CN112858519B - Detection method for related substances of amoxicillin potassium clavulanate granules - Google Patents
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Abstract
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a detection method for related substances of amoxicillin and potassium clavulanate granules. The method provided by the invention comprises the following steps: preparing a test solution, preparing a reference solution and performing gradient elution by high performance liquid chromatography, wherein the mobile phase comprises a mobile phase A and a mobile phase B, and the mobile phase A is a sodium dihydrogen phosphate aqueous solution with the pH value adjusted to 4-4.5 by phosphoric acid and the concentration of 0.05 mol/L; the mobile phase B is a mixed solution prepared by sodium dihydrogen phosphate aqueous solution and methanol, wherein the pH value of the mixed solution is adjusted to 4-4.5 by phosphoric acid, and the concentration of the mixed solution is 0.05 mol/L. The method can effectively detect the related substances contained in the amoxicillin potassium clavulanate particles, has the advantages of simple and convenient integral operation, high separation degree and accurate result, and is suitable for quality monitoring of the amoxicillin potassium clavulanate particles.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a detection method of related substances of amoxicillin and potassium clavulanate granules.
Background
The amoxicillin and clavulanate potassium is a compound preparation of amoxicillin and clavulanate potassium. Amoxicillin is a commonly used broad-spectrum penicillin antibiotic, potassium clavulanate has weak antibacterial activity but has strong broad-spectrum beta lactamase inhibiting effect, and the amoxicillin and the beta lactamase can be protected from being hydrolyzed by the beta lactamase under the combined action of the amoxicillin and the potassium clavulanate, so that the antibacterial effect is enhanced, the amoxicillin has good effects on enzyme-producing staphylococcus aureus, staphylococcus epidermidis, coagulase-negative staphylococcus, enterococcus and the like, and has good antibacterial activity on certain beta lactamase-producing enteromycetaceae bacteria, haemophilus influenzae, moraxella catarrhalis, bacteroides fragilis and the like.
The amoxicillin and clavulanate potassium particles are a common formulation of amoxicillin and clavulanate potassium, relevant regulations including properties, identification, related substance inspection, content measurement and the like are specified in the 2020 edition of Chinese pharmacopoeia, but the amoxicillin and clavulanate potassium particles contain many impurities which can significantly affect the quality and the storage life of a medicine, and on the premise of taking pharmacopoeia standards as a basis, a more precise, more accurate and more effective method is to be provided for monitoring related substances in the amoxicillin and clavulanate potassium particles to ensure that the amoxicillin and clavulanate potassium particles have higher quality.
The related substances to be detected by the invention are mainly amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L, and the main structural formula is as follows:
chinese patent application CN111239265A discloses a liquid chromatography method for determining related substances of clavulanic acid in an amoxicillin potassium clavulanate pharmaceutical composition, which can effectively detect clavulanic acid impurities in the amoxicillin potassium clavulanate pharmaceutical composition, but does not provide a method for detecting amoxicillin impurities in amoxicillin potassium clavulanate medicines.
In summary, amoxicillin and clavulanate potassium granules are commonly used in the drug market, and in order to further perform quality control on the granules, an accurate and reliable detection method is needed.
Disclosure of Invention
The invention aims to provide a method for detecting related substances of amoxicillin and potassium clavulanate granules, which can accurately and effectively detect amoxicillin impurities contained in the amoxicillin and potassium clavulanate granules, has the advantages of simple and convenient integral operation, high separation degree and accurate result, and is suitable for quality monitoring of the amoxicillin and potassium clavulanate granules.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a detection method for related substances of amoxicillin potassium clavulanate granules comprises the following steps:
s1: preparation of a test solution: taking amoxicillin and clavulanate potassium particles, transferring the amoxicillin and clavulanate potassium particles into a volumetric flask, adding water for dissolution, carrying out ice bath ultrasonic treatment for 3-8min, adding water for dilution and fixing the volume to a scale, filtering the prepared solution through a water phase needle type aperture filter, and taking a subsequent filtrate to obtain a test solution;
s2: preparation of control solutions:
1) Preparation of self-control solution: accurately weighing an amoxicillin reference substance into a volumetric flask, adding water, shaking for dissolution, adding water for dilution to a constant volume to scale, accurately transferring into the volumetric flask, adding water for dilution to a constant volume to scale to obtain a self reference substance solution;
2) Preparation of related substance control solution: weighing amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L reference substances respectively, dissolving the reference substances with water and diluting the reference substances to a constant volume to prepare reference substance stock solutions, precisely transferring the impurity stock solutions to a volumetric flask, adding a solvent to dilute the impurity stock solutions to a constant volume to a scale to obtain a reference substance solution of related substances, and taking the reference substance solution as a system adaptive solution;
s3: performing gradient elution by high performance liquid chromatography.
