CN109655544B - Quality control method of metformin hydrochloride and preparation thereof - Google Patents
Quality control method of metformin hydrochloride and preparation thereof Download PDFInfo
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Abstract
The invention discloses a quality control method of metformin hydrochloride and a preparation thereof, which comprises the steps of preparing a sample solution, analyzing the sample solution by adopting a high performance liquid chromatography and finishing the analysis result, wherein the analysis conditions of the high performance liquid chromatography are as follows: a chromatographic column: sulfonic cation exchange bonded silica gel chromatographic column, mobile phase: 2.3% ammonium dihydrogen phosphate solution, ph2.6, flow rate: 1.0-1.7 ml/min, sample injection concentration: 2.5-10 mg/ml, sample injection amount: 10-20 mul, detection wavelength: 218nm, column temperature: at 20 ℃. The method can realize effective separation of various related substances in the test solution of the bulk drug/preparation and the test solution obtained by the damage experiment, and further thinks that the method can simultaneously realize effective quality control of known impurities and unknown impurities which are generated/potentially generated in the preparation and storage processes of the bulk drug or the preparation, and has universality compared with the method disclosed by the prior art.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to metformin hydrochloride and a quality control method of a preparation thereof.
Background
Diabetes is a symptom of a series of metabolic disorders such as sugar, protein, fat, water, electrolyte and the like in a human body caused by hypofunction of pancreatic islets, insulin resistance and the like. Recent epidemiological investigations have shown that diabetic patients have grown year by year in our country, and have become the second largest non-infectious disease beyond cardiovascular diseases.
Metformin hydrochloride (Metformin hydrochloride), CAS: 1115-70-4, belonging to biguanide compounds, having the functions of reducing blood sugar, reducing triacylglycerol, cholesterol and very low density lipoprotein, and increasing fibrinolysis, is clinically used for treating II-type diabetes mellitus which is ineffective in single diet control and physical exercise treatment of adults, particularly can be used for treating obesity II-type diabetes mellitus, is an oral hypoglycemic drug which is clinically preferred for treating II-type diabetes mellitus, and has common dosage forms of oral normal-release tablets and oral slow-release tablets.
Research on substances in chemicals is an important part in the process of drug development, and includes qualitative research and quantitative research on known and unknown impurities, and development of related detection methods and methodological research. The research on related substances can control the impurities within safe and reasonable limits in a normative way, and the quality and the clinical use safety of the marketed medicine are directly influenced. The existing research shows that the metformin hydrochloride and the preparation thereof are easy to generate impurities in the preparation and storage processes based on the chemical properties of the compound, so that the safety of clinical medication is influenced, the pharmacopoeias of various countries set a detection method for investigating the conditions of related substances in the metformin hydrochloride raw material drug and the preparation, and the contents of active ingredients and impurities are regulated.
Common related substances of metformin hydrochloride
The prior art discloses a method for detecting related substances in various metformin hydrochloride raw material medicaments and preparations. The second part of the Chinese pharmacopoeia (2015 edition) discloses a High Performance Liquid Chromatography (HPLC) detection method for related substances of metformin hydrochloride tablets, wherein an analytical column using sulfonic cation exchange bonded silica gel as a filler is adopted, a 1.7% ammonium dihydrogen phosphate solution (with the pH value adjusted to 3.0 by phosphoric acid) is used as a mobile phase, the detection wavelength is 218nm, a peak which is consistent with the retention time of a dicyandiamide peak in a chromatogram of a reference solution is simultaneously determined in the chromatogram of a test solution, the peak area is calculated by an external standard method, the peak area of other single impurities is not more than 0.02% of the labeled amount of metformin hydrochloride, the peak area of other single impurities is not more than 0.2 times (0.1%) of the main peak area of the reference solution, and the sum of the peak areas of other impurities is not more than 1.2 times (0.6%) of the main peak area of the reference solution. The same detection methods are also disclosed in the Japanese pharmacopoeia (JP XVII) which sets a column temperature of an analytical column at 40 ℃ and the United states pharmacopoeia (USP41) which sets a column temperature of an analytical column at 30 ℃.
Chinese patent CN104337811A discloses an HPLC detection method for related substances of repaglinide-metformin hydrochloride tablets, which comprises the following steps: a chromatographic column: sulfonic acid group cation exchange bonded silica gel Capcell Pak5 μ SCX UG80A column (4.6 mm. times.150 mm,5 μm), mobile phase: 0.35mol/L (3.9%) ammonium dihydrogen phosphate buffer (pH 3.0); the detection wavelength is 230nm, and the quality control of the metformin hydrochloride and related substances in the preparation can be realized by adopting the method.
