CN114609272A - Detection method of suplatast tosilate impurity JH-ZZD - Google Patents
Detection method of suplatast tosilate impurity JH-ZZD Download PDFInfo
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- CN114609272A CN114609272A CN202210163607.6A CN202210163607A CN114609272A CN 114609272 A CN114609272 A CN 114609272A CN 202210163607 A CN202210163607 A CN 202210163607A CN 114609272 A CN114609272 A CN 114609272A
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Abstract
The invention relates to a detection method of impurity JH-ZZD in suplatast tosilate, which comprises the steps of detecting impurity JH-ZZD in a suplatast tosilate sample by 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. The detection method has the advantages that JH-ZZD is reserved, impurities JH-ZZD which are higher than 0.0009% of suplatast tosilate can be quantitatively detected, the sensitivity is high, the practicability is high, and the detection process is simple and rapid.
Description
Technical Field
The invention belongs to the field of pharmaceutical analytical chemistry, relates to a method for detecting a suplatast tosilate impurity JH-ZZD, and particularly relates to a detection method for separating and determining the impurity JH-ZZD in the suplatast tosilate by adopting liquid chromatography-mass spectrometry (LC-MS).
Background
Sulfast, its chemical name is: (±) - [2-4- (3-ethoxy-2-hydroxypropoxy) phenylacetamido ] dimethyl sulfonium p-toluenesulfonate with the chemical structural formula:
sulfast is a novel antiallergic drug developed by the pharmaceutical industry corporation of Japan Roc in 1995, and exerts an antiallergic effect by inhibiting T cell-induced production of interleukin-4 (IL-4) and interleukin-5 (IL-5), thereby inhibiting infiltration of acidic granulocytes and IgE antibody production. It is mainly used for treating bronchial asthma of children and adults. According to clinical manifestations, the suplatast tosilate can completely or partially replace hormone drugs, and has the characteristics of good curative effect, and safety and convenience in long-term administration.
The existence of certain impurities in the medicine can greatly influence the medication safety, so that the establishment of a corresponding analysis method by directionally preparing target impurities has important significance for effectively controlling the quality of the bulk drugs and related preparations.
Disclosure of Invention
During the quality study of suplatast tosilate, the following impurities were involved:
the invention provides a detection method for controlling the content of impurity JH-ZZD in suplatast tosilate. The inventor finds that the impurity JH-ZZD only absorbs ultraviolet and is p-toluenesulfonate, and the suplatast is also p-toluenesulfonate per se, so that the conventional high-efficiency liquid phase method is adopted to interfere with the detection of the impurity JH-ZZD in the suplatast.
The invention adopts a high performance liquid chromatography-mass spectrometer, selects a proper ion source and a proper 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, and can effectively realize the detection of the impurity JH-ZZD in the suplatast tosilate.
The invention provides a detection method of impurity JH-ZZD in suplatast tosilate, which comprises the following steps:
(1) weighing a proper amount of the suplatast tosilate sample, precisely weighing, adding the weighed sample into a volumetric flask, and mixing with 60-90 vol% (preferably 90 vol%) acetonitrile water solution to prepare a solution containing 0.1-1 mg, such as 0.5mg, of the suplatast tosilate per ml, wherein the solution is used as a test solution;
(2) weighing a proper amount of impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 60-90 vol% (preferably 90 vol%) acetonitrile aqueous solution to prepare a solution containing 0.1-1 μ g, for example 0.5 μ g, of impurity JH-ZZD 0.1 per ml as a reference substance solution;
(3) weighing appropriate amount of the suplatast tosilate sample and an impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 60-90 vol% (preferably 90 vol%) acetonitrile water solution to prepare a solution containing 0.1-1 mg, such as 0.5mg, of suplatast tosilate and 0.1-1 μ g, such as 0.5 μ g, of the impurity JH-ZZD 0.1 per ml as a mixed solution;
(4) and (3) taking 10-50 mul of the solution obtained in the step (1), the step (2) and the step (3), respectively injecting the solution into a liquid chromatograph, recording a chromatogram, and reading at least one piece of the following information of the impurities from the chromatogram: the amount of impurities, the types of impurities, the peak emergence time between spectral peaks of the impurities, and the peak area of each spectral peak.
In the detection method provided by the present invention, the detection method further comprises:
(5) calculating the content of the impurity JH-ZZD according to the impurity information read in the step (4) and an external standard method;
(6) the calculation formula of the impurity content is as follows: the peak area of the impurity in the test solution in the step (1) is multiplied by the concentration of the impurity in the impurity reference solution in the step (2)/the peak area of the impurity in the impurity reference solution in the step (2)/the concentration of the test solution in the step (1).
According to the detection method provided by the invention, the chromatographic column used by the liquid chromatography-mass spectrometry is a chromatographic column with silica gel as a filler.
