CN111505154B - Detection method for mosapride citrate and five key impurities in preparation thereof - Google Patents
Detection method for mosapride citrate and five key impurities in preparation thereof Download PDFInfo
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Abstract
A method for detecting five key impurities in mosapride citrate and a preparation thereof. The invention belongs to the technical field of medicine quality detection methods, and particularly relates to a method for detecting 5 key impurities in mosapride citrate and a preparation thereof by adopting a high performance liquid chromatography. The method has the advantages of good separation degree of related substances, high sensitivity, simple and convenient operation, stable baseline and short analysis time.
Description
Technical Field
The invention relates to the field of drug detection, in particular to a method for detecting related substances of mosapride citrate.
Technical Field
Mosapride citrate is a potent and selective 5-HT4 receptor agonist that stimulates acetylcholine release, enhances the stomach andthe duodenum is a novel, safe and effective digestive tract power drug. Mosapride citrate tablets (trade name: Gaussun) were developed by Sumitomo pharmaceutical Co., Ltd, and were first marketed in Japan in 10 months of 1998. Chemical name of Chinese 4-amino-5-chloro-2-ethoxy-N- { [4- (4-fluorobenzyl) -2-morpholinyl]Methyl benzamide citrate; the molecular formula is as follows: c 21 H 25 ClFN 3 O 3 ·C 6 H 8 O 7 ·2H 2 O, molecular weight: 650.05, having the formula:
the synthesis route of the mosapride citrate bulk drug is as follows. In the synthesis process, process impurities are introduced from the aspects of starting materials, side reactions and the like, and degradation impurities are generated due to the influence of environmental factors such as oxidation and the like in the storage process. The presence of these impurities not only affects the quality of the product, but also poses a major risk in terms of safety of the medication, and therefore, it is necessary to control it.
According to the analysis of the structure of the mosapride citrate and the combination of the information of related products of the mosapride citrate of the Nippon Sumitomo pharmaceutical Co., Ltd, the main process impurities and degradation impurities in the mosapride citrate can be determined as follows:
impurity A is an intermediate for synthesizing mosapride and is also a degradation product, the degradation path is generated by hydrolyzing mosapride, and the reaction formula is as follows:
the impurity B is a defluorinated product of the mosapride and is a byproduct generated in the synthesis process of the bulk drug mosapride. In the synthesis process of mosapride, starting materialsPreparation of intermediate 1 by reductive amination of p-fluorobenzaldehyde and ethanolamine in NaBH 4 And (3) reducing and removing fluorine atoms on the benzene ring under the reducing condition to obtain a byproduct 1. The by-product 1 and the intermediate 1 have similar structures and similar polarities, are not easy to completely remove during separation and purification, remain in the intermediate 1, and participate in the next three-step reaction until the defluorination by-product impurity B of the mosapride is generated.
The route of formation of impurity B is as follows:
impurity C is a degradation product of mosapride, and is generated under the conditions of heating, illumination or acidity by the following routes:
the impurity D is a condensation product of mosapride and citric acid, and is generated under the heating condition by the following steps:
impurity E is an oxidation product of mosapride, and is generated under the condition of illumination or oxidation by the following way:
at present, certain reports are provided for high performance liquid chromatography methods for detecting related substances in mosapride citrate, but the methods cannot locate the specific impurities and cannot effectively evaluate the detection capability of the methods. Analysis methods adopted in literatures such as Wangcong 'related substances in Mosapride citrate tablet by HPLC' (Chin J Pharm Anal 2011, 31(12)), Chen Steel et al 'related substances in Mosapride citrate capsule by HPLC' (Chin JMAP,2010 September, Vol.27No.9), Sun Ling et al 'related substances in Mosapride hydrochloride' (Chinese Journal of Pharmaceuticals 2004,35(6)), and the like, only the raw material drugs were subjected to forced degradation experiments. When the method is adopted to detect the impurities A-E, effective separation cannot be realized.
In addition, impurity detection is carried out by adopting a gradient elution method in a detection method (ZL201410312949.5) of related substances of the mosapride citrate, which is disclosed in Japanese pharmacopoeia standard of the mosapride citrate, Liuwen et al, research on impurities related to the mosapride citrate, and Kopika et al. Researches find that the gradient elution method has long analysis time and large baseline fluctuation, and influences the accuracy of impurity detection.
Therefore, an analysis method which can effectively separate various impurities, is simple and convenient to operate, has small interference and short analysis time is sought, and has important significance for controlling related substances in the mosapride citrate and related products thereof.
