CN112526013B - Method for detecting concentration of related substances in ibuprofen medicament by using ultra-high liquid chromatography - Google Patents
Method for detecting concentration of related substances in ibuprofen medicament by using ultra-high liquid chromatography Download PDFInfo
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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
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- G—PHYSICS
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- 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
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Abstract
The invention discloses a method for detecting the concentration of related substances in an ibuprofen medicament based on an ultra-high liquid chromatography, and belongs to the technical field of analytical chemistry. The detection method is based on high performance liquid chromatography to detect related substances in the ibuprofen medicament, and further adopts ultra-high performance liquid chromatography to qualitatively and quantitatively detect related substances in the ibuprofen medicament, such as impurity C, impurity J, impurity M and impurity ibuprofen sorbitol ester, so that the analysis time of a sample can be reduced to one third of that of an HPLC analysis method, and impurities with different structures can be separated and detected in a shorter time; the UPLC has a low-diffusion and low-cross-contamination automatic sample injector, and is provided with an in-needle sample injection probe and a pressure auxiliary sample injection technology, so that the repeatability and the stability of the detection method designed by the invention are better, and the effective detection of impurities is realized.
Description
The invention relates to detection of impurities in a medicine, belongs to the technical field of analytical chemistry, and particularly relates to a method for detecting the concentration of related substances in an ibuprofen medicine based on an ultra-high liquid chromatography.
Background
Ibuprofen (Ibuprofen) is a non-steroidal anti-inflammatory drug with antipyretic and analgesic effects. It can inhibit cyclooxygenase, reduce prostaglandin synthesis, and has analgesic and antiinflammatory effects; acting as a antipyretic through the hypothalamic thermoregulatory center. The ibuprofen medicament, such as the soft capsule, comprises a rubber skin and an ibuprofen-containing content which is wrapped in the rubber skin, has the advantages of good stability, convenient taking, high bioavailability and the like, and is a preparation formulation which is widely applied clinically at present.
The substances of interest are process impurities introduced during the production of the pharmaceutical product or degradation products produced during storage, and are known or unknown, volatile or nonvolatile organic impurities. Such impurities are referred to as related substances because their chemical structures are generally similar or have a profound relationship with the active ingredient. The detection of related substances is one of the key items in the medicine quality research, and the content of the related substances is a direct index reflecting the purity of the medicine. The related substances in the ibuprofen medicament are various, and by analyzing the impurities mentioned in the ibuprofen bulk drugs by pharmacopoeia of various countries and combining with actual production processes, the organic impurities possibly existing in the ibuprofen medicament can be known to be impurities A { (2RS) -2- [3- (2-methylpropyl) phenyl ] propionic acid }, impurities B { (2RS) -2- (4-butylphenyl) propionic acid }, impurities C {1- [4- (2-methylpropyl) phenyl ] ethanone }, impurities D { (2RS) -2- (4-methylphenyl) propionic acid }, impurities J { (2RS) -2- [4- (2-methylpropyl) phenyl ] propionic acid }, impurities L {2- [4- (1-hydroxy-2-methylpropyl) phenyl ] propionic acid }, and impurities L { (2- [4- (1-hydroxy-2-methylpropyl) phenyl ] propionic acid } Impurities M { (2RS) -2-hydroxy-2- [4- (2-methylpropyl) phenyl ] propanoic acid }, ibuprofen sorbitol ester and ibuprofen polyethylene glycol 400 copolymer.
