CN114609272B - Method for detecting mesilate impurity JH-ZZD - Google Patents
Method for detecting mesilate impurity JH-ZZD Download PDFInfo
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- CN114609272B CN114609272B CN202210163607.6A CN202210163607A CN114609272B CN 114609272 B CN114609272 B CN 114609272B CN 202210163607 A CN202210163607 A CN 202210163607A CN 114609272 B CN114609272 B CN 114609272B
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- G—PHYSICS
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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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/8624—Detection of slopes or peaks; baseline correction
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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
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Abstract
The invention relates to a detection method of an impurity JH-ZZD in a mesilate sample, which comprises the steps of using a liquid chromatography-mass spectrometry method, using acetonitrile-ammonium salt buffer solution as a mobile phase as a liquid phase condition, using electrospray as an ion source, adopting a positive ion scanning mode, and selecting an ion detection mode as a mass spectrum condition to detect the impurity JH-ZZD in the mesilate sample. The detection method has the advantages of retaining JH-ZZD, quantitatively detecting the impurity JH-ZZD which is higher than 0.0009% in the mesilate, along with high sensitivity, strong practicability and simple and quick detection process.
Description
Technical Field
The invention belongs to the field of pharmaceutical analytical chemistry, relates to a method for detecting a methylsulfonylmet impurity JH-ZZD, and in particular relates to a method for detecting the impurity JH-ZZD in methylsulfonylmet by adopting liquid chromatography-mass spectrometry (LC-MS) separation.
Background
Methanesulfonsertraline, its chemical name is: (±) - [2-4- (3-ethoxy-2-hydroxypropoxy) phenylacetamido ] dimethyl sulfonium p-toluenesulfonate, and the chemical structural formula is as follows:
the methylsulfonylmest is a novel antiallergic agent developed by Dapeng pharmaceutical industry Co., ltd., japan in 1995, and has antiallergic effects by inhibiting T cell-induced production of interleukin-4 (IL-4) and interleukin-5 (IL-5), thereby inhibiting infiltration of acid granulocytes, inhibiting IgE antibody production, and the like. Is mainly used for treating bronchial asthma of children and adults. According to clinical manifestations, the mesilate can completely or partially replace hormone medicines, and has the characteristics of good curative effect, long-term medication safety and convenience.
The existence of certain impurities in the medicine can greatly influence the medication safety, so that the method has important significance in effectively controlling the quality of the raw material medicine and related preparations by directionally preparing target impurities and establishing a corresponding analysis method.
Disclosure of Invention
The mass study of mesilate involved the following impurities:
the invention provides a detection method for controlling the content of impurity JH-ZZD in mesilate. The inventor finds that the impurity JH-ZZD has ultraviolet absorption only to tosylate, and the mesilate is also to tosylate, so that the detection of the impurity JH-ZZD in the mesilate is interfered by adopting a conventional high-efficiency liquid phase method.
The invention adopts a high performance liquid chromatography-mass spectrometer, selects proper ion source and detection mode by detecting the trimethyl sulfur positive ion part, for example adopts an electron spray type ion source, and selects the ion mode for detection, thereby effectively realizing the detection of the impurity JH-ZZD in the mesilate.
The invention provides a detection method of an impurity JH-ZZD in mesilate, which comprises the following steps:
(1) Weighing a proper amount of the mesilate sample, precisely weighing, adding the mesilate sample into a volumetric flask, and mixing with 60-90% (preferably 90%) acetonitrile water solution to prepare 0.1-1 mg, for example 0.5mg, of solution containing the mesilate per ml as a sample solution;
(2) Weighing a proper amount of an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 60-90% (preferably 90%) acetonitrile water solution to prepare a solution containing 0.1-1 μg, such as 0.5 μg, of the impurity JH-ZZD per ml as a reference substance solution;
(3) Weighing a proper amount of a mesilate sample and an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 60-90% (preferably 90%) acetonitrile water solution to prepare a solution containing 0.1-1 mg, such as 0.5mg, of mesilate and 0.1-1 μg, such as 0.5 μg, of impurity JH-ZZD per ml as a mixed solution;
(4) Taking 10-50 mu l of the solution obtained in the step (1), the step (2) and the step (3), respectively injecting into a liquid chromatograph, recording a chromatogram, and reading at least one of the following information of impurities from the chromatogram: the number of impurities, the types of impurities, the peak outlet time between the chromatographic peaks of the impurities and the peak area of each chromatographic peak.
In the detection method provided by the invention, the detection method further comprises the following steps:
(5) According to the impurity information read in the step (4), calculating the content of the impurity JH-ZZD according to an external standard method;
(6) The impurity content calculation formula is: the peak area of the impurity in the sample solution in step (1) is multiplied by the concentration of the impurity in the impurity reference solution in step (2)/the peak area of the impurity in the impurity reference solution in step (2)/the concentration of the sample solution in step (1).