Disclosure of Invention
In order to solve the technical problems, the invention provides a detection method of mosapride citrate related substances, which has stable baseline, short analysis time and high reproducibility, can effectively separate various impurities, and comprises the following steps:
dissolving the mosapride citrate test sample in methanol, diluting the solution to a solution containing about 1mg per 1ml, and filtering to obtain a subsequent filtrate as a solution to be detected.
Taking a solution to be detected, and detecting by using a high performance liquid chromatography, wherein the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; the mixed solution of the buffer salt solution and the organic solvent is taken as a mobile phase, isocratic elution is adopted, the column temperature is 30-40 ℃, the flow rate is 0.8-1.2 ml/min, and the detection wavelength is 274 nm.
The invention provides a method for detecting related substances of mosapride citrate, wherein in the chromatographic condition, a buffer salt solution is a citric acid solution.
The method for detecting the mosapride citrate related substances, provided by the invention, comprises the step of detecting a citric acid solution by using a chromatographic condition, wherein the concentration of the citric acid solution is 30-60 mmol/L, preferably 40-50 mmol/L, and further preferably 50 mmol/L.
The detection method of the mosapride citrate related substances, provided by the invention, comprises the step of taking a buffer salt solution as a citric acid solution under the chromatographic condition, wherein the pH value of the citric acid solution is 3.5-4.5, preferably 3.8-4.2, and further preferably 4.0. The pH regulator is phosphoric acid and sodium hydroxide solution, and the pH regulator is preferably sodium hydroxide solution.
The method for detecting related substances of mosapride citrate provided by the invention is characterized in that in the chromatographic condition, an organic solvent mixture is a mixed solution of methanol and acetonitrile, and the volume ratio of the methanol to the acetonitrile is 30-40: 15-5, preferably 35: 10.
The invention provides a detection method of mosapride citrate related substances, wherein in the chromatographic condition, the volume ratio of citric acid buffer salt to a mixture of methanol and acetonitrile is 50-60: 50-40, and preferably 55: 45.
The detection method of related substances of mosapride citrate provided by the invention is characterized in that in the chromatographic condition, the column temperature is 30-45 ℃, the flow rate is 0.8-1.2 ml/min, preferably the column temperature is 40 ℃, and the flow rate is 1 ml/min.
The invention further provides a method for detecting related substances of mosapride citrate, which comprises the following steps:
(a) preparation of system suitability solution: weighing 10mg of related substances A-E of the mosapride citrate respectively, placing the related substances A-E into 5 measuring bottles with the volume of 20ml, adding methanol to dissolve and dilute the related substances to the scale, and shaking up; and then respectively taking 1ml of the solution and placing the solution in a 100ml measuring flask, adding 100mg of mosapride citrate, adding methanol to dissolve the solution and dilute the solution to a scale, and shaking the solution uniformly to obtain the compound. (containing mosapride citrate 1mg/ml, each impurity 5. mu.g/ml)
(b) Preparation of a test solution: taking a proper amount of mosapride citrate test sample, grinding, weighing a proper amount of fine powder (about 10mg equivalent to mosapride citrate), precisely weighing, adding methanol for dissolving, diluting to prepare 1ml of solution containing about 1mg, filtering, and taking a subsequent filtrate to obtain the mosapride citrate.
(c) Chromatographic conditions are as follows: the chromatographic column takes octadecylsilane chemically bonded silica as a filler; adopting isocratic elution, wherein the mobile phase is citric acid solution: methanol: acetonitrile (55:35:10), column temperature 40 ℃, flow rate 1ml/min, detection wavelength 274nm, sample volume 10. mu.l.
Wherein, in the mobile phase, the components are in volume ratio; the citric acid solution was adjusted to pH4.0 with sodium hydroxide solution.
(d) And (3) determination: sucking the system applicability solution and the sample solution, injecting into a liquid chromatograph, and measuring according to high performance liquid chromatography.