High Performance Liquid Chromatography (HPLC) is a common means for measuring related substances in ibuprofen medicaments, the accuracy and stability of the separation technology are good, and almost all organic impurities can be well separated and detected; however, due to more impurities, the analysis time for HPLC (high performance liquid chromatography) determination of related substances in the ibuprofen medicament is longer, the running time of one injection of sample is 90min, and the detection time cost and the solvent cost are higher; meanwhile, the analysis time is long, so that the high performance liquid chromatograph and the chromatographic column have high requirements on durability. In addition, when HPLC is used for determining related substances in the ibuprofen medicament, the relative retention time of the impurity M and ibuprofen sorbitol ester is relatively close, the separation degree is low, and in the product detection releasing process, when the impurity is positioned by using the relative retention time, the impurity M and ibuprofen sorbitol ester are easily confused due to the influence of the retention time drift of each peak, so that the accurate quantification of the impurity M and ibuprofen sorbitol ester in the ibuprofen medicament is influenced. Therefore, a more efficient and rapid separation technology is explored, and the method can be more sensitively, stably and accurately suitable for detecting related substances in the ibuprofen soft capsule.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a method for detecting the concentration of related substances in an ibuprofen medicament based on an ultra-high liquid chromatography. Compared with the traditional HPLC, the UPLC can realize faster analysis speed, obtain higher sensitivity and resolution, shorten the analysis time, reduce the using amount of a solvent and reduce the analysis cost.
In order to achieve the technical purpose, the invention discloses a method for detecting the concentration of related substances in an ibuprofen medicament based on an ultrahigh liquid chromatography, wherein the related substances comprise an impurity C, an impurity J, an impurity M and an impurity ibuprofen sorbitol ester, and the method comprises the steps of respectively sampling a diluent, a standard ibuprofen solution, an auxiliary material blank solution and an ibuprofen solution by the ultrahigh liquid chromatography to obtain a qualitative detection chromatogram of each component;
preparing an ibuprofen standard stock solution, an impurity C standard stock solution, an impurity J standard stock solution, an impurity M standard stock solution and an impurity ibuprofen sorbitol ester standard stock solution, then respectively diluting the ibuprofen standard stock solution, the impurity J standard stock solution and the impurity ibuprofen sorbitol ester standard stock solution into linear standard solutions by adopting a diluent, and respectively sampling to obtain linear working curves;
wherein, the detection conditions are as follows:
and (3) chromatographic column: c 18 ，2.1×50mm，1.7μm；
Column temperature: 30-45 ℃;
mobile phase A: acetonitrile; mobile phase B: 0.01mol/L potassium dihydrogen phosphate solution with pH value of 2.0-3.0; gradient elution;
flow rate: 0.3-0.5 mL/min;
sample introduction volume: 4.0 mu L;
further, the column temperature was 40 ℃.
Further, the pH of the potassium dihydrogen phosphate solution in the mobile phase B was 2.0.
Further, the flow rate was 0.3 mL/min.
Further, the detection wavelength was 214 nm; the detector is an ultraviolet detector.
Further, the diluent is a mixed solution of acetonitrile and water with the volume ratio of 50: 50; still include before the appearance of a sample wash needle 10 ~ 20s, after the appearance of a sample wash needle 25 ~ 35s, and wash the solvent and be 50 for the volume ratio: 50 of acetonitrile and water; the cleaning solvent is a mixed solution of acetonitrile and water with the volume ratio of 10: 90.
Further, the impurity C is 1- [4- (2-methylpropyl) phenyl ] ethanone, the impurity J is (2RS) -2- [4- (2-methylpropyl) phenyl ] propionic acid, and the impurity M is (2RS) -2-hydroxy-2- [4- (2-methylpropyl) phenyl ] propionic acid.
Further, the ibuprofen medicament comprises any one of ibuprofen soft capsules, ibuprofen tablets, ibuprofen suspension or ibuprofen suppositories.
Has the advantages that:
1. the UPLC-based detection method is applied to qualitative determination of related substances in ibuprofen drugs, can shorten the analysis time of a sample to one third of that of an HPLC analysis method, and separates and detects impurities with different structures in a shorter time; the UPLC has a low-diffusion and low-cross-contamination automatic sample injector, and is provided with an in-needle sample injection probe and a pressure auxiliary sample injection technology, so that the repeatability and the stability of the detection method designed by the invention are better, and the effective detection of impurities is realized.
2. The detection method designed by the invention has the advantages of high sensitivity, small required sample amount, and good precision and accuracy, and can realize quantitative detection of related substances in the ibuprofen medicament.
