CN114062554A - Analysis method for simultaneously determining acetaminophen ibuprofen-related substances - Google Patents
Analysis method for simultaneously determining acetaminophen ibuprofen-related substances Download PDFInfo
- Publication number
- CN114062554A CN114062554A CN202111380949.5A CN202111380949A CN114062554A CN 114062554 A CN114062554 A CN 114062554A CN 202111380949 A CN202111380949 A CN 202111380949A CN 114062554 A CN114062554 A CN 114062554A
- Authority
- CN
- China
- Prior art keywords
- ibuprofen
- reference substance
- impurity
- minutes
- equal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- 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
- G01N30/02—Column chromatography
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an analysis method for simultaneously measuring related substances of acetaminophen ibuprofen, which is simple and convenient to operate, has good specificity, stable solution, high sensitivity and good durability, and can be used for quality control of acetaminophen ibuprofen tablets.
Description
1. Field of the invention
The invention belongs to the technical field of drug analysis, and particularly relates to an analysis method for simultaneously determining related substances of acetaminophen ibuprofen.
2. Background of the invention
Acetaminophen is an acetanilide antipyretic analgesic, is an epoxidase inhibitor, and achieves antipyretic effect by selectively inhibiting synthesis of hypothalamic thermoregulation central prostaglandin to cause peripheral vasodilation and sweating; the analgesic drug has analgesic effect by inhibiting synthesis and release of prostaglandin and the like and increasing pain threshold, and belongs to peripheral analgesics. Ibuprofen is a nonsteroidal anti-inflammatory analgesic drug, and has analgesic, anti-inflammatory and antipyretic effects. The mechanism of action is mainly as follows: can inhibit the action of cyclooxygenase of cell membrane to metabolize arachidonic acid into inflammatory mediator prostaglandin, thereby relieving local tissue congestion and swelling caused by prostaglandin. It also reduces pain sensitivity of local peripheral nerve to bradykinin, and has antiinflammatory and analgesic effects. Ibuprofen and acetaminophen have different mechanisms of action, are well known for safety and effectiveness, and are commonly recommended by the world health organization and the U.S. FDA to be antipyretic for children. Acetaminophen ibuprofen tablets (each containing 125mg ibuprofen and 250mg Acetaminophen, OTC product) are OTC type fixed dose compound preparations developed by GSK and Pfizer together, and are approved by the United states FDA under the special name 'Advil Dual Action with Acetaminophen' on 28 days 2 and 28 months 2020, and are the first compound preparations of ibuprofen and Acetaminophen approved by the United states and used for relieving various mild pains.
The chemical name of the acetaminophen is 4' -hydroxyacetanilide, and the structural formula is as follows (the compound shown in the formula I):
the chemical name of ibuprofen is alpha-methyl-4- (2-methylpropyl) phenylacetic acid, and the structural formula is as follows (the compound of formula II):
acetaminophen introduces two impurities, p-aminophenol and p-chlorophenylacetamide (genotoxic impurities).
P-aminophenol, of the formula:
p-chlorophenyl acetamide, the structural formula is as follows:
5 ibuprofen impurities including an ibuprofen impurity A, an ibuprofen impurity B, an ibuprofen impurity E, an ibuprofen impurity J and an ibuprofen impurity N are introduced.
Ibuprofen impurity a, chemically (2RS) -2- [3- (2-methylpropyl) phenyl ] propionic acid, of the formula:
ibuprofen impurity B, chemically (2RS) -2- (4-butylphenyl) propionic acid, of the formula:
ibuprofen impurity E, chemically known as 1- [4- (2-methylpropyl) phenyl ] ethanone, of the formula:
ibuprofen impurity J, chemically (2RS) -2- [4- (2-methylpropanoyl) phenyl ] propionic acid, of the formula:
ibuprofen impurity N, chemically known as (2RS) -2- (4-ethylphenyl) propionic acid, of the formula:
ibuprofen and acetaminophen are both impurities which may be generated by esterification reaction, i.e. impurity I.
Impurity I, chemically known as 4-acetamidophenyl 2- [4- (2-ethylpropyl) phenyl ] propionate, having the formula:
at present, the detection method of acetaminophen ibuprofen related substances is not collected by all pharmacopoeia standards, and no related literature reports the detection method of the compound related substances. Therefore, a stable, effective and simple method for detecting related substances of the acetaminophen ibuprofen compound preparation is needed to be newly established so as to realize quality control of acetaminophen ibuprofen tablets.
