173 A CN 202010308173A CN 111458436 A CN111458436 A CN 111458436A
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
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Abstract
The invention belongs to the field of drug detection, and particularly relates to a method for determining photodegradation impurities in a levofloxacin raw material and a preparation, which comprises the following steps of (1) preparing a standard solution of the levofloxacin photodegradation impurities, (2) injecting the standard solution into a high performance liquid chromatograph for determination, and constructing a standard curve by taking the concentration of the standard solution as a horizontal coordinate and the peak area as a vertical coordinate, (3) preparing a sample solution to be determined, and (4) injecting the sample solution to be determined into the high performance liquid chromatograph for determination, recording the peak area, and calculating by using the standard curve to obtain the content of the photodegradation impurities.
Description
Technical Field
The invention belongs to the field of drug detection, and particularly relates to a method for determining photodegradation impurities in a levofloxacin raw material and a levofloxacin preparation.
Background
Levofloxacin with the chemical name (-) - (S) -3-methyl-9-fluoro-2, 3-dihydro-10- (4-methyl-1-piperazinyl) -7 oxo-7H-pyrido [1, 2, 3-de]-1, 4-benzoxazine-6-carboxylic acid hemihydrate of the formula
Has a molecular weight of 370.38 and a chemical structural formula:
levofloxacin has been marketed in japan in 1993. The medicine has good curative effect on respiratory tract infection, genitourinary infection, skin soft tissue infection and the like. The effective rate and the bacterial clearance rate for treating acute and chronic lower respiratory tract infection reach 80-100%, the clearance rate for haemophilus influenzae, catarrh moraxella, staphylococcus aureus and pneumococcus is high, and the clearance rate for pseudomonas aeruginosa is poor. The effective rate and the bacterial clearance rate for complicated and simple urinary tract infection are 80-100%. The effective rate for treating skin soft tissue infection is 80-91%, and the clearance rate of methicillin-sensitive staphylococcus is close to 90%. The effective rate of treating infection of obstetrics and gynecology department, ears, nose, throat and the like is about 90 percent.
The diformyl body of levofloxacin is one of the products of levofloxacin solution photodegradation, hereinafter referred to as diformyl body impurity, and the structural formula and the production route are as follows:
in the existing quality standards of levofloxacin raw materials and preparations, including standards of Chinese pharmacopoeia, United states Pharmacopeia, Japanese pharmacopoeia, European Pharmacopeia and the like, and related substance inspection methods listed, the impurity response value of the diformyl body is low, and the requirement of the limit detection sensitivity cannot be met, so that the method for detecting the impurity of the diformyl body of levofloxacin needs to be provided.
Disclosure of Invention
In view of the above disadvantages, the present invention aims to provide a method for determining photodegradation impurities in a levofloxacin raw material and a preparation, which has the characteristics of simple operation, strong specificity, high precision and good accuracy, and can effectively detect the content of photodegradation impurities in the levofloxacin raw material and the preparation.
The method for determining photodegradation impurities in levofloxacin raw materials and preparations comprises the following steps:
(1) preparing standard solution of levofloxacin photodegradation impurities;
(2) injecting the standard solution into a high performance liquid chromatograph for determination, and constructing a standard curve by taking the concentration of the standard solution as a horizontal coordinate and taking a peak area as a vertical coordinate;
(3) preparing a sample solution to be detected;
(4) injecting the sample solution to be measured into a high performance liquid chromatograph for measurement, recording the peak area of the sample solution, and calculating by using a standard curve to obtain the content of photodegradation impurities;
wherein, the chromatographic conditions of the high performance liquid chromatograph are as follows:
a chromatographic column: adopting amino silane bonded silica gel as a filling agent;
the mobile phase is acetonitrile-0.05 mol/L potassium dihydrogen phosphate solution;
and (3) an elution mode: isocratic elution;
the flow rate is 0.5-0.9m L/min;
detection wavelength: 250-260 nm;
column temperature: 25-35 ℃;
the injection volume is 5-100 mu L.