The inventor of the application examines the influence of the mobile phase composition on the detection result in the detection of related substances of the mosapride citrate in detail, when the mobile phase is a mixed solution of 50mmol/L citric acid/acetonitrile with a volume ratio of 65:35, and isocratic elution is adopted, the base line is good, the separation degree of a main peak and impurities is good, but when the mobile phase is used, the impurities C are not retained and are eluted together with a solvent peak, and accurate quantification cannot be realized. When the mixed solution of 50mmol/L citric acid/methanol with the volume ratio of 65:35 is adopted as the mobile phase, the base line fluctuation is large, the retention time of each component is too long, and the peak shape is distorted. When the mobile phase is a mixed solution of 50mmol/L citric acid/methanol/acetonitrile with the volume ratio of 55:30:15, the base line is smooth when isocratic elution is carried out, but the separation degree of the impurity A and the impurity D is poor. When the mobile phase is a mixed solution of 50mmol/L citric acid/methanol/acetonitrile with the volume ratio of 55:35:10, isocratic elution is carried out, the base line is stable, impurities are detected, the separation degree between a main peak and the impurities and between the impurities is good, and the peak shape is good. By comparison, when a 50mmol/L citric acid/methanol/acetonitrile mixed solution with a volume ratio of 55:35:10 is selected as a mobile phase, the detection result is optimal.
Compared with the prior art, the method for detecting the mosapride citrate related substances has the following advantages;
1. the method for detecting related substances of mosapride citrate has good separation degree, can detect more impurities and can more effectively control related substances in a test sample;
2. compared with the prior art, the method for detecting the related substances of the mosapride citrate has the advantages of more stable baseline and small background interference;
3. compared with the prior art, the method for detecting the related substances of the mosapride citrate adopts isocratic elution, is simple and convenient to operate, has better adaptability to instruments, and is easier to reproduce and popularize.
Drawings
FIG. 1 is a high performance liquid chromatogram of example 1;
FIG. 2 is a high performance liquid chromatogram of example 2;
FIG. 3 is a high performance liquid chromatogram of example 3;
FIG. 4 is a high performance liquid chromatogram of a thermally compromised sample of example 4;
FIG. 5 is a high performance liquid chromatogram of an acid-damaged sample of example 4;
FIG. 6 is a high performance liquid chromatogram of a base-destroyed sample of example 4;
FIG. 7 is a high performance liquid chromatogram of an oxidative destruction sample of example 4;
FIG. 8 is a high performance liquid chromatogram of a sample of example 4 photo-disrupted;
FIG. 9 is a high performance liquid chromatogram under high temperature conditions of example 5;
FIG. 10 is a high performance liquid chromatogram under high humidity conditions of example 5;
FIG. 11 is a high performance liquid chromatogram under light conditions of example 5.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
In the following embodiments, the drugs, reagents and instruments used are as follows:
mosapride citrate (lot: 520170104, manufacturer: Shandong New Times pharmaceutical Co., Ltd.), Mosapride citrate-related substance A (TLC, lot: 0004-, LC-20AT), chromatography column (Diamonsil 5 μm C (18)4.6 × 150mm), analytical balance (BT25S/BSA224S, derosidic sars), pH meter (PHS-3C, shanghai meter).
A related substance A:
the related substance B:
the related substance C:
a related substance D:
a related substance E:
example 1 screening of high Performance liquid chromatography conditions
System applicability solution preparation: weighing 10mg of related substances A-E of the mosapride citrate respectively, putting the related substances into 5 measuring bottles with the volume of 20ml, adding methanol to dissolve and dilute the related substances to the scale, and shaking up; and putting 1ml of the solution into a 100ml measuring flask respectively, adding 10mmg of mosapride citrate, adding methanol to dissolve and dilute the solution to a scale, and shaking up the solution to obtain the compound. (containing 1mg/ml of mosapride citrate and 5. mu.g/ml of each impurity).
High performance liquid chromatography conditions: mobile phase: 50mmol/L citric acid solution (pH adjusted to 4.0 with sodium hydroxide solution) -acetonitrile (65:35), flow rate of 1ml/min, detection wavelength of 274nm, column temperature of 40 deg.C, injection volume of 10. mu.l.
The sample of the system applicability solution is taken for detection, and the result is shown in figure 1, wherein the impurity B and the impurity E cannot be separated.
Example 2 screening of high Performance liquid chromatography conditions
High performance liquid chromatography conditions: mobile phase: 50mmol/L citric acid solution (pH adjusted to 4.0 with sodium hydroxide solution) -methanol-acetonitrile (55:35:10) at a flow rate of 1ml/min, detection wavelength of 274nm, column temperature of 40 deg.C, injection volume of 10. mu.l.
The method of example 1 was followed to prepare a system-applicable solution, and the results of sample injection and detection are shown in fig. 2, where known impurities were detected, the baseline was stable, and the separation of impurities from the main peak and impurities was good.