Further, the ice bath ultrasonic process of step S1 requires continuous shaking of the volumetric flask to avoid the adhesion of insoluble excipients to the bottom of the flask.
Furthermore, the material of the water phase needle type aperture filter in the step S1 is polyether sulfone, and the specification is 25mm x 0.45 μm.
Further, the chromatographic conditions of the high performance liquid chromatography of the step S3 for gradient elution are as follows: octadecylsilane chemically bonded silica is used as a filling agent, a mobile phase comprises a mobile phase A and a mobile phase B, the detection wavelength is 230nm, the column temperature is 20-25 ℃, the flow rate is 0.5-1.5mL/min, and the temperature of an automatic sample injector is controlled at 2-8 ℃.
Further, the types of the octadecylsilane chemically bonded silica are as follows: SHIMASZU Shim GIST C18X 4.6mm,3 μm.
Further, the mobile phase A is sodium dihydrogen phosphate aqueous solution with the pH value adjusted to 4-4.5 by phosphoric acid and the concentration of 0.05 mol/L; the mobile phase B is a mixed solution prepared by sodium dihydrogen phosphate aqueous solution and methanol, wherein the pH value of the mixed solution is adjusted to 4-4.5 by phosphoric acid, and the concentration of the mixed solution is 0.05 mol/L.
Further, the preparation method of the mobile phase B comprises the following steps: the pH value of the mixture is adjusted to 4-4.5 by phosphoric acid, and the mixture of 0.05mol/L sodium dihydrogen phosphate solution and methanol is mixed according to a volume ratio of 46.
Further, the order of the gradient elution is:
0-18min:100% of mobile phase A;
18-45min:50% mobile phase a and 50% mobile phase B;
45-50min:100% mobile phase a.
System applicability solution requirements: the separation degree between amoxicillin impurities D1 and D2 is not lower than 2.0, and the separation degree between the impurities is not lower than 1.5; the amoxicillin impurity J is not more than 2.0 percent of amoxicillin, the amoxicillin impurity D, the amoxicillin impurity E and the amoxicillin impurity C are not more than 1.0 percent of amoxicillin, other single known impurity is not more than 1.0 percent of amoxicillin, and other unknown impurity is not more than 0.2 percent of amoxicillin; the total impurities are not more than 5.0 percent of amoxicillin, and the peak less than 0.03 percent in the chromatogram of the test solution is negligible. Co-elution may occur in the two chromatographic peaks of the impurity B and the impurity D, and the content and the limit of the co-eluted impurities are combined and calculated for judgment.
Compared with the prior art, the invention has the following advantages:
(1) Compared with the Chinese pharmacopoeia, the invention provides a more accurate and strict detection method for related substances, and the method can be used for detecting amoxicillin impurities A, B, C, D, E, F, G, H, I, J, L and the like, thereby greatly improving the detection standard and laying a foundation for obtaining high-quality medicines.
(2) The invention carries out gradient elution by using a mobile phase A and a mobile phase B, particularly uses a sodium dihydrogen phosphate aqueous solution with the pH value adjusted to 4.2 by using phosphoric acid and the concentration of 0.05mol/L as the mobile phase A, uses a mixed solution prepared by the sodium dihydrogen phosphate aqueous solution with the pH value adjusted to 4.2 by using phosphoric acid and the concentration of 0.05mol/L and methanol as the mobile phase B, and further limits the composition ratio of the mobile phase B.