The impurity of the benzopiperazine, which is another process impurity in the raw material and the preparation of the levofloxacin, has the peak emergence time which is closer to that of the impurity of the diformyl, and the levofloxacin and the impurity of the benzopiperazine can be separated by the method.
The structural formula of the impurity of the benzopiperazine is as follows:
preferably, the volume ratio of acetonitrile to 0.05 mol/L of potassium dihydrogen phosphate solution is 67:33-73:27, preferably 70: 30.
Preferably, the pH value of the 0.05 mol/L potassium dihydrogen phosphate solution is 5.1-5.5, preferably 5.3, and the pH value of the 0.05 mol/L potassium dihydrogen phosphate solution is adjusted by using a sodium hydroxide test solution.
Preferably, the size of the chromatographic column is 4.6 × 250mm, 5 μm.
Preferably, the column temperature is: at 30 ℃.
Preferably, the flow rate is 0.7m L/min.
Preferably, the detection wavelength is: 257 nm.
Preferably, the sample injection volume is 10 mu L.
Preferably, the levofloxacin reference, the dibenzoyl impurity reference and the benzopiperazine impurity reference are dissolved and diluted by a mobile phase as a system suitability solution.
Compared with the prior art, the invention has the following beneficial effects:
the method for measuring the photodegradation impurities in the levofloxacin raw material and the preparation has the characteristics of simple operation, strong specificity, high precision and good accuracy, can effectively detect the content of the photodegradation impurities in the levofloxacin raw material and the preparation, and is favorable for safe popularization and application of the levofloxacin.
Drawings
FIG. 1 is a chromatogram of a blank solvent (mobile phase) according to the invention;
FIG. 2 is a chromatogram of a blank adjuvant solution of levofloxacin tablets;
FIG. 3 is a chromatogram of a system suitability solution of the present invention;
FIG. 4 is a standard curve of the impurity levels of the dibenzoyl species for a linear range of investigation.
Detailed Description
The present invention is further described below with reference to examples. Are provided for illustration only and are not intended to limit the scope of the present invention.
Example 1
The method for measuring photodegradation impurities in the levofloxacin raw material and the preparation adopts high performance liquid chromatography for measurement, and the chromatographic conditions are as follows:
chromatographic column, using amino silane bonded silica gel as filler, 4.6 × 250mm, 5 μm;
mobile phase acetonitrile-0.05 mol/L potassium dihydrogen phosphate solution (pH adjusted to 5.3 with sodium hydroxide test solution) (70: 30);
detection wavelength: 257 nm;
the flow rate is 0.7m L/min;
column temperature: 30 ℃;
blank solvent: the mobile phase was taken as the blank solvent.
(1) Specificity test
Blank adjuvant solution is prepared by precisely weighing about 18mg of blank adjuvant, placing into a 50m L measuring flask, adding mobile phase for dissolving, diluting to scale, shaking, and filtering to obtain blank adjuvant solution.
The system applicability solution is prepared by taking appropriate amount of each of levofloxacin, dibenzoyl impurity and benzopiperazine impurity reference substance, adding mobile phase for dissolving and diluting to obtain a solution containing levofloxacin 1.0mg, diformyl impurity 2 μ g and benzopiperazine impurity 2 μ g per 1m L.
And (3) positioning solution, namely respectively taking appropriate amounts of levofloxacin, dibenzoyl impurities and a benzopiperazine impurity reference substance, adding a mobile phase for dissolving, and respectively diluting to prepare a solution containing 1.0mg of levofloxacin, 20 mu g of diformyl impurities and 20 mu g of benzopiperazine impurities in every 1m L, wherein the solution is used as the positioning solution of the levofloxacin, the dibenzoyl impurities and the benzopiperazine impurities.
Adding standard sample solution, precisely weighing about 10mg of dibenzoyl impurity reference substance, placing in 100m L measuring flask, adding mobile phase for dissolving and diluting to scale, shaking to obtain reference substance stock solution, precisely weighing appropriate amount of levofloxacin tablet fine powder (about equivalent to levofloxacin 50mg), placing in 50m L measuring flask, adding appropriate amount of mobile phase for dissolving, precisely weighing 1m L of reference substance stock solution, placing in 50m L measuring flask, diluting with mobile phase to scale, shaking, filtering, and making into standard sample solution.
