CN111077261A - Method for rapidly detecting impurities in risperidone raw material - Google Patents
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- CN111077261A CN111077261A CN201911368723.6A CN201911368723A CN111077261A CN 111077261 A CN111077261 A CN 111077261A CN 201911368723 A CN201911368723 A CN 201911368723A CN 111077261 A CN111077261 A CN 111077261A
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
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Abstract
The invention discloses a method for rapidly detecting impurities in a risperidone raw material, which comprises the following steps: (1) preparing a test solution: precisely weighing a risperidone raw material to be detected, dissolving the risperidone raw material with methanol and diluting the risperidone raw material to obtain a test solution; (2) preparation of control solutions: precisely measuring a test solution, and diluting with methanol to obtain a control solution; (3) liquid chromatography detection: precisely measuring a reference solution and a test solution with the same volume, respectively injecting into a liquid chromatograph, injecting and recording a chromatogram, and calculating the content of impurities by using a self-reference method. The method adopts low flow rate measurement, not only is efficient and accurate, but also saves the cost of the solvent and reduces the pollution of the solvent to the environment.
Description
Technical Field
The invention relates to the technical field of risperidone production, and particularly relates to a method for rapidly detecting impurities in a risperidone raw material.
Background
Drug quality control is an important part of the drug production process, and with the increasing strictness of the drug evaluation and approval system in each country, drug production enterprises also face urgent needs for developing drugs meeting higher quality standards and corresponding quality control and analysis methods. The control of related substances, especially the types and contents of impurities in the bulk drugs is of great importance for improving the quality of the drugs.
Risperidone is a new generation of atypical antipsychotics, First-in-class, a second generation of anti-schizophrenia drug, used to treat acute and chronic schizophrenia. Especially has better curative effect on positive and negative symptoms and accompanying emotional symptoms (such as anxiety, depression and the like). The affective symptoms associated with schizophrenia may also be alleviated. According to statistics of a mental health center of a disease control center, the number of severe mental disease patients in China is as high as 1600 thousands of patients, wherein 800 thousands of patients are schizophrenia patients. Because schizophrenia patients need to be administered continuously for life, the risperidone dosage accounts for about 20% of the 6 antipsychotic drugs commonly used in hospitals at present.
Risperidone is a benzisoxazole derivative with the chemical name of 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidyl ] ethyl ] -6,7,8, 9-tetrahydro-2-methyl-4H-pyrido [1,2- α ] pyrimidine-4-one.
The JP, USP and ChP pharmacopoeias contain risperidone and related substance detection methods of preparations thereof, and the EP contains risperidone raw material medicine, and the related substance detection methods are conventional HPLC methods. According to different synthetic routes, production processes and stability investigation results, impurities in the bulk drug include risperidone E-oxime (EP impurity A), risperidone Z-oxime (EP impurity B), 9-hydroxyrisperidone (EP impurity C), 5-fluororisperidone (EP impurity D), 6-methylrisperidone (EP impurity E), defluorination risperidone (EP impurity K), 2-fluoroketorisperidone (USP), impurity H, I, J, L, M (EP) and the like. There are other unknown impurities.
The chemical formulas of impurities of known structures, namely risperidone E-oxime, risperidone Z-oxime, 9-hydroxy risperidone, 5-fluoro risperidone and 6-methyl risperidone are respectively as follows:
the risperidone E-oxime is introduced into the reaction kettle,
the risperidone Z-oxime is prepared by the following steps,
9-hydroxy risperidone (9-hydroxy risperidone),
5-fluororisperidone (5-flurbipenem),
6-methyl risperidone.
For so many potential impurities, the current detection technology cannot completely separate all impurities, and the separation efficiency is always a technical problem which puzzles researchers in the industry. In other words, the conventional detection method needs to be further improved in terms of peak capacity, separation efficiency, and the like. Therefore, a better and faster detection and analysis method is needed to be developed for impurities in the risperidone bulk drug to control the types and contents of related substances in a finished drug product, improve the progress of drug development and ensure the quality of the product effectively.
Disclosure of Invention
The invention aims to provide a method for rapidly detecting impurities in a risperidone raw material, which adopts low-flow-rate measurement, is efficient and accurate, saves the cost of a solvent, and reduces the pollution of the solvent to the environment.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the invention adopts the short-diameter column chromatographic column, has short column passing time and combines low flow velocity column passing, thereby greatly reducing the dosage of the solvent.