(3) The method is not only suitable for detecting related substances in the amoxicillin and clavulanate potassium particles, but also provides technical inspiration for detection or monitoring of similar substances.
Drawings
FIG. 1 is a liquid chromatogram for detecting related substances mixed solution of amoxicillin and potassium clavulanate granules according to the detection method provided by the invention.
Detailed Description
The present invention will be further explained by way of specific embodiments in the form of examples. The scope of the above-described subject matter of the present invention is not limited to the following examples.
The technical means used in the examples are conventional means well known to those skilled in the art, and the starting materials used are commercially available products.
Example 1 detection method of related substances of amoxicillin and potassium clavulanate granules
The detection method of related substances of amoxicillin potassium clavulanate granules comprises the following steps:
s1: preparation of a test solution: taking 1 bag of amoxicillin and potassium clavulanate particles (selected from Shijiazhuang limited company in Shiyao pharmaceutical group, the specification is 156.25mg (amoxicillin 125mg and clavulanic acid 31.25 mg)), transferring the particles into a 200mL volumetric flask, adding a proper amount of water, carrying out ice bath ultrasound for 3min (shaking continuously in the ultrasound process to avoid insoluble auxiliary materials from adhering to the bottom of the flask), adding water to dilute to a constant volume to reach a scale, taking a proper amount of solution, filtering the solution by a water phase needle type aperture filter (polyether sulfone, 25mm x 0.45 mu m), and taking a subsequent filtrate to obtain a sample solution;
s2: preparation of control solutions:
1) Preparation of self-control solution: accurately weighing an amoxicillin reference substance in a volumetric flask with the volume of 12mg to 100mL, adding a proper amount of water, shaking for dissolving, adding water for diluting to a constant volume to scale, accurately transferring into a volumetric flask with the volume of 1mL to 10mL, adding water for diluting to a constant volume to scale, and obtaining a self reference substance solution;
2) Preparation of related substance control solution: weighing appropriate amount of amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L as reference substances, respectively dissolving with water, diluting to constant volume to obtain solutions containing 0.1mg of each 1mL, precisely transferring 5mL of each impurity stock solution to a 100mL volumetric flask, adding solvent, diluting to constant volume to scale, and preparing solutions containing 5 μ G of each impurity in each 1mL to obtain related substance reference substance solutions, and using the solutions as system adaptability solutions;
s3: gradient elution by high performance liquid chromatography:
chromatographic conditions are as follows: octadecylsilane bonded silica (SHIMASZU Shim pack GIST C18X 4.6mm,3 μm) was used as a filler; the mobile phase A is 0.05mol/L sodium dihydrogen phosphate aqueous solution (the pH value is adjusted to 4 by using phosphoric acid), the mobile phase B is prepared by mixing 0.05mol/L sodium dihydrogen phosphate aqueous solution and methanol according to the volume ratio of 46; the flow rate is 0.5mL/min; controlling the temperature of the automatic sample injector at 2 ℃ and carrying out linear gradient elution;
the order of the gradient elution is: 0-18min:100% mobile phase a;18-45min:50% mobile phase a and 50% mobile phase B;45-50min:100% mobile phase a;
20 mu L of sample solution is injected into a liquid chromatograph, and the chromatogram is recorded.