3. Summary of the invention
The invention solves the technical problem existing in the detection method of related substances of acetaminophen ibuprofen tablets, and provides an analysis method for simultaneously determining related substances of acetaminophen ibuprofen tablets, wherein the analysis method can effectively separate acetaminophen, p-chlorobenzoacetamide, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E, ibuprofen impurity J, ibuprofen impurity N and impurity I, so that each impurity peak, the chlorobenzene acetamide peak and the ibuprofen peak are not overlapped, the peak shape is good, and the separation requirement is met. The method simultaneously detects common impurities and genotoxic impurities, namely p-chlorophenyl acetamide, by adopting double wavelengths, and has the advantages of high sensitivity, good specificity and simple and convenient operation. Can be used for the quality control of paracetamol ibuprofen tablets and meets the existing requirements.
The invention provides an analysis method for simultaneously determining related substances of acetaminophen ibuprofen tablets, which comprises the following steps:
(1) preparation of system applicability solution: taking an appropriate amount of an ibuprofen reference substance, an acetaminophen reference substance, a p-aminophenol reference substance, a p-chlorobenzoacetamide reference substance, an ibuprofen impurity A reference substance, an ibuprofen impurity B reference substance, an ibuprofen impurity E reference substance, an ibuprofen impurity J reference substance, an ibuprofen impurity N reference substance and an impurity I reference substance, and adding a solvent to dissolve and dilute the ibuprofen reference substance, the acetaminophen reference substance, the p-chlorobenzoacetamide reference substance, the ibuprofen impurity A reference substance, the ibuprofen impurity B reference substance, the ibuprofen impurity E reference substance, the ibuprofen impurity J reference substance, the ibuprofen impurity N reference substance and the impurity I reference substance to prepare a system applicability solution;
(2) preparing a test solution: taking a proper amount of the product, adding a solvent to dissolve and dilute the product to prepare a test solution;
(3) preparing a blank auxiliary material solution: weighing a proper amount of blank auxiliary materials, adding a solvent to dissolve and diluting to prepare a blank auxiliary material solution;
(4) and (3) testing the applicability of the system: measuring a proper amount of system applicability solution, injecting the system applicability solution into a liquid chromatograph, and recording a chromatogram;
(5) testing a test solution: measuring a proper amount of a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram;
(6) blank adjuvant solution test: measuring a proper amount of blank auxiliary material solution, injecting the blank auxiliary material solution into a liquid chromatograph, and recording a chromatogram;
the solvent in the steps (1) - (3) is one or more of acetonitrile, water and methanol. Preferably, the solvent is acetonitrile and water, and the volume ratio of the acetonitrile to the water is 4: 6.
In the steps (4) to (6), the chromatographic conditions were analyzed by a reversed-phase high performance liquid chromatograph.
The chromatographic conditions described in the present invention are specifically as follows:
a detector: an ultraviolet detector;
a chromatographic column: chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: mobile phase A: phosphoric acid aqueous solution; mobile phase B: acetonitrile; gradient elution;
detection wavelength: 214nm and 245nm (detection of p-chlorophenyl acetamide);
sample introduction volume: 10 μ l.
The chromatographic column of the liquid chromatograph is YMC-Pack ODS-AQ, 4.6mm multiplied by 150mm, 3 μm.
The concentration of the phosphoric acid of the mobile phase A is 0.3-1.0%, preferably 0.4-0.6%.
The conditions of the gradient elution are as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100～90 | 0～10 |
| A | 100～90 | 0～10 |
| B | 80～50 | 20～50 |
| C | 80～50 | 20～50 |
| D | 50～10 | 50～90 |
| E | 50～10 | 50～90 |
| F | 100～90 | 0～10 |
| G | 100～90 | 0～10 |
Wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, E is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
Preferably, the conditions for gradient elution are:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100～90 | 0～10 |
| A | 100～90 | 0～10 |
| B | 70～55 | 30～45 |
| C | 70～55 | 30～45 |
| D | 45～30 | 55～60 |
| E | 45～30 | 55～60 |
| F | 100～90 | 0～10 |
| G | 100～90 | 0～10 |
Wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, E is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
More preferably, the conditions for gradient elution are:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 5 | 90 | 10 |
| 15 | 60 | 40 |
| 35 | 60 | 40 |
| 50 | 40 | 60 |
| 60 | 40 | 60 |
| 65 | 90 | 10 |
| 75 | 90 | 10 |
More preferably, the conditions for gradient elution are:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 5 | 95 | 5 |
| 15 | 65 | 35 |
| 35 | 65 | 35 |
| 50 | 40 | 60 |
| 60 | 40 | 60 |
| 65 | 95 | 5 |
| 75 | 95 | 5 |
The column temperature of the liquid chromatograph is 15-60 ℃, preferably 35-45 ℃.
The flow rate is 1.0 ml/min-2.0 ml/min.