Example 3 Baseline comparison of the present method with the gradient elution method
(1) Gradient elution method (japanese pharmacopoeia method):
high performance liquid chromatography conditions: mobile phase A: 0.03mol/L sodium citrate buffer solution (prepared by taking 8.82g of sodium citrate trihydrate, dissolving in 800ml of water, adjusting the pH to 4.0 by using dilute hydrochloric acid, and adding water to dilute to 1000 ml), and a mobile phase B: acetonitrile; the column temperature is 40 ℃, and the flow rate is 1 ml/min; the detection wavelength was 274nm and the gradient elution was carried out according to the following table.
(2) The patented method
High performance liquid chromatography conditions: mobile phase: 50mmol/L citric acid solution (pH adjusted to 4.0 with sodium hydroxide solution) -methanol-acetonitrile (55:35:10), column temperature 40 deg.C, flow rate 1ml/min, detection wavelength 274 nm.
A blank solution is prepared according to the method in example 1, and the result of sample injection detection is shown in FIG. 3, and the gradient method of the Nippon pharmacopoeia has large baseline fluctuation and may interfere with the detection of impurities in a sample.
Example 4 forced degradation experiments of mosapride citrate formulations
Preparation of a test solution: the mosapride citrate preparation is taken and is forcedly degraded according to the following methods respectively:
(1) thermal destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into water 5ml for dispersing, placing in water bath (95 deg.C), taking out, cooling, diluting with methanol to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(2) Acid destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into 5ml hydrochloric acid solution for dispersion, shaking, standing at room temperature, adding 5mol/L sodium hydroxide for neutralization, adding methanol for diluting to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(3) Alkali destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) and sodium hydroxide solution 5ml for dispersion, shaking, standing at room temperature, adding 5mol/L hydrochloric acid for neutralization, adding methanol for diluting to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(4) And (3) oxidative destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into hydrogen peroxide solution 5ml for dispersion, shaking, standing at room temperature, adding methanol to dilute to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(5) Light damage: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into water 5ml for dispersing, shaking, standing under strong light, adding methanol to dilute to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
The above solutions were taken and subjected to the measurement under the conditions in example 2. the results of thermal destruction of the sample are shown in FIG. 4, the results of acid destruction of the sample are shown in FIG. 5, the results of alkali destruction of the sample are shown in FIG. 6, the results of oxidative destruction of the sample are shown in FIG. 7, and the results of light destruction of the sample are shown in FIG. 8, respectively. The results show that the mosapride citrate sample mainly degrades the impurity A under the heating condition, degrades the impurity E under the oxidizing condition, has A, C, E degradation impurities under the illumination condition and is stable under the acid and alkali conditions. Impurities generated under each forced degradation can be effectively separated from the main peak
Example 5 detection of Mosapride citrate drug substance samples
A sample of mosapride citrate bulk drug is taken and placed for 30 days under the conditions of high temperature (60 ℃), high humidity (RH 92.5%) and illumination (4500Lx), a test sample is prepared according to the conditions in example 1, and the test is carried out according to the conditions in example 2, wherein the results under the high temperature condition are shown in figure 9, the results under the high humidity condition are shown in figure 10, and the results under the illumination condition are shown in figure 11. The result shows that the impurities in the sample placing process can be effectively detected, and the impurities are well separated from the main peak.
Claims (4)
1. A method for detecting five key impurities in mosapride citrate and a preparation thereof is characterized by comprising the following steps: taking a mosapride citrate test sample, preparing a solution to be tested, adopting high performance liquid chromatography, taking octadecylsilane chemically bonded silica as a filler, and taking a 50mmol/L pH4.0 citric acid solution with a volume ratio of 55:35: 10: methanol: the acetonitrile mixed solution is a mobile phase, the column temperature is 30-45 ℃, the flow rate is 0.8-1.2 ml/min, and the detection wavelength is 274 nm; the mobile phase adopts an isocratic elution mode; the 5 key impurities are related substances A-E of mosapride citrate, and the structure of the impurities is as follows:
a related substance A:
the related substance B:
the related substance C:
a related substance D:
a related substance E:
2. the method of claim 1, wherein the column temperature is 40 ℃ and the flow rate is 1.0 ml/min.
3. The method of claim 1, wherein the mosapride citrate test sample comprises a mosapride citrate bulk drug, a mosapride citrate granule, a mosapride citrate tablet and an intermediate.
4. The method of claim 1, wherein the citric acid solution is adjusted to a pH of 4.0 with phosphoric acid and sodium hydroxide solution.
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| JP2012201597A (en) * | 2011-03-23 | 2012-10-22 | Nihon Generic Co Ltd | Solid preparation comprising mosapride |
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