Drawings
FIG. 1 is a chromatogram of a blank diluent solution;
FIG. 2 is a chromatogram of a standard solution;
FIG. 3 is a chromatogram of a blank solution of excipients;
fig. 4 is a chromatogram of the sample solution.
Detailed Description
As mentioned above, the invention aims to provide a method for determining the concentration of related substances in an ibuprofen medicament based on ultra-high liquid chromatography, wherein the related substances comprise C, J, M and ibuprofen sorbitol ester, and the method can realize effective separation of chromatographic peaks of various impurities and can accurately determine the quality and quantity of ibuprofen and related impurity conditions.
The instruments and drugs selected for use in the present invention are performed under the conditions of no indication, according to the conventional conditions or the conditions suggested by the manufacturer, or by the conventional products commercially available. The measurement instrument chosen in the present invention is Waters acquire UPLC.
The chemical structural formula of the impurities detected by the invention is shown in the following table 1:
TABLE 1 list of chemical structures of related substances in ibuprofen drugs
In the following, the method for detecting ibuprofen and its impurity C, J, M and ibuprofen sorbitol ester according to the present invention will be described with emphasis.
(1) Screening of detection conditions:
a proper amount of ibuprofen sample and each impurity reference substance are respectively taken and placed in a measuring flask with a certain volume, and then the ibuprofen sample and each impurity reference substance are dissolved and diluted to a scale by adding a mobile phase, and then the ibuprofen sample and each impurity reference substance are shaken up and filtered. In order to realize effective separation of ibuprofen and its impurity C, J, M and ibuprofen sorbitol ester, the invention discusses chromatographic column, mobile phase, pH value, flow rate, elution procedure, column temperature, sample amount and the like to screen chromatographic conditions, and the specific screening process is shown in Table 2:
table 2 chromatographic conditions screening list
From the above table 2 it is determined that the chromatographic conditions of the present invention are as follows:
a chromatographic column: ACQUIYUPLC BEH C18, 2.1X 50mm, 1.7 μm;
column temperature: 40 ℃;
flow rate: 0.3 mL/min;
wavelength: 214 nm;
a detector: UV;
sample introduction volume: 4.0 mu L;
the specific elution procedure is shown in table 3:
TABLE 3 elution procedure List
Cleaning solvent: acetonitrile/water (50/50, v/v);
removing the solvent: acetonitrile/water (10/90, v/v);
needle washing before sample introduction: 15 s;
and (3) needle washing after sample injection: for 30 s.
Wherein, the mobile phase A is acetonitrile, the mobile phase B is 0.01mol/L and is a potassium dihydrogen phosphate solution with the pH value of 2.0, and the specific preparation process of the potassium dihydrogen phosphate solution is that 1.36g of potassium dihydrogen phosphate is taken to 1000mL of water, fully dissolved, and the pH value is adjusted to 2.0 by phosphoric acid, and the solution is filtered by a 0.22um filter membrane before use.
(2) Selection of test solutions:
diluent agent: acetonitrile: water (volume ratio 50: 50);
control solution: 1.2 μ g/mL ibuprofen and 1.2 μ g/mL ibuprofen impurity C;
sample solution: 0.6mg/mL ibuprofen, specifically, the total weight of 20 ibuprofen capsules was accurately weighed and the average weight was calculated. Then 6 grains are taken and weighed accurately, put into a 200mL volumetric flask, added with 150mL diluent, placed in a water bath or an ultrasonic instrument at 65 ℃ and shaken without time until the capsule is completely dissolved, taken out, cooled to room temperature, diluted to the scale with the diluent, shaken up, and then 5.0mL of the solution is taken out to a 50mL volumetric flask and diluted to the scale with the diluent. Filtering with 0.22 μm filter membrane (diameter 25mm, PTFE material or suitable, Jinteng or foreign known brand), discarding 4mL of the primary filtrate, and collecting the clear subsequent filtrate.