The invention further provides an analysis method for simultaneously measuring paracetamol ibuprofen tablets, which comprises the following steps
(1) Preparation of system applicability solution: taking an appropriate amount of an ibuprofen reference substance, an acetaminophen reference substance, a p-aminophenol reference substance, a p-chlorobenzoacetamide reference substance, an ibuprofen impurity A reference substance, an ibuprofen impurity B reference substance, an ibuprofen impurity E reference substance, an ibuprofen impurity J reference substance, an ibuprofen impurity N reference substance and an impurity I reference substance, adding a solvent, ultrasonically dissolving and diluting to prepare a mixed solution containing 2.5mg of ibuprofen, 5mg of acetaminophen and 5 mu g of other impurities per 1ml, and shaking uniformly;
(2) preparing a test solution: dissolving 1 tablet (containing ibuprofen 0.125g and acetaminophen 0.25g) in solvent, and diluting to obtain test solution;
(3) preparing a blank auxiliary material solution: weighing a proper amount of blank auxiliary materials, adding a solvent to dissolve and diluting to prepare a blank auxiliary material solution;
(4) and (3) testing the applicability of the system: measuring a proper amount of system applicability solution, injecting the system applicability solution into a liquid chromatograph, and recording a chromatogram;
(5) testing a test solution: measuring a proper amount of a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram;
(6) blank adjuvant solution test: measuring a proper amount of blank auxiliary material solution, injecting the blank auxiliary material solution into a liquid chromatograph, and recording a chromatogram;
the solvent in the steps (1) - (3) is one or more of acetonitrile, water and methanol. Preferably, the solvent is acetonitrile and water, and the volume ratio of the acetonitrile to the water is 4: 6.
In the steps (4) to (6), the chromatographic conditions were analyzed by a reversed-phase high performance liquid chromatograph.
The chromatographic conditions described in the present invention are specifically as follows:
a detector: an ultraviolet detector;
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler, YMC-Pack ODS-AQ, 4.6mm × 150mm, 3 μm;
mobile phase: mobile phase A: phosphoric acid aqueous solution; mobile phase B: acetonitrile, gradient elution;
detection wavelength: 214nm and 245nm (detection of p-chlorophenyl acetamide);
sample introduction volume: 10 μ l.
The concentration of the phosphoric acid of the mobile phase A is 0.3-1.0%, preferably 0.4-0.6%.
The conditions of the gradient elution are as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100～90 | 0～10 |
| A | 100～90 | 0～10 |
| B | 80～50 | 20～50 |
| C | 80～50 | 20～50 |
| D | 50～10 | 50～90 |
| E | 50～10 | 50～90 |
| F | 100～90 | 0～10 |
| G | 100～90 | 0～10 |
Wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, F is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
Preferably, the conditions for gradient elution are:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100～90 | 0～10 |
| A | 100～90 | 0～10 |
| B | 70～55 | 30～45 |
| C | 70～55 | 30～45 |
| D | 45～30 | 55～60 |
| E | 45～30 | 55～60 |
| F | 100～90 | 0～10 |
| G | 100～90 | 0～10 |
Wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, E is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
More preferably, the conditions for gradient elution are:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 5 | 90 | 10 |
| 15 | 60 | 40 |
| 35 | 60 | 40 |
| 50 | 40 | 60 |
| 60 | 40 | 60 |
| 65 | 90 | 10 |
| 75 | 90 | 10 |
More preferably, the conditions for gradient elution are:
the column temperature of the liquid chromatograph is 15-45 ℃, preferably 35-45 ℃.
The flow rate is 1.0 ml/min-2.0 ml/min.
The beneficial technical effects of the invention are as follows:
(1) the invention can adopt the same HPLC method to separate the p-aminophenol, the p-chlorophenyl acetamide, the ibuprofen impurity A, the ibuprofen impurity B, the ibuprofen impurity E, the ibuprofen impurity J, the ibuprofen impurity N and the impurity I, so that each impurity peak and the p-chlorophenyl acetamide peak and the ibuprofen peak are well separated, and meanwhile, two main peak-forming related substances are controlled, thereby saving the analysis time.
(2) The invention adopts double wavelengths to simultaneously detect common impurities and genotoxic impurities, namely p-chlorophenyl acetamide, and the method has high sensitivity.
4. Description of the drawings
FIG. 1 is the interference test pattern of the blank excipients of example 1.
FIG. 2 is a map of the suitability test of the system in example 2.
FIG. 3 is a test pattern of the test solution of the test article in example 2.
FIG. 4 is a chart of the suitability test of the system in example 3.
FIG. 5 is a chart of the suitability test of the system of example 4.
FIG. 6 is a map of the suitability test of the system in example 5.
FIG. 7 is a map of the suitability test of the system in example 6.
FIG. 8 is a stability test chart of the test solution in example 7.
FIG. 9 is a graph showing the quantitative limit test of p-chlorophenyl acetamide in example 8.