In northern pharmacy, Zhangrongqin, 2018, 15(8), P1, and the determination of dicyandiamide and related substances in metformin hydrochloride sustained-release tablets, the literature discloses an HPLC detection method for related substances in metformin hydrochloride tablets, which comprises the following steps: a chromatographic column: hypersil SCX column (4.6 mm. times.150 mm,5 μm), mobile phase: 0.43mol/L (4.7%) ammonium dihydrogen phosphate buffer (pH 2.5); the detection wavelength is 218nm, and the separation degree of the metformin hydrochloride and the dicyandiamide impurity thereof can be more than or equal to 1.5 by adopting the method.
The prior art also discloses other HPLC detection methods for the metformin hydrochloride bulk drug or preparation, and the methods can realize the quality control of the metformin hydrochloride bulk drug or preparation by adopting gradient elution, or adopting a mobile phase system containing organic solvents (such as acetonitrile, methanol and the like), or adopting other packed analytical columns.
Although the methods disclosed in the prior art can realize quality control of conventional impurities, based on the diversity of the production processes, storage conditions and the like of the raw material drugs and preparations thereof from different sources, the related substance conditions are relatively diverse, and in addition, the differences of detection instruments and experimental equipment exist in the analysis process, so that a more universal HPLC method is purposefully found to realize better qualitative and quantitative research on known and unknown impurities in the metformin hydrochloride raw material drug and the preparations, which is a technical problem to be solved by the prior art.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a High Performance Liquid Chromatography (HPLC) quality control method for metformin hydrochloride and a preparation thereof, which has universality compared with the method disclosed by the prior art and is represented as follows: by adopting the method, the relevant substances can be better separated, and the more accurate quantitative analysis of the relevant substances in the raw material medicines or preparations can be realized; on the basis, the method further shows that the method can realize effective separation of the unknown impurities newly generated in the damage experiment, and is further favorable for realizing effective quality control of the unknown impurities potentially generated in the preparation and storage processes of the bulk drugs or the preparations.
The above object of the present invention is achieved by the following technical solutions:
a quality control method for metformin hydrochloride and a preparation thereof comprises the following steps:
(1) preparing a sample solution;
(2) analyzing the sample solution by a high performance liquid chromatography;
(3) sorting the analysis results;
wherein the analysis conditions of the high performance liquid phase method are as follows:
a chromatographic column: sulfonic cation exchange bonded silica gel chromatographic column
Mobile phase: 2.3% ammonium dihydrogen phosphate solution, pH2.6
Flow rate: 1.0 to 1.7ml/min
Sample introduction concentration: 2.5-10 mg/ml
Sample injection amount: 10 to 20. mu.l
Detection wavelength: 218nm
Column temperature: at 20 ℃.
In the quality control method of the metformin hydrochloride and the preparation thereof, the concentration of ammonium dihydrogen phosphate in a mobile phase, the pH value of the mobile phase, the column temperature and a chromatographic column adopted by a high performance liquid chromatography are important factors influencing the detection effect.
Specifically, the concentration and the pH value of ammonium dihydrogen phosphate in the mobile phase adopted by the high performance liquid chromatography can influence the detection effect; for the concentration of ammonium dihydrogen phosphate in the mobile phase, a detection sample is a test solution prepared from a raw material medicine or a preparation, and when the pH value is kept unchanged, the low-concentration ammonium dihydrogen phosphate mobile phase cannot realize baseline separation of all impurities; particularly, when the method reported by pharmacopoeia of various countries is adopted, the peak of the impurity 1-methyl biguanide cannot be effectively separated, and the detection efficiency is influenced due to longer peak-producing time of the mobile phase of ammonium dihydrogen phosphate with high concentration although better impurity separation degree can be realized; in addition, the inventor also discovers accidentally in the experiment that when a test sample is used for destroying the test solution of the experiment, and ammonium dihydrogen phosphate with lower concentration is used as a mobile phase, a part of original bulk drugs or preparations can detect a newly-appeared unknown impurity peak, which indicates that the potential possibility of generating the unknown impurity exists in the preparation and storage of the product, and further researches show that the separation degree of the unknown impurity peak is reduced along with the increase of the concentration of the ammonium dihydrogen phosphate, and when the concentration of the ammonium dihydrogen phosphate is 2.8%, the unknown impurity completely overlaps with the main peak; by integrating the detection effect and the detection efficiency, the inventor obtains that: when the concentration of the ammonium dihydrogen phosphate in the mobile phase is 2.3%, the best separation of impurities in each test solution is favorably realized by detection, and the detection efficiency is higher. Unless otherwise specified, the concentrations of monoammonium phosphate in the present invention are all referred to as mass percent concentrations.