According to the detection method provided by the invention, the chromatographic column used in the liquid chromatography-mass spectrometry is a chromatographic column filled with silica gel.
According to the detection method provided by the invention, the chromatographic column packing particle size used by the liquid chromatography-mass spectrometry is 2-10 mu m, and the packing particle size is preferably 3 mu m.
According to the detection method provided by the invention, the inner diameter of the chromatographic column used by the liquid chromatography-mass spectrometry is 2-10 mm, and the inner diameter of the chromatographic column is 3.0mm.
According to the detection method provided by the invention, the column length of the chromatographic column used by the liquid chromatography-mass spectrometry is 75-150 mm, and the column length of the chromatographic column is preferably 100mm.
According to the detection method provided by the invention, the packing granularity of the chromatographic column used by the liquid chromatography-mass spectrometry is 3 mu m, the inner diameter of the chromatographic column is 3.0mm, and the column length of the chromatographic column is 100mm. The above model parameters may be abbreviated as 3 μm, 3.0X100 mm, or abbreviated as 3.0X100 mm,3 μm, or other similar abbreviations.
According to the detection method provided by the invention, the chromatographic column used by the liquid chromatography-mass spectrometry is a polar 3Si-A chromatographic column with the brand of Agilent.
According to the detection method provided by the invention, the column temperature of the chromatographic column is 30-50 ℃, preferably 38-42 ℃ during separation detection by using the liquid chromatography.
According to the detection method provided by the invention, the liquid chromatography-mass spectrometry is carried out by using two mobile phases A and B, wherein the mobile phase A is an ammonium salt buffer solution, and the mobile phase B is acetonitrile; the concentration of the mobile phase A is 0.003 to 0.010mol/L, for example 0.005mol/L; has good separation effect in the concentration range of 0.004-0.006 mol/L of the mobile phase A.
According to the detection method provided by the invention, the liquid chromatography-mass spectrometry is carried out by using two mobile phases A and B, wherein the mobile phase A is an ammonium acetate solution, and the mobile phase B is acetonitrile; the elution mode is gradient elution, and the linear elution is performed as follows:
| time/min | 0 | 15 | 15.1 | 20 |
| Mobile phase a (vol%) | 35 | 45 | 35 | 35 |
| Mobile phase B (vol%) | 65 | 55 | 65 | 65 |
The inventors have found that the present product is eluted linearly in the above specific elution mode and JH-ZZD is well detected, and in the following experiments of the present invention, as not specifically described, the mobile phase elution is performed according to the above linear elution procedure.
In one embodiment, the column temperature is from 30 ℃ to 50 ℃, such as from 38 ℃ to 40 ℃; the flow rate is 0.2 ml/min-1.2 ml/min, such as 0.48 ml/min-0.50 ml/min; the initial volume ratio of gradient elution is 35-45:65-55, such as 37:63; the present invention has found that a good separation effect is obtained in the range of the column temperature of 38℃and the flow rate of 0.48ml/min and the initial gradient elution ratio of 37:63.
In one embodiment, the column temperature is from 30 ℃ to 50 ℃, such as from 40 ℃ to 42 ℃; the flow rate is 0.2 ml/min-1.2 ml/min, such as 0.50 ml/min-0.52 ml/min; the initial gradient elution ratio is 35-45:65-55, e.g. 33:67; the present invention has found that a good separation effect is obtained in the range of a column temperature of 42℃and a flow rate of 0.52ml/min and a gradient elution initiation ratio of 33:67.
In one embodiment, the ammonium acetate concentration is from 0.003 to 0.010mol/L, for example from 0.0045 to 0.0055mol/L, and the present invention has found that there is a good separation effect in the range of from 0.0045 to 0.0055mol/L.
The present invention is described in further detail below.
In the invention, a silica gel column (Si-A) is adopted to detect the impurity JH-ZZD in the methylsulfonyrt, LC-MS is adopted to measure, and gradient elution is adopted to ensure that the impurity JH-ZZD has response, and the methylsulfonyrt does not interfere with the detection. Under the condition, the quality of the impurity JH-ZZD in the mesilate can be accurately and effectively controlled.
In the invention, the test sample solution and the reference sample solution are dissolved by using 90% acetonitrile water solution. The solution of the test sample is prepared into a solution containing 0.5mg of the methylsulfonylmet per ml, so that the related impurities contained in the test sample can be completely dissolved, and the quality of the impurity JH-ZZD in the methylsulfonylmet can be accurately and effectively controlled.