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Apparatus and chromatographic conditions
The instrument comprises the following steps: agilent 1260 liquid chromatograph, ultraviolet detector;
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler, YMC-Pack ODS-AQ 4.6mm × 150mm, 3 μm;
detection wavelength: 214nm and 245nm (detection of p-chlorophenyl acetamide);
sample introduction volume: 10 mu l of the mixture;
flow rate: 1.0 ml/min-2.0 ml/min.
Reagent
Preparation of a solvent: mixing acetonitrile and water in a volume ratio of 4:6, and shaking up to obtain the product.
Preparing a test solution: taking 1 tablet (containing ibuprofen 0.125g and acetaminophen 0.25g), placing in a 50ml measuring flask, adding about 40ml of solvent, performing ultrasonic treatment, shaking for 5 minutes, diluting with solvent to scale, shaking uniformly, filtering, and taking the subsequent filtrate. Preparation of system applicability solution: taking an appropriate amount of an ibuprofen reference substance, an acetaminophen reference substance, a p-aminophenol reference substance, a p-chlorobenzoacetamide reference substance, an ibuprofen impurity A reference substance, an ibuprofen impurity B reference substance, an ibuprofen impurity E reference substance, an ibuprofen impurity J reference substance, an ibuprofen impurity N reference substance and an impurity I reference substance, adding a solvent, ultrasonically dissolving and diluting to prepare a mixed solution containing 2.5mg of ibuprofen, 5mg of acetaminophen and 5 mu g of other impurities per 1ml, and shaking up.
Preparing a blank auxiliary material solution: weighing about 56mg of blank auxiliary materials, placing the blank auxiliary materials in a 25ml measuring flask, adding about 20ml of solvent, carrying out ultrasonic treatment for about 10 minutes, diluting the mixture to a scale with the solvent, shaking up, filtering, and taking the subsequent filtrate.
Preparation of a control solution: precisely measuring a proper amount of the test solution, adding a solvent for quantitative dilution to prepare a solution containing 2.5 mu g of ibuprofen and 5 mu g of acetaminophen in each 1ml, and shaking up to obtain a control solution.
Preparing a reference substance solution: taking a proper amount of p-aminophenol and p-chlorophenyl acetamide as reference substances, precisely weighing, dissolving with a solvent, quantitatively diluting to obtain a solution containing about 5 mu g of p-aminophenol and 0.05 mu g of p-chlorophenyl acetamide per 1ml, and shaking up to obtain a reference substance solution.
Examples1Blank auxiliary material interference test
Taking 1 tablet of the product, placing in a 50ml measuring flask, adding about 40ml of solvent, performing ultrasonic treatment, shaking for 5 minutes, diluting to scale with solvent, shaking, filtering, and taking the subsequent filtrate as sample solution; weighing about 56mg of blank auxiliary material, placing the blank auxiliary material in a 25ml measuring flask, adding about 20ml of solvent, carrying out ultrasonic treatment for about 10 minutes, diluting the mixture to a scale with the solvent, shaking up, filtering, and taking the subsequent filtrate as a blank auxiliary material solution. Performing high performance liquid chromatography (China pharmacopoeia 2020 edition general regulation 0512) test with octadecylsilane chemically bonded silica gel as filler (YMC-Pack ODS-AQ 4.6mm × 150mm, 3 μm or chromatographic column with equivalent efficiency); taking 0.05% phosphoric acid water solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table; the column temperature was 40 ℃; the detection wavelengths were 214nm and 245nm (for p-chlorophenyl acetamide). Precisely measuring 10 μ l of the test solution, injecting into a liquid chromatograph, recording chromatogram, precisely measuring 10 μ l of the blank adjuvant solution, injecting into the liquid chromatograph, recording chromatogram, and comparing the results shown in figure 1. The result shows that the blank auxiliary materials do not interfere the detection of related substances of the test sample.
Example 2System applicabilityTest of
Taking an appropriate amount of an ibuprofen reference substance, an acetaminophen reference substance, a p-aminophenol reference substance, a p-chlorobenzoacetamide reference substance, an ibuprofen impurity A reference substance, an ibuprofen impurity B reference substance, an ibuprofen impurity E reference substance, an ibuprofen impurity J reference substance, an ibuprofen impurity N reference substance and an impurity I reference substance, adding a solvent, ultrasonically dissolving and diluting to prepare a mixed solution containing about 2.5mg of ibuprofen, 5mg of acetaminophen and about 5 mu g of other impurities per 1ml, and shaking up to obtain a system applicability solution. Precisely measuring a proper amount of the test solution, adding a solvent for quantitative dilution to prepare a solution containing 2.5 mu g of ibuprofen and 5 mu g of acetaminophen in each 1ml, and shaking up to obtain a control solution. Taking a proper amount of p-aminophenol and p-chlorophenyl acetamide as reference substances, precisely weighing, dissolving with a solvent, quantitatively diluting to obtain a solution containing about 5 mu g of p-aminophenol and 0.05 mu g of p-chlorophenyl acetamide per 1ml, and shaking up to obtain a reference substance solution.