A method for rapidly detecting impurities in a risperidone raw material comprises the following steps:
(1) preparing a test solution: precisely weighing a risperidone raw material to be detected, dissolving the risperidone raw material with methanol and diluting the risperidone raw material to obtain a test solution;
(2) preparation of control solutions: precisely measuring a test solution, and diluting with methanol to obtain a control solution;
(3) liquid chromatography detection: precisely measuring a reference solution and a test solution with the same volume, respectively injecting into a liquid chromatograph, injecting and recording a chromatogram, and calculating the content of impurities by using a self-reference method;
wherein the conditions of the liquid chromatography detection are as follows:
using an ultrahigh pressure liquid chromatograph and an ultraviolet detector;
by C18Chromatographic column, column length: 50-150 mm, inner diameter: 1-3 mm, particle size: 1.7-3 μm; the chromatographic column packing is octadecylsilane chemically bonded silica.
Said C is18The chromatographic column is X-Select CSH, the length of the column is 150mm, the inner diameter is 2.1mm, and the particle size is 2.5 mu m. The selection of the chromatographic column is the core of the invention, and the chromatographic column with a short-diameter column is adopted, so that the detection process can be obviously accelerated, and the solvent is saved.
And performing gradient elution by using methanol (mobile phase B) as an organic solvent and an ammonium acetate solution (mobile phase A) as a buffer solution in the liquid chromatography detection at a flow rate of 0.2-0.4 ml/min. The concentration of the ammonium acetate aqueous solution is 10 mmol/L-100 mmol/L. Ammonium acetate aqueous solution is used as buffer solution. Preferably, the ammonium acetate molar concentration is 20 mmol/L.
Gradient elution parameters were set as:
0-1 min, wherein the volume ratio of the methanol is changed from 30% to 45%;
1-4 min, wherein the volume ratio of the methanol is changed from 45% to 60%;
4-10 min, wherein the volume ratio of the methanol is changed from 60% to 70%;
the volume ratio of the methanol is changed from 70% to 30% within 10-12 min;
12-15 min, and the volume of the methanol is 30%.
When the liquid chromatography detection is carried out, the sample volume of the test solution is 1-5 mul.
Preferably, the sample amount of the sample solution is 2. mu.l.
The risperidone concentration in the test solution is 1.0-3.0 mg/ml.
Preferably, the risperidone concentration in the test solution is 1.5 mg/ml.
The impurities at least comprise risperidone E-oxime, risperidone Z-oxime, 9-hydroxy risperidone, 5-fluororisperidone and 6-methyl risperidone.
The invention has the beneficial effects that: the method can efficiently detect 5 known impurities in the risperidone raw material, namely risperidone E-oxime, risperidone Z-oxime, 9-hydroxy risperidone, 5-fluororisperidone and 6-methyl risperidone, and can separate a plurality of unknown impurities; short detection time, low cost and many separated impurities.
Drawings
FIG. 1 is a map of the applicability of the system under the process of the present invention;
FIG. 2 is a map of system suitability under the EP process;
FIG. 3 is a control profile of defluorinated risperidone under EP procedures;
FIG. 4 is a risperidone E-oxime control plot under EP method;
FIG. 5 is a risperidone Z-oxime control plot under EP method;
FIG. 6 is a control profile of 9-hydroxyrisperidone under EP method;
FIG. 7 is a control profile of 5-fluororisperidone under EP method;
FIG. 8 is a risperidone control profile under EP method;
FIG. 9 is a control profile of 6-methylrisperidone under EP method.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
Examples
1. Instruments and reagents
The instrument comprises the following steps: waters UHPLC 2489 detector, Waters e2695 pump, Empower chromatography workstation;
reagent: methanol (chromatographically pure); ammonium acetate (analytical grade); and (5) purifying the water.
2. Measurement Process
(1) System applicability solution: taking about 10mg of a risperidone system applicability reference substance (European drug quality administration, batch number: 5.0), placing in a 1ml measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain the risperidone system applicability reference substance;
(2) impurity K (defluorinated risperidone) control solution: weighing 15mg of impurity K reference substance (TLC Standard article of Canada, batch No. 1934-;
(3) test solution: taking 15mg of risperidone raw material medicine, precisely weighing, adding methanol into a 10ml measuring flask for dissolving, then fixing the volume, and shaking up to obtain the risperidone composition;
(4) control solution: precisely measuring 1ml of the test solution, adding methanol to dilute to scale in a 100ml measuring flask, shaking up, precisely measuring 5ml of the solution, placing in a 25ml measuring flask, adding methanol to dilute to scale, and shaking up to obtain a control solution.
3. Chromatographic conditions
The chromatographic column packing is octadecylsilane chemically bonded silica (X-Select CSH: 150mm 2.1mm,2.5 μm), 20mmol/L ammonium acetate solution is used as A phase, methanol is used as B phase, and the gradient elution procedure is as follows: 0-1 min, wherein the volume ratio of the methanol is changed from 30% to 45%; 1-4 min, wherein the volume ratio of the methanol is changed from 45% to 60%; 4-10 min, wherein the volume ratio of the methanol is changed from 60% to 70%; the volume ratio of the methanol is changed from 70% to 30% within 10-12 min; 12-15 min, and the volume of the methanol is 30%. The detection wavelength is 275 nm; the flow rate was 0.3 ml/min.
Precisely taking 2 μ l of each solution, injecting into a liquid chromatograph, and recording chromatogram. The system applicability map is shown in figure 1.
Comparative example-pharmacopoeia (EP) method
1. Instruments and reagents
The instrument comprises the following steps: waters acquisition Arc 2489 detector, Waters e2695 pump, Empower chromatography workstation;
reagent: methanol (chromatographically pure); ammonium acetate (analytical grade); and (5) purifying the water.
2. Measurement Process
(1) System applicability solution: taking about 10mg of a risperidone system applicability reference substance (European drug quality administration, batch number: 5.0), placing in a 1ml measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain the risperidone system applicability reference substance;
(2) impurity K (defluorinated risperidone) control solution: weighing 15mg of impurity K reference substance (TLC Standard article of Canada, batch No. 1934-;
(3) test solution: taking about 100mg of risperidone raw material medicine, precisely weighing, adding methanol into a 10ml measuring flask for dissolving, and then fixing the volume and shaking up to obtain the risperidone composition;
(4) control solution: precisely measuring 1ml of a test solution, adding methanol to dilute to a scale in a 100ml measuring flask, shaking up, precisely measuring 5ml of the solution, placing in a 25ml measuring flask, adding methanol to dilute to a scale, and shaking up to serve as a control solution;
(5) risperidone E-oxime control solution: weighing risperidone E-oxime reference (British government chemist laboratory, batch No. MM 0491.01) 15mg, placing in a 100ml measuring flask, dissolving with methanol, diluting to scale, and shaking;
(6) risperidone Z-oxime control solution: weighing risperidone Z-oxime reference (British government chemist laboratory, batch number: MM 0491.02) 15mg, placing in a 100ml measuring flask, dissolving with methanol, diluting to scale, and shaking;
(7) 9-hydroxy risperidone control solution: weighing 15mg of 9-hydroxy risperidone reference substance (TLC Standard substance, Canada, batch No. 1934-;
(8) 5-Fluororisperidone control solution: weighing 15mg of 5-fluororisperidone reference substance (TLC Standard substance, Canada, lot number: 2418-064A 6), placing in a 100ml measuring flask, dissolving with methanol, diluting to scale, and shaking up to obtain the final product;
(9) risperidone control solution: weighing 15mg of risperidone reference (China institute for food and drug testing, lot number: 100570-201704), placing in a 100ml measuring flask, dissolving and diluting to scale with methanol, and shaking up to obtain the risperidone reference;
(10) 6-Methylisperidone control solution: weighing 15mg of 6-methylrisperidone reference (TLC Standard, Canada, lot: 2056-040A 1), placing in a 100ml measuring flask, dissolving with methanol and diluting to scale, and shaking up to obtain the final product.
3. Chromatographic conditions
The chromatographic column packing was octadecylsilane chemically bonded silica (Thermo, Hypersil: 100 mm. times.4.6 mm,3 μm), 65 mmol/L ammonium acetate solution was used as phase A, methanol was used as phase B, and the gradient elution procedure was: 0-2 min, wherein the volume ratio of the methanol is 30%; 2-17 min, wherein the volume proportion of the methanol is changed from 30% to 70%; 17-22 min, and the volume of the methanol is 70%. The detection wavelength is 260 nm; the flow rate was 1.5 ml/min.
Precisely taking 10 μ l of each solution, injecting into a liquid chromatograph, and recording chromatogram. The map is shown in figures 2-9.
From the results of the above examples and comparative examples, it can be seen that 6 impurities in the risperidone raw material can be effectively separated within 15min by the method of the present invention, and the amount of the organic solvent is 2.1 ml; when the method in the pharmacopoeia is adopted for analysis, the whole process takes 27min, and the dosage of the organic solvent is 13.4ml which is 6.4 times of that of the invention. Moreover, as is apparent from the attached figure 1, the impurities separated by the method have better discrimination, and particularly, the 5-flurrisperidone is separated more cleanly and thoroughly. In addition, the dosage of the test sample is only 1/5-1/10 which is the conventional dosage, and the invention has obvious superiority in detection sensitivity. In addition, as is apparent from FIG. 1, the detection method of the present invention can effectively separate a plurality of unknown impurities, which is not achieved by the conventional pharmacopoeia method.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (9)
1. A method for rapidly detecting impurities in a risperidone raw material is characterized by comprising the following steps:
(1) preparing a test solution: precisely weighing a risperidone raw material to be detected, dissolving the risperidone raw material with methanol and diluting the risperidone raw material to obtain a test solution;
(2) preparation of control solutions: precisely measuring a test solution, and diluting with methanol to obtain a control solution;
(3) liquid chromatography detection: precisely measuring a reference solution and a test solution with the same volume, respectively injecting into a liquid chromatograph, injecting and recording a chromatogram, and calculating the content of impurities by using a self-reference method;
wherein the conditions of the liquid chromatography detection are as follows:
using an ultrahigh pressure liquid chromatograph and an ultraviolet detector;
by C18Chromatographic column, column length: 50-150 mm, inner diameter: 1-3 mm, particle size: 1.7-3 μm; the chromatographic column packing is octadecylsilane chemically bonded silica.
2. The method for rapidly detecting risperidone raw material impurities as claimed in claim 1, wherein: said C is18The chromatographic column is X-Select CSH, the length of the column is 150mm, the inner diameter is 2.1mm, and the particle size is 2.5 mu m.
3. The method for rapidly detecting risperidone raw material impurities as claimed in claim 1, wherein: and performing gradient elution by using methanol as an organic solvent and using an ammonium acetate solution as a buffer solution in the liquid chromatography detection at a flow rate of 0.2-0.4 ml/min.
4. The method for rapidly detecting risperidone raw material impurities as claimed in claim 3, wherein: gradient elution parameters were set as:
0-1 min, wherein the volume ratio of the methanol is changed from 30% to 45%;
1-4 min, wherein the volume ratio of the methanol is changed from 45% to 60%;
4-10 min, wherein the volume ratio of the methanol is changed from 60% to 70%;
the volume ratio of the methanol is changed from 70% to 30% within 10-12 min;
12-15 min, and the volume of the methanol is 30%.
5. The method for rapidly detecting risperidone raw material impurities as claimed in claim 1, wherein: when the liquid chromatography detection is carried out, the sample volume of the test solution is 1-5 mul.
6. The method for rapidly detecting risperidone raw material impurities as claimed in claim 5, wherein: the sample volume of the test solution was 2. mu.l.
7. The method for rapidly detecting risperidone raw material impurities as claimed in claim 1, wherein: the risperidone concentration in the test solution is 1.0-3.0 mg/ml.
8. The method for rapidly detecting risperidone raw material impurities as claimed in claim 7, wherein: the risperidone concentration in the test solution was 1.5 mg/ml.
9. The method for rapidly detecting risperidone raw material impurities as claimed in claim 1, wherein: the impurities at least comprise risperidone E-oxime, risperidone Z-oxime, 9-hydroxy risperidone, 5-fluororisperidone and 6-methyl risperidone.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104965035A (en) * | 2015-04-27 | 2015-10-07 | 公安部物证鉴定中心 | Method for screening toxic substances in sample by using solid phase support liquid-liquid extraction-GC MS |
| CN107422055A (en) * | 2017-07-27 | 2017-12-01 | 天津药物研究院药业有限责任公司 | The detection method of impurity in a kind of Risperidone raw material or preparation |
| CN108445101A (en) * | 2018-03-16 | 2018-08-24 | 安徽新世纪药业有限公司 | A kind of detection method of the Risperidone oral administration solution in relation to substance |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104965035A (en) * | 2015-04-27 | 2015-10-07 | 公安部物证鉴定中心 | Method for screening toxic substances in sample by using solid phase support liquid-liquid extraction-GC MS |
| CN107422055A (en) * | 2017-07-27 | 2017-12-01 | 天津药物研究院药业有限责任公司 | The detection method of impurity in a kind of Risperidone raw material or preparation |
| CN108445101A (en) * | 2018-03-16 | 2018-08-24 | 安徽新世纪药业有限公司 | A kind of detection method of the Risperidone oral administration solution in relation to substance |
Non-Patent Citations (2)
| Title |
|---|
| 欧洲药典委员会: "《European Pharmacopoeia 7.0》", 31 December 2015 * |
| 颜晓丹 等: "HPLC、UPLC测定利培酮片中有关物质的比较研究", 《安徽医药》 * |
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