(3) On the basis of the detection conditions and the test solution, respectively injecting samples by using UPLC qualitative detection blank solution-diluent, standard solution, auxiliary material blank solution and sample solution to obtain figures 1, 2, 3 and 4; as can be seen from FIGS. 1 to 4, the blank solution and the adjuvant solution did not interfere at the target peak position, and the separation between the main peak and each impurity peak was good.
(4) Linear equation for preparing ibuprofen, impurity C, impurity J, impurity M and ibuprofen sorbitol ester:
ibuprofen standard stock solution: 600 mug/mL, specifically precisely weighing a volumetric flask of 60mg to 100mL ibuprofen standard, dissolving with a diluent and fixing the volume to the scale;
ibuprofen impurity C standard stock solution: 400 mu g/mL, specifically, precisely weighing a volumetric flask of about 20mg to 50mL of ibuprofen related substance C standard, dissolving with acetonitrile, and fixing the volume to the scale;
standard stock solutions for each known impurity: 120 mu g/mL, specifically, accurately weighing about 12mg to 100mL volumetric flasks of an ibuprofen related substance J standard, an ibuprofen related substance M standard and an ibuprofen sorbitol ester standard respectively, dissolving by using a diluent, and fixing the volume to a scale;
linear standard stock solutions: and the volume is 12 mu g/mL, specifically 2.0mL of ibuprofen standard stock solution, 3.0mL of ibuprofen impurity C standard stock solution and 10.0mL to 100mL of each known impurity standard stock solution are respectively transferred and diluted to the scale by using a diluent.
Linear standard solutions of various concentrations were prepared as follows:
TABLE 4 List of linear standard solutions for each concentration
The linearity results using UPLC were as follows:
TABLE 5 List of linear equations for each related substance in ibuprofen drugs
(5) Accuracy exploration:
ibuprofen sorbitol ester recovery stock solution (4.8 μ g/mL): precisely weighing a volumetric flask containing ibuprofen sorbitol ester standard substance of about 12mg to 100mL, dissolving with diluent, and fixing to the scale. And (4) transferring 4.0mL to 100mL volumetric flasks of the ibuprofen sorbitol ester standard stock solution, and shaking up.
Impurity recovery stock solution (12. mu.g/mL): respectively transferring 3.0mL of the standard stock solution of the ibuprofen related substance C, and 10.0mL to 100mL of the standard stock solutions of the ibuprofen related substance J and the related substance M, and shaking up.
Sample stock solution: the total weight of 20 capsules was accurately weighed and the average weight was calculated. 6 pellets were weighed out accurately and put into a 200mL volumetric flask. Adding 150mL of diluent, placing in a water bath or an ultrasonic instrument at 65 ℃ and shaking till the capsule is completely dissolved, taking out, cooling to room temperature, diluting to scale with the diluent, and shaking up.
Two sample solutions were prepared in parallel as control sample solutions according to the methods implemented in this document.
Sample recovery solutions of ibuprofen related substance C, related substance J and related substance M were prepared in triplicate according to the table below.
TABLE 6 recovery stock and sample stock concentration List I
Sample solutions for ibuprofen sorbitol ester recovery were prepared in triplicate according to the table below.
TABLE 7 recovered stock solution and sample stock solution concentration List II
Specific recovery results are tabulated below:
TABLE 8 recovery of ibuprofen-related substance J
TABLE 9 ibuprofen phase sorbitol ester recovery
TABLE 10 recovery of ibuprofen-related substance M
TABLE 11 recovery of ibuprofen-related substance C
(6) Precision exploration:
6 sample solutions were prepared in parallel according to the method carried out in this document and the relevant substances were determined.
The results are as follows:
TABLE 12 precision exploration List
(7) Intermediate precision exploration:
another analyst used different columns at different times to measure 6 samples according to the precision method.
The results are as follows:
TABLE 13 intermediate precision exploration List
(7) Durability exploration:
the recovery was determined separately by changing the chromatographic conditions based on the original method using a control sample solution and a 100% level spiked sample solution under the accuracy (recovery) term.