The instrument and chromatographic conditions were as above.
Precisely measuring 10 μ l of the system applicability solution, injecting into a liquid chromatograph, and recording chromatogram, wherein the results are shown in Table 5 and FIG. 2. The separation degrees among the ibuprofen peak, the acetaminophen peak and each impurity peak are all in accordance with requirements, and the separation degrees among the impurity peaks are all in accordance with requirements. The reference solution, the sample solution and the reference solution were measured precisely at 10. mu.l each, and injected into a liquid chromatograph, and the chromatogram was recorded, and the results are shown in Table 6 and FIG. 3. If an impurity peak exists in a chromatogram of a test solution, the p-chlorophenyl acetamide cannot exceed 0.001% at 245nm and the p-aminophenol cannot exceed 0.1% at 214nm according to the calculation of an external standard method; according to the calculation of a self-contrast method, at 214nm, the peak area of the impurity E is not more than 2 times (0.2%) of the peak area of ibuprofen in a contrast solution, the peak areas of the impurity J, the impurity N and the impurity A are not more than 1.5 times (0.15%) of the peak area of ibuprofen in the contrast solution, the peak areas of other single impurities are not more than 0.1% of the peak area of acetaminophen in the contrast solution, and the sum of the peak areas of total impurities is not more than 5 times (0.5%) of the peak area of acetaminophen in the contrast solution.
TABLE 5 System suitability solution test results
TABLE 6 test results of test solutions
| Test article | Paracetamol ibuprofen tablet |
| Batch number | 21041201 |
| Impurity E is less than or equal to 0.2 percent | Not detected out |
| Impurity A is less than or equal to 0.2 percent | Not detected out |
| Impurity B is less than or equal to 0.2 percent | Not detected out |
| Impurity J is less than or equal to 0.2 percent | Not detected out |
| Impurity N is less than or equal to 0.2 percent | Not detected out |
| P-aminophenol less than or equal to 0.1 percent | Not detected out |
| The content of p-chlorobenzene acetamide is less than or equal to 0.001 percent | Not detected out |
| Other single impurities are less than or equal to 0.1 percent | 0.04％ |
| The total amount of impurities is less than or equal to 0.5 percent | 0.09％ |
As a result: in a system applicability solution chromatogram, p-aminophenol, p-acetaminopher, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E and impurity I are subjected to peak discharge in sequence, and the p-aminophenol peak and the ibuprofen peak are well separated from each impurity peak and each impurity peak. In the chromatogram of the test sample, the related substances of the product meet the requirements.
Example 3System applicabilityTest of
The instrument and chromatographic conditions were as above, and the column temperature was 35 ℃.
And (4) injecting the system applicability solution into a liquid chromatograph, and recording the chromatogram. The results are shown in FIG. 4.
As a result: in a system applicability solution chromatogram, p-aminophenol, p-acetaminopher, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E and impurity I are subjected to peak discharge in sequence, and the p-aminophenol peak and the ibuprofen peak are well separated from each impurity peak and each impurity peak.
Example 4System applicabilityTest of
The instrument and chromatographic conditions were as above, with a column temperature of 45 ℃.
And (4) injecting the system applicability solution into a liquid chromatograph, and recording the chromatogram. The results are shown in FIG. 5.
As a result: in a system applicability solution chromatogram, p-aminophenol, p-acetaminopher, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E and impurity I are subjected to peak discharge in sequence, and the p-aminophenol peak and the ibuprofen peak are well separated from each impurity peak and each impurity peak.
Example 5System applicabilityTest of
The instrument and chromatographic conditions are the same as above, the mobile phase A is 0.045% phosphoric acid aqueous solution, and the column temperature is 40 ℃.
And (4) injecting the system applicability solution into a liquid chromatograph, and recording the chromatogram. The results are shown in FIG. 6.
As a result: in a system applicability solution chromatogram, p-aminophenol, p-acetaminopher, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E and impurity I are subjected to peak discharge in sequence, and the p-aminophenol peak and the ibuprofen peak are well separated from each impurity peak and each impurity peak.
Example 6System applicabilityTest of
The instrument and chromatographic conditions are the same as above, the mobile phase A is 0.055% phosphoric acid water solution, and the column temperature is 40 ℃.
And (4) injecting the system applicability solution into a liquid chromatograph, and recording the chromatogram. The results are shown in FIG. 7.