Precisely measuring 10 μ L of each solution, injecting into a high performance liquid chromatograph, and recording chromatogram, wherein the result is shown in Table 1, the mobile phase chromatogram is shown in figure 1, the blank adjuvant solution chromatogram is shown in figure 2, and the system applicability solution chromatogram is shown in figure 3.
TABLE 1 results of specialization
And (4) conclusion: the blank solvent and the blank auxiliary materials do not interfere with the determination of the dibenzoyl impurities, the unknown impurities in the solution of the added sample do not interfere with the dibenzoyl impurities, and the separation degree of the benzopiperazine impurities and the diformyl impurities meets the requirement, which indicates that the method for determining the content of the diformyl impurities in the levofloxacin raw material and the preparation by the high performance liquid chromatography provided by the invention has good specificity.
(2) Linear and range test
The sample solution of impurity of dibenzoyl is prepared by precisely weighing about 10mg of the sample solution of impurity of dibenzoyl, dissolving with mobile phase, diluting to 10m L, precisely weighing the solution 2m L, and bottling in 100m L bottles to obtain the sample solution of impurity of dibenzoyl.
Linear solution: precisely measuring a proper amount of a reference sample stock solution of the dibenzoyl impurities, and preparing a solution with quantitative limit concentration, linearity of 25%, linearity of 50%, linearity of 100%, linearity of 150% and linearity of 200% by using the solution to serve as a linear solution.
Precisely measuring 10 μ L of each solution, injecting into a high performance liquid chromatograph, recording chromatogram, drawing a standard curve with peak area as ordinate and linear solution concentration (μ g/m L) as abscissa, wherein the linear result is shown in Table 2 and the standard curve is shown in FIG. 4.
TABLE 2 Linear results
The conclusion is that the dibenzoyl impurity is in the linear range of 0.059-3.940 mug/m L (about 3-200% of the limit concentration), the linear equation is y-43548 x-53.275, the correlation coefficient r is 0.9999 > 0.990, and the linear relation between the peak area and the concentration is good.
(3) Recovery test
The test is carried out by preparing standard sample adding solutions with quantitative limit concentration, 50 percent limit concentration, 100 percent limit concentration and 150 percent limit concentration.
The reference sample stock solution of impurity of dibenzoyl is prepared by precisely weighing about 10mg of the reference sample of impurity of dibenzoyl, placing into a 100m L measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking to obtain the reference sample stock solution of impurity of dibenzoyl.
Reference solution prepared by precisely measuring the sample solution of the impurity of the dibenzoyl 2m L, placing in a bottle 100m L, diluting with mobile phase to scale, and shaking to obtain reference solution.
Adding standard sample solution, precisely weighing levofloxacin tablet fine powder (about equivalent to levofloxacin 100mg), placing into 9 100m L measuring bottles, adding appropriate amount of mobile phase for dissolving, precisely measuring dibenzoyl impurity reference sample stock solutions 1.0m L, 2.0m L and 3.0m L respectively, placing into the above 100m L measuring bottles, adding mobile phase for diluting to scale, shaking, filtering, taking subsequent filtrate as standard sample solution with concentration of 50%, 100% and 150%, respectively, and preparing 3 parts of solution with different concentrations in parallel.
Each of the solutions 10. mu. L was precisely measured and injected into a high performance liquid chromatograph, and the chromatogram was recorded, and the results are shown in Table 3.
TABLE 3 recovery results
And (4) conclusion: under the quantitative limit, the concentrations of 50%, 100% and 150%, the recovery rate of the impurity of the dibenzoyl body is between 90% and 110%, and the RSD is 1.1%, which shows that the method is used for detecting the impurity of the dibenzoyl body and has good accuracy.
(4) Repeatability test
The test was carried out by preparing 6 solutions of the standard test article with the same concentration of impurities.