For the pH value of the mobile phase, a detection sample is a test solution prepared from a raw material medicine or a preparation, when the concentration of ammonium dihydrogen phosphate is kept unchanged, the mobile phase with a low pH value is compatible with the mobile phase and is easy to damage an analytical column, the service life of the analytical column is shortened, the mobile phase with a high pH value cannot realize baseline separation of all impurities, and when the detection sample is used for destroying the test solution of an experiment, the separation degree of unknown impurities and a main peak is influenced by increasing the pH value, so that the detection effect is influenced; the inventors have concluded that the best separation of impurities in each test solution by detection is advantageously achieved when the mobile phase has a pH of 2.6. The pH value of the mobile phase can be adjusted by using organic acid or inorganic acid commonly used in the field, such as acetic acid, phosphoric acid, sulfuric acid or hydrochloric acid, and the like, and phosphoric acid is preferred.
The column temperature is also one of the important factors for determining the separation effect, specifically, for a test solution prepared from the bulk drug or the preparation, the separation degree of the impurity peak and the main peak is gradually increased along with the reduction of the column temperature, but when the detection sample is a destructive test solution, the separation degree of the unknown impurity and the main peak is gradually decreased along with the reduction of the column temperature until the separation degree is overlapped; the inventor comprehensively obtains that the separation effect is best under the condition that the column temperature is 20 ℃.
The chromatographic column of the sulfonic cation exchange bonded silica gel filler adopted by the high performance liquid chromatography can be understood by those skilled in the art, even if the chromatographic column with the same filler is adopted, the efficiency of the chromatographic column is different, and the detection effect is influenced; more specifically, the inventor proves through multiple experiments that the chromatographic column of the sulfonic acid group cation exchange bonded silica gel filler adopted by the invention is preferably a senkyo CAPCELL PAK SCX UG80(S5) chromatographic column (4.6mm × 250mm,5 μm), and the optimal detection effect can be obtained for each test solution under the detection condition of the invention by using the chromatographic column, possibly related to the physical and chemical properties of the senkyo CAPCELL PAK SCX UG80(S5) chromatographic column (4.6mm × 250mm,5 μm) per se.
The sample injection concentration of the high performance liquid chromatography is 2.5-10 mg/ml (calculated by metformin hydrochloride), and the sample injection amount is 10-20 mu l. Specifically, the product to be detected is injected too little by too low injection concentration and injection amount, so that the detection error is larger, and the separation effect is influenced by too high injection concentration and injection amount, so that the detection error is larger, preferably, when the injection concentration of the high performance liquid chromatography is 5mg/ml and the injection amount is 10 μ l, the best detection effect can be obtained.
By combining the information disclosed by the prior art, the flow rate of the mobile phase in the high performance liquid chromatography can be 1.0-1.7 ml/min, and preferably, when the flow rate of the mobile phase is controlled to be 1.0ml/min, a good separation effect can be obtained, and the analysis efficiency is ensured.
Referring to the information disclosed in the Chinese pharmacopoeia (2015 edition), the detection wavelength of the high performance liquid chromatography is 218 nm.
In a preferred embodiment of the present invention, the High Performance Liquid Chromatography (HPLC) quality control method for metformin hydrochloride and its preparation comprises:
a quality control method for metformin hydrochloride and a preparation thereof comprises the following steps:
(4) preparing a sample solution;
(5) analyzing the sample solution by a high performance liquid chromatography;
(6) sorting the analysis results;
wherein the analysis conditions of the high performance liquid phase method are as follows:
and (3) chromatographic column: zishengtang CAPCELL PAK SCX UG80(S5) chromatographic column 4.6mm × 250mm,5 μm
Mobile phase: 2.3% ammonium dihydrogen phosphate solution, pH2.6
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: at 20 ℃.