As a result: in a system applicability solution chromatogram, p-aminophenol, p-acetaminopher, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity A, ibuprofen impurity B, ibuprofen impurity E and impurity I are subjected to peak discharge in sequence, and the p-aminophenol peak and the ibuprofen peak are well separated from each impurity peak and each impurity peak.
In summary of the above test results, in the chromatographic conditions of examples 2 to 6, p-aminophenol, p-acetaminophen, p-chlorophenyl acetamide, ibuprofen impurity J, ibuprofen impurity N, ibuprofen impurity a, ibuprofen impurity B, ibuprofen impurity E, and impurity I sequentially appeared, and the p-acetaminophen peak and the ibuprofen peak were well separated from each impurity peak and each impurity peak.
Example 7 solution stability test
Test solution: taking 1 tablet of the product, placing in a 50ml measuring flask, adding a proper amount of solvent, performing ultrasonic treatment for 5 minutes to dissolve, diluting to scale with the solvent, and shaking up to obtain the final product.
The sample solution was precisely measured 10. mu.l at room temperature for 0 to 18 hours, and injected into a liquid chromatograph, and the chromatogram was recorded, and the change in the main peak area was calculated. The results are shown in Table 7 and FIG. 8. The result shows that the sample solution is placed at room temperature for 18 hours, the impurities do not obviously change, and the stability of the sample solution is good.
TABLE 7 stability test results (Room temperature) for test solutions
EXAMPLE 8 limit of quantitation test
Taking a proper amount of a p-chlorophenyl acetamide reference substance, and diluting the p-chlorophenyl acetamide reference substance by using a solvent until the response value of the p-chlorophenyl acetamide is about 10 times higher than that of a noise signal, namely the quantitative limit. 10. mu.l of the sample was measured precisely, and the sample was injected into a liquid chromatograph, and a chromatogram was recorded at 245nm, and the results are shown in Table 8 and FIG. 9.
TABLE 8 quantitative limit results of p-chlorophenyl acetamide
Claims (10)
1. An analysis method for simultaneously determining related substances of acetaminophen ibuprofen, which is characterized by comprising the following steps:
(1) preparation of system applicability solution: taking an appropriate amount of an ibuprofen reference substance, an acetaminophen reference substance, a p-aminophenol reference substance, a p-chlorobenzoacetamide reference substance, an ibuprofen impurity A reference substance, an ibuprofen impurity B reference substance, an ibuprofen impurity E reference substance, an ibuprofen impurity J reference substance, an ibuprofen impurity N reference substance and an impurity I reference substance, and adding a solvent to dissolve and dilute the ibuprofen reference substance, the acetaminophen reference substance, the p-chlorobenzoacetamide reference substance, the ibuprofen impurity A reference substance, the ibuprofen impurity B reference substance, the ibuprofen impurity E reference substance, the ibuprofen impurity J reference substance, the ibuprofen impurity N reference substance and the impurity I reference substance to prepare a system applicability solution;
(2) preparing a test solution: taking a proper amount of the product, adding a solvent to dissolve and dilute the product to prepare a test solution;
(3) preparing a blank auxiliary material solution: weighing a proper amount of blank auxiliary materials, adding a solvent to dissolve and diluting to prepare a blank auxiliary material solution;
(4) and (3) testing the applicability of the system: measuring a proper amount of system applicability solution, injecting the system applicability solution into a liquid chromatograph, and recording a chromatogram;
(5) testing a test solution: measuring a proper amount of a test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram;
(6) blank adjuvant solution test: measuring a proper amount of blank auxiliary material solution, injecting the blank auxiliary material solution into a liquid chromatograph, and recording a chromatogram;
in the steps (4) to (6), the chromatographic conditions were analyzed by a reversed-phase high performance liquid chromatograph.
2. The analytical method for simultaneously determining acetaminophen-ibuprofen-related substances according to claim 1, wherein the chromatographic conditions are as follows:
a detector: an ultraviolet detector;
a chromatographic column: chromatographic column with octadecylsilane chemically bonded silica as filler;
mobile phase: mobile phase A: phosphoric acid aqueous solution; mobile phase B: acetonitrile; gradient elution;
detection wavelength: 214nm and 245 nm;
sample introduction volume: 10 μ l.
3. The analytical method for simultaneously measuring acetaminophen-ibuprofen-related substances according to claim 2, wherein the chromatographic column is YMC-Pack ODS-AQ, 4.6mm x 150mm, 3 μm.
4. The method as claimed in claim 2, wherein the concentration of phosphoric acid in mobile phase A is 0.3-1.0%.
5. The method as claimed in claim 4, wherein the concentration of phosphoric acid in mobile phase A is 0.4-0.6%.
6. The analytical method for simultaneously measuring acetaminophen-ibuprofen-related substances according to claim 2, wherein the column temperature of the chromatographic column is 15-60 ℃.