Precisely weighing levofloxacin tablet fine powder (about equivalent to 100mg of levofloxacin), placing the levofloxacin tablet fine powder into 6 100m L measuring bottles, adding a proper amount of mobile phase to dissolve the levofloxacin tablet fine powder, respectively precisely weighing 2.0m L of dibenzoyl impurity reference substance stock solution, placing the dibenzoyl impurity reference substance stock solution into the 100m L measuring bottles, adding the mobile phase to dilute the mixture to a scale, shaking up the mixture, filtering the mixture, taking subsequent filtrate, respectively taking the subsequent filtrate as a standard sample solution, and parallelly preparing 6 parts.
Each of the solutions 10. mu. L was precisely measured and injected into a high performance liquid chromatograph, and the results of the chromatogram analyses are shown in Table 4.
TABLE 4 repeatability results
And (4) conclusion: the RSD of the content of the impurity of the dibenzoyl body is 0.8 percent according to the repeated determination result of 6 times, which meets the requirement and shows that the method is used for detecting the impurity of the dibenzoyl body and has good repeatability.
(5) Durability test
Blank adjuvant solution is prepared by precisely weighing about 18mg of blank adjuvant, placing into a 50m L measuring flask, adding mobile phase for dissolving, diluting to scale, shaking, and filtering to obtain blank adjuvant solution.
The system applicability solution is prepared by taking appropriate amount of levofloxacin, dibenzoyl impurity and benzopiperazine impurity as reference substances, adding mobile phase for dissolving and diluting to obtain solution containing levofloxacin 1.0mg, diformyl impurity 2 μ g and benzopiperazine impurity 2 μ g per 1m L;
reference solution prepared by precisely measuring the sample solution of the impurity of the dibenzoyl 2m L, placing in a 100m L volume bottle, diluting with mobile phase to scale, and shaking to obtain the reference solution of recovery rate.
Adding standard sample solution, precisely weighing appropriate amount of levofloxacin tablet fine powder (about equivalent to levofloxacin 50mg), placing into 50m L measuring flask, adding appropriate amount of mobile phase to dissolve, precisely weighing reference sample stock solution 1m L, placing into the 50m L measuring flask, diluting to scale with mobile phase, shaking, filtering, and making into standard sample solution.
And (5) standing the reference substance solution for 0h, 4.5h, 9h, 13.5h, 18h and 24h at room temperature in a dark environment, and inspecting the stability of the solution.
Each of the solutions was measured precisely at 10. mu. L, and the solutions were injected into a high performance liquid chromatograph under various chromatographic conditions, and chromatograms were recorded, and the results are shown in tables 5 to 6.
TABLE 5 solution stability test results
And (4) conclusion: under the environment of room temperature and light shielding, the RSD of the areas of the two formyl impurity peaks in the reference substance solution and the added standard sample solution is 0.2 percent and 0.4 percent respectively, which meets the requirements and shows that the stability of the two formyl impurity reference substance solution and the added standard sample solution is good within 24 hours.
TABLE 6 durability test results
The conclusion is that when the flow rate changes by +/-0.2 m L/min, the column temperature changes by +/-5 ℃, the acetonitrile-buffer solution ratio changes by +/-3, the pH value of the buffer solution changes by +/-0.2 and the chromatographic columns of different batches are replaced, compared with the normal condition, the content of the diformyl impurity has no obvious difference.
The foregoing is only a preferred embodiment of the present invention, and it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the spirit and scope of the invention as claimed.
Claims (10)
1. A method for measuring photodegradation impurities in levofloxacin raw materials and preparations is characterized in that: the method comprises the following steps:
(1) preparing standard solution of levofloxacin photodegradation impurities;
(2) injecting the standard solution into a high performance liquid chromatograph for determination, and constructing a standard curve by taking the concentration of the standard solution as a horizontal coordinate and taking a peak area as a vertical coordinate;
(3) preparing a sample solution to be detected;
(4) injecting the sample solution to be measured into a high performance liquid chromatograph for measurement, recording the peak area of the sample solution, and calculating by using a standard curve to obtain the content of photodegradation impurities;
wherein, the chromatographic conditions of the high performance liquid chromatograph are as follows:
a chromatographic column: adopting amino silane bonded silica gel as a filling agent;
the mobile phase is acetonitrile-0.05 mol/L potassium dihydrogen phosphate solution;
and (3) an elution mode: isocratic elution;
the flow rate is 0.5-0.9m L/min;
detection wavelength: 250-260 nm;
column temperature: 25-35 ℃;
the injection volume is 5-100 mu L.