In one embodiment, the quality detection method of the present invention may be implemented as follows:
(1) Weighing a proper amount of mesilate sample, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.5mg of mesilate per ml as a sample solution;
(2) Weighing a proper amount of an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.5 mug of the impurity JH-ZZD per ml as a reference substance solution;
(3) The liquid phase conditions are set as follows:
chromatographic column: agilent polar 3 Si-A100×3.0mm,3 μm; mobile phase a:0.005mol/L ammonium acetate solution; mobile phase B: acetonitrile; flow rate: 0.5ml/min; column temperature: 40 ℃; sample injection amount: 10 μl; detection wavelength: 210nm of
The mass spectrum conditions are set as follows:
a detector: single quadrupole mass spectrometer (preferably Agilent 6120MS detection); ion source: electrospray (ESI); scanning mode: a positive ion; detection mode: selecting an ion mode (SIM); drying gas flow rate: 12L/min; atomization gas pressure: 45psig; drying gas temperature: 350 ℃; capillary voltage: 3000V;
positive ions:
| compounds of formula (I) | Retention time (min) | SIM ions | Impact fracture voltage |
| JH-ZZD | 9.2 | 77 | 70 |
(4) Taking 10 mu l of the solution obtained in the step (1) and the step (2), respectively injecting into a mass spectrometer, recording a chromatogram, and reading at least one of the following information of impurities from the chromatogram: the number of impurities, the types of impurities, the degree of separation between the chromatographic peaks of the impurities, and the peak area of each chromatographic peak.
In one embodiment, the column temperature is changed to 38deg.C, the flow rate is changed to 0.48ml/min, and the initial ratio is 37:63;
in one embodiment, the column temperature is changed to 42℃and the flow rate is changed to 0.52ml/min, starting at a ratio of 33:67;
in one embodiment, the ammonium acetate solution concentration is changed to 0.0045mol/L;
in one embodiment, the ammonium acetate solution concentration is changed to 0.0055mol/L.
Drawings
FIG. 1 shows the LC-MS spectrum of a blank solution specific for mesitylene in example 1.
FIG. 2 shows the LC-MS spectrum of the control solution in the special properties of methanesulfonst in example 1.
FIG. 3 shows the LC-MS spectrum of the test solution in the specific properties of methanesulfonst in example 1.
FIG. 4 shows the LC-MS spectrum of the mixed solution of the special properties of methanesulfonst in example 1.
FIG. 5 shows the LC-MS spectrum of the control solution in the sensitivity of mesitylene in example 1.
Detailed Description
The invention is further illustrated by the following examples, but it should be understood that the following examples are not limiting the scope of the invention.
The reagents used in the examples below are readily available on the market.
Example 1
Instrument and equipment samples:
the detection step comprises:
taking a 90% acetonitrile aqueous solution as a blank solution; weighing a proper amount of an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing JH-ZZD 0.5.5 mug per ml as a reference substance solution; weighing a proper amount of mesilate sample, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.5mg of mesilate per ml as a sample solution; weighing a proper amount of mesilate sample and an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile aqueous solution to prepare a solution containing 0.5mg of mesilate and 0.5 mug of JH-ZZD per ml as a mixed solution; precisely measuring 10 mu l of each solution, injecting into a mass spectrometer, and recording a chromatogram; the chromatograms are shown in fig. 1 to 4. The results of each solution are shown in Table 1.
As can be seen from fig. 1, the blank solvent does not interfere with the detection of impurity JH-ZZD; as can be seen from FIG. 2, the impurity JH-ZZD has a peak at about 9.6min, and no interference peak is present in the vicinity; as is clear from FIG. 3, the sample solution showed no interference peak around the peak of the impurity JH-ZZD, and as is clear from FIG. 4, the mixed solution showed no interference peak around the peak.
TABLE 1
Example 2
Instrument and equipment samples: the chromatographic conditions were the same as in example 1,
the impurity JH-ZZD reference substance is weighed in a proper amount, precisely weighed, added into a volumetric flask, and mixed with 90% acetonitrile water solution to prepare a solution containing 0.0047 mug of the impurity JH-ZZD per ml, which is used as a quantitative limiting solution. Precisely measuring 10 μl of quantitative limiting solution, injecting into a mass spectrometer, and recording a chromatogram; the chromatogram is shown in FIG. 5.
As is clear from FIG. 5, this method has high detection sensitivity, and can detect an impurity corresponding to 0.0009% of the concentration of the sample solution.
Example 3
Essentially the same procedure as in example 1, except that the column temperature was changed to 38℃and the flow rate was changed to 0.48ml/min, starting ratio was 37:63, and the other conditions were unchanged. The results are basically the same as those of the example 1, and as a result, the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution does not have adjacent interference peaks, and the content of the warning structure impurity in the sample solution is basically consistent with the detection result of the example 1.