7. The analytical method for simultaneously determining acetaminophen-ibuprofen-related substances according to claim 2, wherein the gradient elution conditions are as follows:
wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, F is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
8. The analytical method for simultaneously determining acetaminophen-ibuprofen-related substances according to claim 7, wherein the gradient elution conditions are as follows:
Wherein A is more than 0 and less than or equal to 10 minutes, B is more than 10 and less than or equal to 30 minutes, C is more than 30 and less than or equal to 40 minutes, D is more than 40 and less than or equal to 55 minutes, E is more than 55 and less than or equal to 62 minutes, F is more than 62 and less than or equal to 70 minutes, and G is more than 70 and less than or equal to 80 minutes.
9. The analytical method for simultaneously determining acetaminophen-ibuprofen-related substances according to claim 8, wherein the gradient elution conditions are as follows:
10. The analytical method for simultaneously determining acetaminophen-ibuprofen-related substances according to claim 8, wherein the gradient elution conditions are as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111380949.5A CN114062554B (en) | 2021-11-20 | 2021-11-20 | Analysis method for simultaneously measuring related substances of acetaminophen ibuprofen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111380949.5A CN114062554B (en) | 2021-11-20 | 2021-11-20 | Analysis method for simultaneously measuring related substances of acetaminophen ibuprofen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114062554A true CN114062554A (en) | 2022-02-18 |
| CN114062554B CN114062554B (en) | 2023-07-21 |
Family
ID=80278632
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111380949.5A Active CN114062554B (en) | 2021-11-20 | 2021-11-20 | Analysis method for simultaneously measuring related substances of acetaminophen ibuprofen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114062554B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114965754A (en) * | 2022-05-13 | 2022-08-30 | 陕西必康制药集团控股有限公司 | Method for detecting related substances and bacteriostatic agent in acetaminophen tablet |
| CN115097049A (en) * | 2022-07-25 | 2022-09-23 | 广西壮族自治区食品药品检验所 | Method for determining related substances in pediatric paracetamol, atificial cow-bezoar and chlorphenamine maleate granules |
| CN115236255A (en) * | 2022-08-04 | 2022-10-25 | 迪沙药业集团有限公司 | Method for detecting loxoprofen sodium related substances |
| CN116735757A (en) * | 2023-08-09 | 2023-09-12 | 则正(上海)生物科技有限公司 | Method for detecting related substances in ibuprofen medicament |
| CN117288868A (en) * | 2023-11-24 | 2023-12-26 | 山东百诺医药股份有限公司 | Detection method of N-acetyl-L-leucine related substances |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114011A (en) * | 2009-12-31 | 2011-07-06 | 北京科信必成医药科技发展有限公司 | Ibuprofen sustained-release preparation and preparation method thereof |
| CN102204882A (en) * | 2011-03-22 | 2011-10-05 | 韩彬 | Pharmaceutical composition containing ibuprofen |
| CN106794163A (en) * | 2014-07-18 | 2017-05-31 | 光大制药有限公司 | Aqueous formulation comprising paracetamol and brufen |
| WO2019108147A1 (en) * | 2017-11-29 | 2019-06-06 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Color stable fixed dose tablet combination of ibuprofen and paracetamol |
-
2021
- 2021-11-20 CN CN202111380949.5A patent/CN114062554B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114011A (en) * | 2009-12-31 | 2011-07-06 | 北京科信必成医药科技发展有限公司 | Ibuprofen sustained-release preparation and preparation method thereof |
| CN102204882A (en) * | 2011-03-22 | 2011-10-05 | 韩彬 | Pharmaceutical composition containing ibuprofen |
| CN106794163A (en) * | 2014-07-18 | 2017-05-31 | 光大制药有限公司 | Aqueous formulation comprising paracetamol and brufen |
| WO2019108147A1 (en) * | 2017-11-29 | 2019-06-06 | İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. | Color stable fixed dose tablet combination of ibuprofen and paracetamol |
Non-Patent Citations (2)
| Title |
|---|
| GNANA RAJA M 等: "Simultaneous, Stability Indicating Method Development and Validation for Related Compounds of Ibuprofen and Paracetamol Tablets by RP-HPLC Method" * |
| 张宏武,郭文敏,杨汉煜,李云立,张莉,周桂荣: "HPLC同时测定复方布洛芬软胶囊中布洛芬、对乙酰氨基酚的含量" * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114965754A (en) * | 2022-05-13 | 2022-08-30 | 陕西必康制药集团控股有限公司 | Method for detecting related substances and bacteriostatic agent in acetaminophen tablet |
| CN114965754B (en) * | 2022-05-13 | 2024-04-09 | 陕西必康制药集团控股有限公司 | Method for detecting related substances and bacteriostat in acetaminophen tablet |