Example 2 detection method of related substances of amoxicillin potassium clavulanate granules
The detection method of related substances of the amoxicillin potassium clavulanate granules comprises the following steps:
s1: preparing a test solution: taking 1 bag of amoxicillin and clavulanate potassium particles (selected from Shijiazhuang limited company in Shiyao medicine group, the specification: 156.25mg (amoxicillin 125mg and clavulanic acid 31.25 mg)), transferring the particles into a 200mL volumetric flask, adding a proper amount of water, carrying out ice bath ultrasound for 8min (shaking continuously in the ultrasound process to avoid insoluble auxiliary materials from adhering to the bottom of the flask), adding water to dilute to a constant volume to a scale, taking a proper amount of solution, filtering the solution by using a water phase needle type aperture filter (polyether sulfone, 25mm x 0.45 mu m), and taking a subsequent filtrate to obtain a sample solution;
s2: preparation of control solutions:
1) Preparation of self-control solution: accurately weighing an amoxicillin reference substance 12mg to a 100mL volumetric flask, adding a proper amount of water, shaking for dissolution, adding water for dilution to a constant volume to scale, accurately transferring to a 1mL to 10mL volumetric flask, adding water for dilution to a constant volume to scale, and obtaining a reference substance solution per se;
2) Preparation of related substance control solution: weighing appropriate amount of amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L as reference substances, respectively dissolving with water, diluting to constant volume to obtain solutions containing 0.1mg of each 1mL, precisely transferring 5mL of each impurity stock solution to a 100mL volumetric flask, adding solvent, diluting to constant volume to scale, and preparing solutions containing 5 μ G of each impurity in each 1mL to obtain related substance reference substance solutions, and using the solutions as system adaptability solutions;
s3: gradient elution by high performance liquid chromatography:
chromatographic conditions are as follows: octadecylsilane bonded silica (SHIMASZU Shim pack GIST C18X 4.6mm,3 μm) was used as a filler; the mobile phase A is 0.05mol/L sodium dihydrogen phosphate aqueous solution (the pH value is adjusted to 4.5 by using phosphoric acid), the mobile phase B is prepared by mixing 0.05mol/L sodium dihydrogen phosphate aqueous solution and methanol according to the volume ratio of 46; the flow rate is 1.5mL/min; controlling the temperature of the automatic sample injector at 8 ℃ and carrying out linear gradient elution;
the order of the gradient elution is: 0-18min:100% mobile phase a;18-45min:50% mobile phase a and 50% mobile phase B;45-50min:100% mobile phase a;
20 mu L of sample solution is injected into a liquid chromatograph, and the chromatogram is recorded.
Example 3 detection method of related substances of amoxicillin and potassium clavulanate granules
The detection method of related substances of amoxicillin potassium clavulanate granules comprises the following steps:
s1: preparing a test solution: taking 1 bag of amoxicillin and clavulanate potassium particles (selected from Shijiazhuang limited company in Shiyao medicine group, the specification: 156.25mg (amoxicillin 125mg and clavulanic acid 31.25 mg)), transferring the particles into a 200mL volumetric flask, adding a proper amount of water, carrying out ice bath ultrasound for 5min (shaking continuously in the ultrasound process to avoid insoluble auxiliary materials from adhering to the bottom of the flask), adding water to dilute to a constant volume to a scale, taking a proper amount of solution, filtering the solution by using a water phase needle type aperture filter (polyether sulfone, 25mm x 0.45 mu m), and taking a subsequent filtrate to obtain a sample solution;
s2: preparation of control solutions:
1) Preparation of self-control solution: accurately weighing an amoxicillin reference substance 12mg to a 100mL volumetric flask, adding a proper amount of water, shaking for dissolution, adding water for dilution to a constant volume to scale, accurately transferring to a 1mL to 10mL volumetric flask, adding water for dilution to a constant volume to scale, and obtaining a reference substance solution per se;
2) Preparation of related substance control solution: weighing appropriate amount of amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L as reference substances, respectively dissolving with water, diluting to constant volume to obtain solutions containing 0.1mg of each 1mL, precisely transferring 5mL of each impurity stock solution to a 100mL volumetric flask, adding solvent, diluting to constant volume to scale, and preparing solutions containing 5 μ G of each impurity in each 1mL to obtain related substance reference substance solutions, and using the solutions as system adaptability solutions;
s3: gradient elution by high performance liquid chromatography:
chromatographic conditions are as follows: octadecylsilane bonded silica (SHIMASZU Shim pack GIST C18X 4.6mm,3 μm) was used as a filler; the mobile phase A is 0.05mol/L sodium dihydrogen phosphate aqueous solution (the pH value is adjusted to 4.2 by using phosphoric acid), the mobile phase B is prepared by mixing 0.05mol/L sodium dihydrogen phosphate aqueous solution and methanol according to the volume ratio of 46; the flow rate is 1.0mL/min; controlling the temperature of the automatic sample injector at 4 ℃ and carrying out linear gradient elution;
the order of the gradient elution is: 0-18min:100% mobile phase a;18-45min:50% mobile phase a and 50% mobile phase B;45-50min:100% mobile phase a;
20 mu L of sample solution is injected into a liquid chromatograph, and the chromatogram is recorded.