2. The method for determining photodegradation impurities in levofloxacin starting materials and formulations according to claim 1, wherein the volume ratio of acetonitrile to 0.05 mol/L of potassium dihydrogen phosphate solution is 67:33-73: 27.
3. The method for measuring photodegradation impurities in levofloxacin raw materials and preparations according to claim 2, wherein the volume ratio of acetonitrile to 0.05 mol/L potassium dihydrogen phosphate solution is 70: 30.
4. The method for measuring photodegradation impurities in levofloxacin raw materials and preparations according to claim 1, wherein the pH value of the 0.05 mol/L potassium dihydrogen phosphate solution is 5.1-5.5.
5. The method for detecting photodegradation impurities in levofloxacin starting materials and formulations as claimed in claim 4, wherein said 0.05 mol/L mole solution of potassium dihydrogen phosphate has a pH of 5.3.
6. The method for measuring photodegradation impurities in levofloxacin raw materials and preparations according to claim 1, wherein the specification of the chromatographic column is 4.6 × 250mm, 5 μm.
7. The method for determining photodegradable impurities in levofloxacin starting materials and formulations according to claim 1, wherein: the column temperature is as follows: at 30 ℃.
8. The method for measuring photodegradation impurities in levofloxacin raw materials and preparations according to claim 1, wherein the flow rate is 0.7m L/min.
9. The method for determining photodegradable impurities in levofloxacin starting materials and formulations according to claim 1, wherein: the detection wavelength is as follows: 257 nm.
10. The method for measuring photodegradation impurities in levofloxacin raw materials and preparations according to claim 1, wherein the injection volume is 10 μ L.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113466365A (en) * | 2021-06-23 | 2021-10-01 | 海南海神同洲制药有限公司 | Method for detecting related impurities in ofloxacin tablets by using HPLC (high performance liquid chromatography) |
| CN113640416A (en) * | 2021-08-12 | 2021-11-12 | 海南海神同洲制药有限公司 | Content determination method of levofloxacin hydrochloride tablets |
| CN114354794A (en) * | 2021-12-29 | 2022-04-15 | 四川美大康佳乐药业有限公司 | Quality control method of pazufloxacin mesilate injection |
| CN117405784A (en) * | 2023-10-12 | 2024-01-16 | 华夏生生药业(北京)有限公司 | Method for detecting related impurities in levofloxacin preparation by HPLC |
| CN118624805A (en) * | 2024-08-08 | 2024-09-10 | 山东齐都药业有限公司 | Method for measuring dissolution curve of compound sodium sulfate tablet |
-
2020
- 2020-04-18 CN CN202010308173.5A patent/CN111458436A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113466365A (en) * | 2021-06-23 | 2021-10-01 | 海南海神同洲制药有限公司 | Method for detecting related impurities in ofloxacin tablets by using HPLC (high performance liquid chromatography) |
| CN113640416A (en) * | 2021-08-12 | 2021-11-12 | 海南海神同洲制药有限公司 | Content determination method of levofloxacin hydrochloride tablets |
| CN114354794A (en) * | 2021-12-29 | 2022-04-15 | 四川美大康佳乐药业有限公司 | Quality control method of pazufloxacin mesilate injection |
| CN117405784A (en) * | 2023-10-12 | 2024-01-16 | 华夏生生药业(北京)有限公司 | Method for detecting related impurities in levofloxacin preparation by HPLC |
| CN118624805A (en) * | 2024-08-08 | 2024-09-10 | 山东齐都药业有限公司 | Method for measuring dissolution curve of compound sodium sulfate tablet |
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Application publication date: 20200728 |