The quality control method of the metformin hydrochloride and the preparation thereof can be used for quality control of a metformin hydrochloride raw material drug and a preparation containing metformin hydrochloride. Specifically, the preparation containing the metformin hydrochloride can be a single preparation or a compound preparation of the metformin hydrochloride, the preparation can be an oral normal-release preparation or an oral sustained-release preparation, and the oral preparation can be common oral preparations such as tablets, capsules and the like; more specifically, the preparation containing the metformin hydrochloride is an oral normal-release preparation or an oral sustained-release preparation with the metformin hydrochloride specification of 250mg, 500mg, 850mg and the like; further, the method can be used for analyzing related substances of metformin hydrochloride tablets (250mg) produced by Guangdong south China pharmaceutical industry group, Inc.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a High Performance Liquid Chromatography (HPLC) quality control method for metformin hydrochloride and a preparation thereof, which can realize effective separation of various related substances in a raw material medicine/preparation test solution and a test solution obtained by a damage experiment, and further think that the method can simultaneously realize effective quality control of known impurities and unknown impurities which are generated/potentially generated in the preparation and storage processes of the raw material medicine or the preparation, and has universality compared with the method disclosed by the prior art.
Drawings
FIG. 1 shows the overlay chromatograms of spiked test solutions in different concentrations of ammonium dihydrogen phosphate (pH 3.0).
FIG. 2 is a chromatogram obtained by superimposing the alkali-destroyed test solutions in ammonium dihydrogen phosphate solutions (pH3.0) having different concentrations.
FIG. 3 is a chromatogram of the overlay of a spiked test solution at different mobile phase pH values.
FIG. 4 is a chromatogram of the base-disruption test solution superimposed over the different mobile phase pH values.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
The sample used in the embodiment of the present invention is metformin hydrochloride tablet (250mg) produced by pharmaceutical group ltd in south china, guangdong, lot number: 181101, 181102, 181103.
The solvents used in the embodiments of the present invention were all commercially available analytical grade.
The high performance liquid chromatograph used in the embodiment of the invention is as follows: agilent 1260 liquid chromatograph
The chromatographic column used in the specific embodiment of the invention is: singapore CAPCELL PAK SCX UG80(S5), 250X 4.6mm,5 μm, sulfonic acid group cation exchange bonded silica gel filler.
The related substances and the corresponding structures thereof in the specific embodiment of the invention are as follows:
TABLE 1 materials and structures thereof
The mobile phase solution used in the embodiment of the invention is prepared by the following method: ammonium dihydrogen phosphate of appropriate weight is weighed, 1000ml of purified water is added for dissolution, the pH value is adjusted to a target value by phosphoric acid, and the mixture is evenly mixed and degassed to be used as a mobile phase. In the present invention, the unit of the ammonium dihydrogen phosphate solution is mass percent.
The test solution used in the specific embodiment of the present invention is prepared by the following method: precisely weighing a proper amount of fine powder (equivalent to 500mg of metformin hydrochloride) obtained by grinding metformin hydrochloride tablets, placing the fine powder into a 100ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic treatment for 15 minutes to dissolve the metformin hydrochloride, diluting the solution to a scale with the mobile phase, shaking up, filtering, discarding 4ml of primary filtrate, and taking a subsequent filtrate as a test solution.
For more clearly studying the detection effect of the quality control method, a test solution (a standard test solution) added with relevant standard substances is adopted as a detection object, the preparation method is similar to the preparation method of the test solution, and the obtained standard test solution and the standard test solution have the metformin concentration of about 5mg/ml, the dicyandiamide concentration of about 1 mug/ml, the 1-methyl biguanide concentration of about 5 mug/ml, the N, N-dimethyl melamine concentration of about 5 mug/ml and the melamine concentration of about 5 mug/ml.
The detection effect of the detection method on the test solution obtained after accelerated destruction of products in acid (alkali) hydrolysis, strong light, high temperature, high humidity, oxidation and the like is verified according to the requirements of the drug quality standard analysis method verification guiding principle.
Example 1
Effect of ammonium dihydrogen phosphate concentration in mobile phase on detection effect of spiked test solution
The specific experimental method and steps are as follows:
(1) preparing a standard adding test solution;
(2) analyzing the standard-added test solution by adopting a high performance liquid chromatography;
(3) sorting the analysis results;
the analysis conditions of the high performance liquid phase method in the step (2) are as follows:
mobile phase: the concentration of ammonium dihydrogen phosphate is 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.8%, 3.3%, and the pH value is 3.0
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml (calculated as metformin hydrochloride)
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: at 20 ℃.