Comparative example 1, method for detecting related substances of amoxicillin and potassium clavulanate particles
This comparative example is similar to example 3 except that the mobile phase A is a 0.05mol/L aqueous ammonium acetate solution, and the mobile phase B is a 0.05mol/L mixed solution of an aqueous ammonium acetate solution and acetonitrile at a volume ratio of 80.
Comparative example 2, method for detecting related substances of amoxicillin potassium clavulanate granules
This comparative example is similar to example 3 except that the 0.05mol/L sodium dihydrogen phosphate solution used for mobile phase A and mobile phase B was not pH-adjusted with phosphoric acid.
Experimental example 1 comparison of results of degrees of separation
The results of the degrees of separation of examples 1-3 and comparative examples 1-2 are compared as shown in Table 1:
table 1: comparison of results of degrees of separation
As can be seen from Table 1, examples 1 to 3 can achieve effective separation of a main peak and an impurity peak without causing coincidence with an amoxicillin impurity peak, while comparative example 1 changes the composition of a mobile phase, so that part of the impurity peak coincides with the main peak, and comparative example 2 does not adjust the pH of a sodium dihydrogen phosphate solution in the examples by using phosphoric acid, and both affect the separation degree of detection.
Experimental example 2 results of amoxicillin potassium clavulanate granules as the main component and each impurity component
The results of the impurity components in example 3 are shown in table 2 (fig. 1 is a corresponding chromatogram):
table 2: results of respective impurity components in example 3
| Name of impurity | Retention time min | Peak area | % area of the Peak | Peak height | Number of theoretical plate |
| amx-A | 5.667 | 39694 | 1.5 | 6708 | 21140.75 |
| amx-D1&amx-B | 8.397 | 224226 | 8.5 | 30560 | 30192.62 |
| amx-C | 20.704 | 167072 | 6.33 | 18410 | 117261.00 |
| amx-D2 | 9.16 | 45162 | 1.71 | 6293 | 37770.29 |
| amx-E1 | 16.206 | 59294 | 2.25 | 6008 | 64993.64 |
| amx-E2 | 19.108 | 78831 | 2.99 | 8315 | 94046.22 |
| amx-F | 22.602 | 174963 | 6.63 | 14409 | 78303.72 |
| amx-G | 15.008 | 223818 | 8.48 | 28043 | 80094.52 |
| amx-H | 23.706 | 202992 | 7.69 | 15317 | 71790.55 |
| amx-I | 1.999 | 260130 | 9.86 | 61977 | 5315.75 |
| amx-J | 32.861 | 73689 | 2.79 | 2755 | 31807.69 |
| amx-L | 27.077 | 83520 | 3.16 | 4379 | 44924.23 |
Note: amx-x refers to amoxicillin related substance.
As can be seen from the table 2 and the figure 1, the detection method has the advantages of good detection effect, high column efficiency, effective separation of impurities, short detection time, and capability of performing detection quickly and efficiently.