| CN115097049A (en) * | 2022-07-25 | 2022-09-23 | 广西壮族自治区食品药品检验所 | Method for determining related substances in pediatric paracetamol, atificial cow-bezoar and chlorphenamine maleate granules |
| CN115236255A (en) * | 2022-08-04 | 2022-10-25 | 迪沙药业集团有限公司 | Method for detecting loxoprofen sodium related substances |
| CN115236255B (en) * | 2022-08-04 | 2023-08-25 | 迪沙药业集团有限公司 | Method for detecting related substances of loxoprofen sodium |
| CN116735757A (en) * | 2023-08-09 | 2023-09-12 | 则正(上海)生物科技有限公司 | Method for detecting related substances in ibuprofen medicament |
| CN117288868A (en) * | 2023-11-24 | 2023-12-26 | 山东百诺医药股份有限公司 | Detection method of N-acetyl-L-leucine related substances |
| CN117288868B (en) * | 2023-11-24 | 2024-01-30 | 山东百诺医药股份有限公司 | Detection method of N-acetyl-L-leucine related substances |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114062554B (en) | 2023-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114062554B (en) | Analysis method for simultaneously measuring related substances of acetaminophen ibuprofen | |
| Razzaq et al. | Stability indicating HPLC method for the simultaneous determination of moxifloxacin and prednisolone in pharmaceutical formulations | |
| Baker et al. | Validated stability-indicating HPLC-DAD method for determination of the recently approved hepatitis C antiviral agent daclatasvir | |
| WO2019242212A1 (en) | Liquid chromatography method for detecting related substances in parecoxib sodium and synthetic intermediates thereof | |
| Kang et al. | Modern methods for analysis of antiepileptic drugs in the biological fluids for pharmacokinetics, bioequivalence and therapeutic drug monitoring | |
| Al-Rimawi | Normal-phase LC method for simultaneous analysis of pseudophedrine hydrochloride, dextromethorphan hydrobromide, chlorpheniramine maleate, and paracetamol in tablet formulations | |
| Shaalan et al. | HPLC-DAD stability indicating determination of nitrofurazone and lidocaine hydrochloride in their combined topical dosage form | |
| Zarghi et al. | Sensitive and rapid HPLC method for determination of memantine in human plasma using OPA derivatization and fluorescence detection: application to pharmacokinetic studies | |
| Mannemala et al. | Development and validation of a HPLC‐PDA bioanalytical method for the simultaneous estimation of Aliskiren and Amlodipine in human plasma | |
| CN110988230A (en) | Liquid chromatography separation detection method for flurbiprofen axetil enantiomer and impurity A | |
| Elzayat et al. | A validated stability-indicating UPLC method for determination of diclofenac sodium in its pure form and matrix formulations | |
| Shaalan et al. | Simultaneous determination of hyoscine, ketoprofen and ibuprofen in pharmaceutical formulations by HPLC-DAD | |
| Lin et al. | Simple and sensitive fluorimetric liquid chromatography method for the determination of valproic acid in plasma | |
| Rao et al. | A validated chiral LC method for the enantioselective analysis of Levetiracetam and its enantiomer R-α-ethyl-2-oxo-pyrrolidine acetamide on amylose-based stationary phase | |
| Qi et al. | Validated liquid chromatography method for assay of tizanidine in drug substance and formulated products | |
| Bahgat et al. | HPLC-DAD technique for the quantification of a recently approved anti-diabetic triple combination along with two toxic official impurities: Toxicity confirmation aided by molecular docking application | |
| Belal et al. | Gradient HPLC-diode array detector stability-indicating determination of lidocaine hydrochloride and cetylpyridinium chloride in two combined oral gel dosage forms | |
| CN114965754B (en) | Method for detecting related substances and bacteriostat in acetaminophen tablet | |
| Yang et al. | A gas chromatography flame ionization detector method for rapid simultaneous separation and determination of six active ingredients of anticold drug | |
| Wang et al. | Detection of two genotoxic impurities in drug substance and preparation of imatinib mesylate by LC–MS/MS | |
| Alswayeh et al. | Rapid determination of acetaminophen levels in human plasma by high performance liquid chromatography | |
| Ganesh et al. | Quantitation of alfuzosin hydrochloride in pharmaceutical formulations by RP-HPLC. | |
| Hegazy et al. | Studying the compatibility of a metoclopramide-HCl–paracetamol mixture via IHCMC and establishing a validated RP-HPLC method for its determination in tablets | |
| Din et al. | Validated reversed-phase liquid chromatographic method for simultaneous determination of dextromethorphan and chlorpheniramine in non-biological and biological matrices using PDA detector | |
| CN115494174B (en) | Method for detecting thiourea in meloxicam by high performance liquid chromatography |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |