CN109613163B - Detection method for pimavanserin tartrate and impurities thereof - Google Patents
Detection method for pimavanserin tartrate and impurities thereof Download PDFInfo
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Abstract
The invention discloses a method for detecting pimavanserin tartrate and impurities thereof. The method comprises the following steps: 1) preparing a standard reference substance solution of pimavanserin tartrate and impurities thereof; 2) preparing a test sample solution; 3) determining a chromatogram of the pimavanserin tartrate and impurities thereof in the standard reference substance solution by using a reversed-phase high performance liquid chromatograph, so that the separation degree between any adjacent substances is more than or equal to 1.5; 4) determining a chromatogram of the test sample solution using a reverse phase high performance liquid chromatograph; 5) and determining the content of the pmovanserin tartrate and impurities thereof in the sample solution by using an external standard method. The method can effectively separate the pimavanserin tartrate from impurities thereof and impurities, so that the method can accurately determine the content of the pimavanserin tartrate and the impurities, is simple and convenient to operate, is rapid, has high repeatability, accuracy and stability, and provides a reliable detection method for industrial production of the pimavanserin tartrate.
Description
Technical Field
The invention relates to the field of drug analysis, in particular to a method for detecting pimavanserin tartrate and impurities thereof.
Background
At present, the number of Parkinson's disease patients is about 700 to 1000 thousands around the world, 260 thousands in China exist, and 10 thousands of new patients are increased every year when the patients live in the world first. More than 50% of Parkinson's disease patients have mental symptoms (PDP). These mental symptoms are manifested primarily as hallucinations and delusions, presenting greater challenges to the treatment and care of parkinson's disease patients. Parkinsonian psychosis is a major cause of parkinson's disease patients entering elderly care apartments. Currently, Parkinson's disease psychosis has no approval for other drugs except low dose clozapine (clozapine), which has serious side effects that lead to a decrease in white blood cell count and lethargy.
Pimavanserin tartrate (Nuolazid), developed by acadia, is used to treat the psychotic symptoms of parkinson's disease, and is a non-dopamine neurotransmitter analogue that selectively blocks the 5-hydroxytryptamine 2A receptor without affecting the effect of dopamine.
At present, no patent literature report related to the pimavanserin tartrate and an impurity analysis method thereof exists, and with the deep research on the product in China, in order to strengthen the quality control of the pimavanserin tartrate, a sensitive and stable detection method is needed.
Disclosure of Invention
The invention aims to provide a method for detecting pimavanserin tartrate and impurities thereof.
The technical scheme adopted by the invention is as follows:
the invention aims to provide a method for detecting pimavanserin tartrate and impurities thereof, which comprises the following steps:
1) preparing a standard reference substance solution of pimavanserin tartrate and impurities thereof;
2) preparing a test sample solution;
3) determining a chromatogram of the pimavanserin tartrate and impurities thereof in the standard reference substance solution by using a reversed-phase high performance liquid chromatograph, so that the separation degree between any adjacent substances is more than or equal to 1.5;
4) determining a chromatogram of the test sample solution using a reverse phase high performance liquid chromatograph;
5) determining the contents of the pinomofannserin tartrate and impurities thereof in the sample solution by using an external standard method according to the chromatogram of the standard reference solution and the chromatogram of the sample solution;
wherein, step 3) and step 4) utilize acetonitrile: potassium dihydrogen phosphate solution 44: 56(v/v), and carrying out equal gradient elution, wherein the concentration of the potassium dihydrogen phosphate solution is 0.02mol/L, and the pH value is 5-6.
Preferably, the impurities are selected from at least one of 4-isobutoxybenzonitrile, 4-isobutoxybenzylamine, 4- (4-fluorobenzylamino) -1-methylpiperidine, 1, 3-bis (4-isobutoxybenzyl) urea, and 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) urea.
Preferably, the method further comprises the step of filtering the standard control solution and the test sample solution before adding the standard control solution and the test sample solution; preferably, the filtration is performed through a 0.2 μm filter.
Preferably, the concentration of the test sample is 0.8 to 1.5 mg/mL.
Preferably, the flow rate in the reversed-phase high performance liquid chromatography is 0.8-1.0 mL/min.
More preferably, the flow rate in the above-mentioned reversed-phase high performance liquid chromatography is 0.8 mL/min.
Preferably, the temperature of a chromatographic column in the reversed-phase high performance liquid chromatography is 20-30 ℃;
more preferably, the column temperature in the above-mentioned reversed-phase high performance liquid chromatography is 25 ℃.
Preferably, the sample amount in the reversed-phase high performance liquid chromatography is 8-15 μ L.
More preferably, the amount of the sample to be applied to the reversed-phase high-performance liquid chromatography is 10. mu.L.
Preferably, the solvents of the standard control solution and the test sample solution are mixed solutions of acetonitrile and water.
Preferably, the volume ratio of the acetonitrile to the water is (6-7): (3-4).
Preferably, the volume ratio of acetonitrile to water is 6: 4 or 7: 3.
preferably, the column of the reversed-phase high performance liquid chromatography is an XDB CN column: 4.6mm by 250mm, 5 μm.
Preferably, the detection wavelength of the reversed-phase high performance liquid chromatography is 210-220 nm.
More preferably, the detection wavelength of the reversed-phase high performance liquid chromatography is 215 nm.
The invention has the beneficial effects that:
the invention adopts the high performance liquid chromatography to detect the pimavanserin tartrate and the impurities thereof, and the method can realize effective separation between the pimavanserin tartrate and the impurities thereof and between the impurities, so that the method can accurately determine the content of the pimavanserin tartrate and the impurities, and the method has the advantages of simple and convenient operation, rapidness, high repeatability, high accuracy and high stability, and provides a reliable detection method for the industrial production of the pimavanserin tartrate.
Drawings
FIG. 1 is a chromatogram of a standard solution;
FIG. 2 is a chromatogram of a test sample solution of pimavanserin tartrate in example 1;
FIG. 3 is a chromatogram of a test sample solution of pimavanserin tartrate in example 2;
FIG. 4 is a chromatogram of a test sample solution of pimavanserin tartrate in example 3;
FIG. 5 is a chromatogram of a test sample solution of pimavanserin tartrate in comparative example 1.
Detailed Description
The present invention will be described in further detail with reference to examples. It will also be understood that the following examples are included merely for purposes of further illustrating the invention and are not to be construed as limiting the scope of the invention, as the invention extends to insubstantial modifications and adaptations of the invention following in the light of the principles set forth herein. The specific process parameters and the like of the following examples are also only one example of suitable ranges, and the skilled person can make a selection within the suitable ranges through the description herein, and are not limited to the specific data of the following examples.
In the following examples and comparative examples, impurity A was 4-isobutoxybenzonitrile, impurity B was 4-isobutoxybenzylamine, impurity C was 4- (4-fluorobenzylamino) -1-methylpiperidine, impurity D was 1, 3-bis (4-isobutoxybenzyl) urea, and impurity E was 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) urea.
Example 1
1) Preparing a standard reference substance solution: accurately weighing the pimavanserin tartrate standard substance, the impurities A, B, C, D and E, adding a mixed solution of acetonitrile and water (the volume ratio is 7: 3, the mixed solution is acetonitrile aqueous solution for short) for dissolving, and preparing a solution containing 1mg of the pimavanserin tartrate standard substance, 0.1mg of each of the impurities A, B, C, D and E as a standard reference substance solution;
2) preparation of a test sample solution: accurately weighing 20mg of pimavanserin tartrate into a 20mL volumetric flask, adding acetonitrile aqueous solution to dissolve and dilute the pimavanserin tartrate to a scale mark to be used as a sample solution to be tested;
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 5) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the solution;
injecting the standard reference substance solution (10 mu L) in the step 1) into a high performance liquid chromatograph, and recording a chromatogram (as shown in figure 1);
injecting the test sample solution (10 μ L) in the step 2) into a high performance liquid chromatograph, and recording a chromatogram (as shown in figure 2);
comparing the peak area of each substance in the standard reference substance solution with the peak area of each substance in the test sample solution (external standard method), and determining the content of the brivaracetam and impurities thereof in the test sample;
as can be seen from fig. 1: the retention time of tartaric acid is 2.737min, the retention time of pimavanserin is 9.488min, the retention time of impurity A is 12.740min, the retention time of impurity B is 5.570min, the retention time of impurity C is 4.165min, the retention time of impurity D is 20.771min, the retention time of impurity E is 13.542min, and the separation degree between any two adjacent peaks is greater than 2.0, so that good separation is realized between the pimavanserin tartrate and the impurities and between the impurities, and very favorable precondition is provided for accurately testing the content of the pimavanserin tartrate and the impurities;
the content of the pmovanserin tartrate is 99.3 percent, the content of the impurity A is 0.002 percent, the content of the impurity B is 0.01 percent, the content of the impurity C is 0.11 percent, the content of the impurity D is 0.02 percent, the content of the impurity E is 0.01 percent, and the content of each impurity is less than 0.2 percent.
Example 2
The detection method of example 2 is the same as that of example 1, except for the chromatographic conditions in step 2) and step 3):
2) preparation of a test sample solution: accurately weighing 20mg of pimavanserin tartrate into a 20mL volumetric flask, adding acetonitrile aqueous solution to dissolve and dilute the pimavanserin tartrate to a scale mark to be used as a sample solution to be tested;
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 5.5) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 μ L, chromatogram of test sample solution is shown in FIG. 3;
as can be seen from fig. 3: the retention time of tartaric acid is 2.748min, the retention time of pimavanserin is 9.367min, the retention time of impurity A is 12.570min, the retention time of impurity B is 5.518min, the retention time of impurity C is 4.140min, the retention time of impurity D is 20.473min, the retention time of impurity E is 13.367min, and the separation degree between peaks is greater than 2.0, which indicates that good separation is realized between pimavanserin tartrate and impurities and between impurities and impurities, and provides very favorable precondition for accurately testing the content of pimavanserin tartrate and impurities;
the content of the pimavanserin tartrate is 99.1 percent, the content of the impurity A is 0.011 percent, the content of the impurity B is 0.01 percent, the content of the impurity C is 0.09 percent, the content of the impurity D is 0.01 percent, the content of the impurity E is 0.01 percent, and the content of each impurity is less than 0.2 percent.
Example 3
Example 3 the detection method was the same as that of example 1, except for the chromatographic conditions in step 2) and step 3):
2) preparation of a test sample solution: accurately weighing 20mg of pimavanserin tartrate into a 20mL volumetric flask, adding acetonitrile aqueous solution to dissolve and dilute the pimavanserin tartrate to a scale mark to be used as a sample solution to be tested;
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: second stepNitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 6) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 μ L, chromatogram of test sample solution is shown in FIG. 4;
as can be seen from fig. 4: the retention time of tartaric acid is 2.726min, the retention time of pimavanserin is 9.830min, the retention time of impurity A is 12.617min, the retention time of impurity B is 5.754min, the retention time of impurity C is 4.392min, the retention time of impurity D is 20.567min, the retention time of impurity E is 13.434min, and the separation degree between peaks is greater than 2.0, which indicates that good separation is realized between pimavanserin tartrate and impurities and between impurities and impurities, and provides very favorable precondition for accurately testing the content of pimavanserin tartrate and impurities;
the content of the pmodanserin tartrate is 99.2 percent, the content of the impurity A is 0.009 percent, the content of the impurity B is 0.01 percent, the content of the impurity C is 0.13 percent, the content of the impurity D is 0.03 percent, the content of the impurity E is 0.01 percent, and the content of each impurity is less than 0.2 percent.
Comparative example 1
The test methods of comparative example 1 and example 1 are the same, except that: chromatographic conditions in step 2) and step 3):
2) preparation of a test sample solution: accurately weighing 20mg of pimavanserin tartrate into a 20mL volumetric flask, adding acetonitrile aqueous solution to dissolve and dilute the pimavanserin tartrate to a scale mark to be used as a sample solution to be tested;
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 6) ═ 45 to 70): (55-30) (v/v), performing gradient elution, wherein the gradient elution time and the volume ratio sequence of mobile phase acetonitrile are as follows: 45% operation is carried out in 0-15 min, 45% -70% operation is carried out in 15-25 min, and 70% -45% operation is carried out in 25-30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 μ L, chromatogram of the test sample solution is shown in FIG. 5;
as can be seen from fig. 5: tartaric acid retention time of 2.742min, pimavanserin retention time of 9.524min (resolution of 18.29), impurity a undetected and possibly overlapping with the main peak, impurity B retention time of 3.692min (resolution of 0.66), impurity C retention time of 3.581min (resolution of 0.73), impurity D retention time of 24.148min (resolution of 45.73), impurity E retention time of 10.612min (resolution of 2.90), this method does not satisfy that the resolution between the peaks is greater than or equal to 1.5, and pimavanserin tartrate and its impurities cannot be separated efficiently.
Comparative example 2
The detection method of comparative example 2 and example 1 is the same except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: methanol: KH (Perkin Elmer)2PO4(0.02mol/L, pH 6) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: the main peak shape is poor, and impurities cannot reach baseline separation.
Comparative example 3
The detection method of comparative example 3 is the same as that of example 1, except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 4) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: the main peak has poor peak shape, obvious tailing, partial impurities cannot be detected, and the main peak cannot be separated from the impurities.
Comparative example 4
The detection method of comparative example 4 is the same as that of example 1, except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: chromatographic test conditions are as followsThe following: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 6) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.5 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: the main peak has poor peak shape and obvious tailing.
Comparative example 5
The detection method of comparative example 5 is the same as that of example 1, except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: KH (Perkin Elmer)2PO4(0.02mol/L, pH 6) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 35 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: part of impurities can not be detected, the peak shape is poor, and baseline separation can not be achieved.
Comparative example 6
The detection method of comparative example 6 is the same as that of example 1, except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: NaH2PO4(0.02mol/L, pH 6) ═ 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 1.2 mL/min; column temperature: 25 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: part of impurities can not be detected, the peak shape is poor, and baseline separation can not be achieved.
Comparative example 7
The detection method of comparative example 7 is the same as that of example 1, except for the chromatographic conditions in step 3):
3) high performance liquid chromatography determination: the chromatographic test conditions were as follows: XDB CN chromatography column: 4.6mm × 250mm, 5 μm; mobile phase: acetonitrile: NaH2PO4(0.02mol/L，pH＝6) 44: 56(v/v), performing equal gradient elution, wherein the elution time is 30 min; flow rate: 0.8 mL/min; column temperature: 15 ℃; detection wavelength of the ultraviolet detector: 215 nm; sample introduction amount: 10 mu L of the mixture is added into the solution,
and (3) test results: the column temperature is too low, the pressure is too high, and the stability of a base line is influenced; part of impurities can not be detected, the peak shape is poor, and baseline separation can not be achieved.
Claims (11)
1. A method for detecting pimavanserin tartrate and impurities thereof is characterized by comprising the following steps: the method comprises the following steps:
1) preparing a standard reference substance solution of pimavanserin tartrate and impurities thereof;
2) preparing a test sample solution;
3) determining a chromatogram of the pimavanserin tartrate and impurities thereof in the standard reference substance solution by using a reversed-phase high performance liquid chromatograph, so that the separation degree between any adjacent substances is more than or equal to 1.5;
4) determining a chromatogram of the test sample solution using a reverse phase high performance liquid chromatograph;
5) determining the contents of the pinomofannserin tartrate and impurities thereof in the sample solution by using an external standard method according to the chromatogram of the standard reference solution and the chromatogram of the sample solution;
wherein, the step 3) and the step 4) utilize mobile phase acetonitrile: potassium dihydrogen phosphate solution 44: 56(v/v) performing equal gradient elution, wherein the concentration of the potassium dihydrogen phosphate solution is 0.02mol/L, and the pH value is 5-6;
the chromatographic column of the reversed-phase high performance liquid chromatography is an XDB CN chromatographic column: 4.6mm × 250mm, 5 μm;
the impurities are selected from at least one of 4-isobutoxybenzonitrile, 4-isobutoxybenzylamine, 4- (4-fluorobenzylamino) -1-methylpiperidine, 1, 3-bis (4-isobutoxybenzyl) urea and 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) urea.
2. The detection method according to claim 1, characterized in that: the concentration of the sample solution is 0.8-1.5 mg/mL.
3. The detection method according to claim 1, characterized in that: the flow rate in the reversed-phase high performance liquid chromatography is 0.8-1.0 mL/min.
4. The detection method according to claim 3, characterized in that: the flow rate in the reverse phase high performance liquid chromatography was 0.8 mL/min.
5. The detection method according to claim 1, characterized in that: the temperature of a chromatographic column in the reversed-phase high-performance liquid chromatography is 20-30 ℃.
6. The detection method according to claim 5, characterized in that: the column temperature in the reversed-phase high performance liquid chromatography is 25 ℃.
7. The detection method according to claim 1, characterized in that: the sample injection amount in the reversed-phase high-performance liquid chromatography is 8-15 mu L.
8. The detection method according to claim 1, characterized in that: the solvents of the standard reference substance solution and the test sample solution are mixed solution of acetonitrile and water.
9. The detection method according to claim 8, characterized in that: the volume ratio of the acetonitrile to the water is 6-7: 3 to 4.
10. The detection method according to claim 1, characterized in that: the detection wavelength of the reversed-phase high performance liquid chromatography is 210-220 nm.
11. The detection method according to claim 10, characterized in that: the detection wavelength of the reversed-phase high performance liquid chromatography is 215 nm.
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| Title |
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| Geetha Bhavani Koduri et al.Quantification of Pimavanserin in Bulk and Tablet Dosage Form Using A Stability Indicating High Performance Liquid Chromatographic Method.《Pharmaceutical Sciences》.2018,第24卷 * |
| Quantification of Pimavanserin in Bulk and Tablet Dosage Form Using A Stability Indicating High Performance Liquid Chromatographic Method;Geetha Bhavani Koduri et al;《Pharmaceutical Sciences》;20181231;第24卷;291-297 * |
| 匹莫范色林的降解动力学及降解产物的研究;张明洁 等;《沈阳药科大学学报》;20180930;第35卷(第9期);756-762 * |
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