The chromatographic conditions were changed as follows:
flow rate: plus or minus 0.1 mL/min;
column temperature: plus or minus 5 ℃;
organic phase (acetonitrile) ratio in mobile phase: plus or minus 1 percent;
mobile phase buffer salt: pH is +/-0.1;
the results were as follows:
TABLE 14 durability exploration List
(8) Solution stability exploration:
the sample solution with 100% level under the accuracy (recovery) item is placed for 24h, 48h and 72h respectively to determine related substances.
The results are as follows:
TABLE 15 investigation List of solution stability
As can be seen from the description, the detection method designed by the invention has the advantages of high sensitivity, small required sample amount, good precision and accuracy, and can realize quantitative detection of related substances in the ibuprofen medicament.
Claims (6)
1. A method for detecting the concentration of related substances in an ibuprofen medicament based on an ultra-high liquid chromatography, wherein the related substances comprise an impurity C, an impurity J, an impurity M and an impurity ibuprofen sorbitol ester, and is characterized in that the method comprises the steps of respectively sampling a diluent, a standard ibuprofen solution, an auxiliary material blank solution and the ibuprofen solution by using the ultra-high liquid chromatography to obtain a qualitative detection chromatogram map of each component;
preparing an ibuprofen standard stock solution, an impurity C standard stock solution, an impurity J standard stock solution, an impurity M standard stock solution and an impurity ibuprofen sorbitol ester standard stock solution, then respectively diluting the ibuprofen standard stock solution, the impurity J standard stock solution and the impurity ibuprofen sorbitol ester standard stock solution into linear standard solutions by adopting a diluent, and respectively sampling to obtain linear working curves;
wherein the detection conditions are as follows:
and (3) chromatographic column: c 18 ，2.1×50mm，1.7μm；
Column temperature: 30-45 ℃;
mobile phase A: acetonitrile; mobile phase B: 0.01mol/L potassium dihydrogen phosphate solution with pH value of 2.0-3.0; gradient elution;
flow rate: 0.3-0.5 mL/min;
sample introduction volume: 4.0 mu L;
the elution procedure was:
the impurity C is 1- [4- (2-methylpropyl) phenyl ] ethanone, the impurity J is (2RS) -2- [4- (2-methylpropanoyl) phenyl ] propionic acid, and the impurity M is (2RS) -2-hydroxy-2- [4- (2-methylpropyl) phenyl ] propionic acid; the ibuprofen medicament comprises any one of ibuprofen soft capsules, ibuprofen tablets, ibuprofen suspension or ibuprofen suppositories.
2. The method for detecting the concentration of related substances in ibuprofen medicament based on ultra-high liquid chromatography as claimed in claim 1, wherein said column temperature is 40 ℃.
3. The method for detecting the concentration of related substances in the ibuprofen medicament based on the ultra-high liquid chromatography as claimed in claim 1, wherein the pH of the potassium dihydrogen phosphate solution in the mobile phase B is 2.0.
4. The method for detecting the concentration of related substances in ibuprofen medicament based on ultra-high liquid chromatography, according to claim 1, wherein said flow rate is 0.3 mL/min.
5. The method for detecting the concentration of a related substance in an ibuprofen medicament based on ultra-high liquid chromatography according to claim 1, wherein the detection wavelength is 214 nm; the detector is an ultraviolet detector.
6. The method for detecting the concentration of a related substance in an ibuprofen medicament based on the ultra-high liquid chromatography as claimed in any one of claims 1-5, wherein the diluent is a mixed solution of acetonitrile and water in a volume ratio of 50: 50; the method also comprises the steps of washing the needle for 10-20 s before sample injection and washing the needle for 25-35 s after sample injection, wherein a cleaning solvent is a mixed solution of acetonitrile and water in a volume ratio of 50: 50; the cleaning solvent is a mixed solution of acetonitrile and water with the volume ratio of 10: 90.
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