Claims (3)
1. A detection method for related substances of amoxicillin potassium clavulanate granules is characterized by comprising the following steps:
s1: preparing a test solution: taking amoxicillin and clavulanate potassium particles, transferring the amoxicillin and clavulanate potassium particles into a volumetric flask, adding water for dissolution, carrying out ice bath ultrasonic treatment for 3-8min, adding water for dilution and fixing the volume to a scale, filtering the prepared solution through a water phase needle type aperture filter, and taking a subsequent filtrate to obtain a test solution;
s2: preparation of control solutions:
1) Preparation of self-control solution: accurately weighing an amoxicillin reference substance into a volumetric flask, adding water, shaking for dissolution, adding water for dilution to a constant volume to scale, accurately transferring into the volumetric flask, adding water for dilution to a constant volume to scale, and obtaining a self reference substance solution;
2) Preparation of related substance control solution: weighing amoxicillin impurities A, B, C, D, E, F, G, H, I, J and L reference substances respectively, dissolving the reference substances with water and diluting the reference substances to a constant volume to prepare reference substance stock solutions, precisely transferring the impurity stock solutions to a volumetric flask, adding a solvent to dilute the impurity stock solutions to a constant volume to a scale to obtain a reference substance solution of related substances, and taking the reference substance solution as a system adaptive solution;
s3: performing gradient elution by high performance liquid chromatography;
the chromatographic conditions of the high performance liquid chromatography of the step S3 for gradient elution are as follows: octadecylsilane chemically bonded silica is used as a filling agent, a mobile phase comprises a mobile phase A and a mobile phase B, the detection wavelength is 230nm, the column temperature is 20-25 ℃, the flow rate is 0.5-1.5mL/min, and the temperature of an automatic sample injector is controlled at 2-8 ℃;
the mobile phase A is sodium dihydrogen phosphate aqueous solution with the pH value adjusted to 4-4.5 by phosphoric acid and the concentration of 0.05 mol/L; the mobile phase B is a mixed solution prepared by sodium dihydrogen phosphate aqueous solution and methanol, wherein the pH value of the mixed solution is adjusted to 4-4.5 by phosphoric acid, and the concentration of the mixed solution is 0.05 mol/L;
the order of the gradient elution is:
0-18min:100% of mobile phase A;
18-45min:50% mobile phase a and 50% mobile phase B;
45-50min:100% mobile phase a;
the chromatographic column model of the octadecylsilane chemically bonded silica is as follows: SHIMASZU Shim GIST C18X 4.6mm,3 μm;
the preparation method of the mobile phase B comprises the following steps: mixing a sodium dihydrogen phosphate solution with the pH value adjusted to 4-4.5 by phosphoric acid and the concentration of 0.05mol/L and methanol according to the volume ratio of 46;
the structural formula of the amoxicillin impurity A is as follows:
；
the structural formula of the amoxicillin impurity B is as follows:
；
the structural formula of the amoxicillin impurity C is as follows:
；
the structural formula of the amoxicillin impurity D is as follows:
；
the structural formula of the amoxicillin impurity E is as follows:
；
the structural formula of the amoxicillin impurity F is as follows:
；
the structural formula of the amoxicillin impurity G is as follows:
；
the structural formula of the amoxicillin impurity H is as follows:
；
the structural formula of the amoxicillin impurity I is as follows:
；
the structural formula of the amoxicillin impurity J is as follows:
；
the structural formula of the amoxicillin impurity L is as follows:
。
2. the method for detecting substances related to amoxicillin and potassium clavulanate granules in claim 1, wherein the ice bath ultrasound process of step S1 requires continuous shaking of the volumetric flask to avoid insoluble excipients from adhering to the bottom of the flask.
3. The method for detecting substances related to amoxicillin and potassium clavulanate granules as claimed in claim 1, wherein the water phase needle type pore size filter in the step S1 is made of polyether sulfone and has a specification of 25mm x 0.45 μm.
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| CN105518010A (en) * | 2013-09-03 | 2016-04-20 | 中化帝斯曼制药有限公司荷兰公司 | Micronized amoxicillin |
| CN108693292A (en) * | 2018-07-25 | 2018-10-23 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of detection method of amoxil capsule impurity |
| CN111239265B (en) * | 2018-11-28 | 2022-07-26 | 江苏先声药业有限公司 | Liquid chromatography method for determining clavulanic acid related substances in amoxicillin and potassium clavulanate pharmaceutical composition |
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