Example 4
Essentially the same procedure as in example 1, except that the column temperature was changed to 42℃and the flow rate was changed to 0.52ml/min, starting ratio 33:67, and the other conditions were unchanged. The results are basically the same as those of the example 1, and as a result, the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution does not have adjacent interference peaks, and the content of the warning structure impurity in the sample solution is basically consistent with the detection result of the example 1.
Example 5
The procedure was essentially as in example 1, except that the ammonium acetate salt concentration was changed to 0.0045mol/L and 0.0055mol/L, with the other conditions unchanged. The results are basically the same as those of the example 1, and as a result, the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution does not have adjacent interference peaks, and the content of the warning structure impurity in the sample solution is basically consistent with the detection result of the example 1.
Claims (10)
1. The method for detecting the impurity JH-ZZD in the mesilate comprises the following steps:
the method is characterized in that: the detection method adopts a liquid chromatography-mass spectrometry method, and comprises the following steps:
(1) Preparing a mobile phase:
mobile phase a: ammonium salt buffer solution with 0.003-0.010 mol/L
Mobile phase B: acetonitrile;
(2) Preparing a test solution: weighing a mesilate sample, and mixing with 60-90% acetonitrile water solution by volume to prepare 0.1-1 mg of test solution containing mesilate per ml for later use;
(3) Preparing an impurity JH-ZZD reference substance solution: weighing an impurity JH-ZZD reference substance, adding the reference substance into a volumetric flask, and mixing with 60-90% by volume of acetonitrile aqueous solution to prepare a reference substance solution containing 0.1-1 mug of the impurity JH-ZZD per ml for later use;
(4) Preparing a mixed solution: weighing a mesilate sample and an impurity JH-ZZD reference substance, adding the mesilate sample and the impurity JH-ZZD reference substance into a volumetric flask, and mixing the mixture with 60-90% by volume of acetonitrile water solution to prepare a mixed solution containing 0.1-1 mg of mesilate and 0.1-1 mug of impurity JH-ZZD per ml for later use;
(5) Respectively sucking the same amount of sample solution, reference substance solution and mixed solution, and injecting into a liquid chromatograph-mass spectrometer for determination, wherein the chromatographic conditions comprise:
liquid chromatography conditions:
chromatographic column: silica gel column
Flow rate: 0.4-0.6 ml/min;
column temperature: 30-50 ℃;
detection wavelength: 195nm to 220nm
Using the chromatographic conditions described above, a linear gradient elution was performed using mobile phase a and mobile phase B according to the following procedure:
the gradient is as follows, wherein 6.5-13 min cuts into mass spectrum, 0-6.5 min, 13-20 min cuts into waste liquid; the valve cutting time can be properly adjusted according to the actual peak time;
Mass spectrometry conditions
A detector: a single quadrupole mass spectrometer;
ion source: electrospray (ESI);
scanning mode: a positive ion;
detection mode: selecting an ion mode (SIM);
drying gas flow rate: 9-12L/min;
atomization gas pressure: 40-50 psig;
drying gas temperature: 330-360 ℃;
capillary voltage: 3000V;
positive ions:
。
2. The method of claim 1, wherein: in the step (5), the chromatographic column is: the length is 75-150 mm, the inner diameter is 2-10 mm, and the particle size of the filling material is 2-10 mu m.
3. The method of claim 1, wherein: in the step (5), the detection wavelength is 210nm.
4. The method of claim 1, wherein: in the step (5), the column temperature is 40 ℃.
5. The method of claim 1, wherein: in the step (5), the flow rate is 0.5ml/min.
6. The detection method according to any one of claims 1 to 5, characterized in that: in the step (1), the ammonium salt buffer solution is an ammonium acetate solution with the concentration of 0.005mol/L.
7. The detection method according to any one of claims 1 to 5, characterized in that: the concentration of the sample solution in the step (2) is 0.01mg/ml to 10mg/ml.
8. The detection method according to any one of claims 1 to 5, characterized in that: in the step (3), the concentration of each impurity in the reference substance solution is 0.01-1 mug/ml.
9. The detection method according to any one of claims 1 to 5, characterized in that: in the step (4), the concentration of the impurity JH-ZZD in the mixed solution is 0.01-1 mug/ml, and the concentration of the mesilate is 0.1-1 mg/ml.
10. The detection method according to any one of claims 1 to 5, characterized in that: wherein 10-50 mu l of each of the sample solution, the reference solution and the mixed solution; injection liquid chromatography-mass spectrometry.
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| AU2016305590A1 (en) * | 2015-08-13 | 2018-02-15 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds |
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| CA2573481A1 (en) * | 2004-07-13 | 2006-01-19 | Taiho Pharmaceutical Co., Ltd. | Method of evaluating evenness of suplatast tosilate crystal, even crystal, and process for producing the same |
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| CN112552220A (en) * | 2020-12-17 | 2021-03-26 | 植恩生物技术股份有限公司 | Preparation method of suplatast tosilate |
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