The results of the tests are given in the following table:
TABLE 2 Effect of ammonium dihydrogen phosphate concentration in the mobile phase on impurity separation
From the above table data it can be found that: when the pH value of the mobile phase is fixed, the separation degree of the related substance B from the main peak is reduced along with the reduction of the concentration of the ammonium dihydrogen phosphate (the pH value of the mobile phase is fixed to be 3.0), when the concentration of the ammonium dihydrogen phosphate is 1.7 percent and the pH value is fixed to be 3.0 (the method of pharmacopoeia of various countries), the related substance B is overlapped with the main peak, and the superposed chromatogram obtained by each concentration is shown in detail in figure 1, wherein 3 is the peak corresponding to the related substance B.
In summary, when the pharmacopoeia method (1.7%, ph3.0) is used, the relevant substance B cannot be separated from the main peak, while too high a concentration indicates that effective separation of part of the unknown impurities cannot be achieved for destruction of the experimental test solution.
Example 2
Influence of alkali on deterioration of detection effect of test solution due to concentration of ammonium dihydrogen phosphate in mobile phase
The specific experimental method and steps are as follows:
(1) preparing an alkali destruction test solution;
(2) analyzing the alkali destruction test solution by adopting a high performance liquid chromatography method;
(3) sorting the analysis results;
the analysis conditions of the high performance liquid phase method in the step (2) are as follows:
mobile phase: the concentration of ammonium dihydrogen phosphate is 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.8%, 3.3%, and the pH value is 3.0
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml (calculated as metformin hydrochloride)
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: at 20 ℃.
The results of the tests are given in the following table:
TABLE 3 influence of the pH value of the ammonium dihydrogen phosphate concentration in the mobile phase on the degree of separation of impurities
From the above table data it can be found that: in the alkali destruction experiment, a new unknown impurity (such as unknown impurity 1) is found, when the pH value of the mobile phase is fixed, the separation degree of the unknown impurity 1 from the main peak is reduced along with the increase of the concentration of the ammonium dihydrogen phosphate (when the pH value of the mobile phase is fixed to be 3.0), when the concentration of the ammonium dihydrogen phosphate is more than 2.8%, the unknown impurity 1 is overlapped with the main peak, and the superposed chromatogram obtained by each concentration is shown in detail in figure 2.
In the subsequent further research on the test solution of the alkaline hydrolysis, strong light, high temperature, high humidity and oxidation destruction experiments, the result which is basically consistent with the test solution of the alkaline destruction experiments is obtained.
Combining the results of example 1 and example 2, and considering the increase of the loss of the chromatographic column and chromatograph due to the too high concentration of ammonium dihydrogen phosphate in the mobile phase, a 2.3% ammonium dihydrogen phosphate solution was selected as the mobile phase for the next optimization of the process for substance analysis.
Example 3
Effect of mobile phase pH on the detection effects of spiked and alkaline-destroyed test solutions
The specific experimental method and steps are as follows:
(1) preparing a standard adding test solution and an alkali destruction test solution respectively;
(2) analyzing each test solution by adopting a high performance liquid chromatography;
(3) sorting the analysis results;
the analysis conditions of the high performance liquid phase method in the step (2) are as follows:
mobile phase: ammonium dihydrogen phosphate concentration is 2.3%, and pH values are 2.6, 2.8, 3.0, and 3.5 respectively
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml (calculated as metformin hydrochloride)
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: at 20 ℃.
The results of the tests are given in the following table:
table 4 influence of mobile phase pH on impurity separation
From the above table data it can be found that: along with the reduction of the pH value of the mobile phase, the separation degree of the related substance B in the standard-added test solution from the main peak is increased, when the pH value of the mobile phase changes in a range from 3.0 to 3.5, the related substance B in the standard-added test solution overlaps with the main peak, when the pH value of the mobile phase is 3.5, the separation degree is 0.7, and a superposed chromatogram obtained by each pH value is shown in detail in FIG. 3, wherein 3 is a peak corresponding to the related substance B;
for the alkali destruction test solution, the separation degree of the unknown impurity 1 and the main peak is reduced along with the increase of the pH value of the mobile phase, when the pH value of the mobile phase is increased from 3.0 to 3.5, the unknown impurity 1 and the main peak are completely overlapped, a superposed chromatogram obtained by each pH value is shown in detail in figure 4, and in the subsequent further research on the alkali hydrolysis, strong light, high temperature, high humidity and oxidation destruction test solution, a result basically consistent with the alkali destruction test solution is obtained.
With reference to the test results of examples 1-3 on the influence of the concentration change of the mobile phase ammonium dihydrogen phosphate and the change of the pH value on the separation degree of the impurities, when the concentration of the mobile phase ammonium dihydrogen phosphate is 2.3%, the effective separation of the raw material drug, the preparation test solution and the impurities in the damage test solution can be realized, and the detection effect can be better achieved, so that the 2.3% ammonium dihydrogen phosphate (pH2.6) is selected as the standard condition.
Example 4
The influence of the column temperature on the detection effect of the spiked test solution and the alkali-damaged test solution was examined by adjusting the column temperature to 20 ℃,25 ℃, 30 ℃ with 2.3% ammonium dihydrogen phosphate solution (pH2.6) as the mobile phase.
The specific experimental method and steps are as follows:
(1) preparing a standard adding test solution and an alkali destruction test solution respectively;
(2) analyzing each test solution by a high performance liquid chromatography;
(3) sorting the analysis results;
the analysis conditions of the high performance liquid phase method in the step (2) are as follows:
mobile phase: ammonium dihydrogen phosphate concentration is 2.3%, and pH is 2.6
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml (calculated as metformin hydrochloride)
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: respectively at 20 deg.C, 25 deg.C and 30 deg.C.
The results of the tests are given in the following table:
TABLE 5 influence of column temperature on impurity separation degree
From the above table data it can be found that: for the standard-added test solution, the separation degree of the related substance B and the main peak is gradually reduced along with the increase of the column temperature, and the separation degree is 0.9 when the temperature reaches 30 ℃;
the alkali destruction test solution has good separation degree in the range of column temperature, and the result basically consistent with the alkali destruction test solution is obtained in the subsequent further research on the alkali hydrolysis, strong light, high temperature, high humidity and oxidation destruction test solution.
From the comprehensive examples 1 to 4, it can be seen that when the mobile phase in the high performance liquid chromatography is 2.3% ammonium dihydrogen phosphate solution, the ph is 2.6, the flow rate is 1.0ml/min, the injection concentration is 5.0mg/ml, the injection amount is 10 μ l, the detection wavelength is 218nm, and the column temperature is 20 ℃, the detection effect is optimal, which shows that the method can achieve better separation effects of labeling the test solution and destroying various related substances in the test solution, and the detection efficiency is higher, further methodological verification shows that the method meets the related requirements of drug detection in the aspects of precision, detection limit, and the like, and the method can achieve more effective quality control on unknown impurities potentially generated in the preparation and storage processes of the metformin hydrochloride bulk drug or preparation on the basis of the prior art.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (1)
1. A quality control method of a metformin hydrochloride single oral constant-release tablet is characterized by comprising the following steps:
(1) preparing a test solution, wherein the test solution is prepared by adopting the following preparation method, precisely weighing and taking the metformin hydrochloride tablet, grinding the obtained fine powder which is equivalent to 500mg of metformin hydrochloride, placing the obtained fine powder into a 100ml measuring flask, adding a mobile phase, carrying out ultrasonic treatment for 15 minutes to dissolve the metformin hydrochloride, diluting the obtained solution to a scale by using the mobile phase, shaking up, filtering, discarding 4ml of primary filtrate, and taking subsequent filtrate as the test solution;
(2) analyzing the sample solution by a high performance liquid chromatography;
(3) sorting the analysis results;
wherein the analysis conditions of the high performance liquid phase method are as follows:
a chromatographic column: sinshengtang CAPCELL PAK SCX UG80(S5) chromatographic column 4.6mm × 250mm,5 μm
Mobile phase: 2.3% ammonium dihydrogen phosphate solution, pH2.6
Flow rate: 1.0ml/min
Sample introduction concentration: 5mg/ml
Sample introduction amount: 10 μ l
Detection wavelength: 218nm
Column temperature: 20 ℃;
the pH of the mobile phase is adjusted by phosphoric acid, and the specifications of the metformin hydrochloride in the single oral controlled release tablet are 250mg, 500mg and 850 mg;
the high performance liquid chromatography method is used for analyzing related substances of metformin hydrochloride, wherein the related substances and the structure thereof are
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