According to the detection method provided by the invention, the granularity of the chromatographic column packing used by the liquid chromatography-mass spectrometry is 2-10 μm, and the preferred granularity of the packing is 3 μm.
The detection method provided by the invention is characterized in that the inner diameter of a chromatographic column used for the liquid chromatography-mass spectrometry is 2 mm-10 mm, and preferably the inner diameter of the chromatographic column is 3.0 mm.
The detection method provided by the invention, wherein the column length of the chromatographic column used in the liquid chromatography-mass spectrometry is 75 mm-150 mm, and preferably the column length of the chromatographic column is 100 mm.
According to the detection method provided by the invention, the particle size of the filler of the chromatographic column used in the liquid chromatography-mass spectrometry is 3 μm, the inner diameter of the chromatographic column is 3.0mm, and the column length of the chromatographic column is 100 mm. The above model parameters may be abbreviated as 3 μm, 3.0 × 100mm, or 3.0 × 100mm, 3 μm, or other similar shorthand means.
The detection method provided by the invention is characterized in that the chromatographic column used by the liquid chromatography-mass spectrometry is a Polaris 3Si-A chromatographic column with the brand name of Agilent.
According to the detection method provided by the invention, the temperature of the chromatographic column during the separation detection by the LC-MS (liquid chromatography-mass spectrometry) is 30-50 ℃, preferably 38-42 ℃.
According to the detection method provided by the invention, the liquid chromatography-mass spectrometry uses 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 0.003-0.010 mol/L, such as 0.005 mol/L; the concentration of the mobile phase A is in the range of 0.004-0.006 mol/L, and the good separation effect is achieved.
According to the detection method provided by the invention, the liquid chromatography-mass spectrometry uses 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 procedure of linear elution is as follows:
| time/ |
0 | 15 | 15.1 | 20 |
| Mobile phase a (% by volume) | 35 | 45 | 35 | 35 |
| Mobile phase B (% by volume) | 65 | 55 | 65 | 65 |
The inventors have found that this product is linear eluted according to the above-specified elution pattern, JH-ZZD being well detectable, and in the following detailed experiments of the invention, the mobile phase elution used was performed according to the above-described linear elution procedure, unless otherwise specified.
In one embodiment, the column temperature is from 30 ℃ to 50 ℃, e.g., from 38 ℃ to 40 ℃; the flow rate is 0.2ml/min to 1.2ml/min, such as 0.48ml/min to 0.50 ml/min; the gradient elution starting volume ratio is 35-45: 65-55, such as 37: 63; the present inventors have found that good separation is achieved at a column temperature of 38 deg.C, a flow rate of 0.48ml/min, and a gradient elution start ratio of 37: 63.
In one embodiment, the column temperature is from 30 ℃ to 50 ℃, e.g., from 40 ℃ to 42 ℃; the flow rate is 0.2ml/min to 1.2ml/min, such as 0.50ml/min to 0.52 ml/min; the initial ratio of gradient elution is 35-45: 65-55, such as 33: 67; the present inventors have found that good separation is achieved at a column temperature of 42 deg.C, a flow rate of 0.52ml/min, and a gradient elution start ratio of 33: 67.
In one embodiment, the ammonium acetate concentration is 0.003 to 0.010mol/L, such as 0.0045 to 0.0055mol/L, and the present inventors have found that a good separation effect is obtained in the range of 0.0045 to 0.0055 mol/L.
The present invention is described in further detail below.
In the invention, the impurity JH-ZZD in the suplatast tosilate is detected by a silica gel column (Si-A), the detection is carried out by LC-MS, and gradient elution is adopted, so that the impurity JH-ZZD has response, and the suplatast tosilate does not interfere with the detection. Under the condition, the quality of the impurity JH-ZZD in the suplatast tosilate can be accurately and effectively controlled.
In the present invention, the test solution and the control solution are both dissolved in 90% acetonitrile aqueous solution. The test solution is prepared into a solution containing 0.5mg of the suplatast tosilate per ml, so that the complete dissolution of related impurities contained in the test solution can be ensured, and the method can accurately and effectively control the quality of the impurity JH-ZZD in the suplatast tosilate.
In one embodiment, the quality detection method of the present invention can be implemented as follows:
(1) weighing a proper amount of the suplatast tosilate sample, precisely weighing, adding the weighed sample into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.5mg of the suplatast tosilate per ml to serve as a test solution;
(2) weighing a proper amount of 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 mu g of impurity JH-ZZD 0.5 per ml as reference substance solution;
(3) the liquid phase conditions are set as follows:
a chromatographic column: agilent Polaris 3 Si-A100X 3.0mm, 3 μm; mobile phase A: 0.005mol/L ammonium acetate solution; and (3) mobile phase B: acetonitrile; flow rate: 0.5 ml/min; column temperature: 40 ℃; sample injection amount: 10 mu l of the mixture; detection wavelength: 210nm
Setting mass spectrum conditions as follows:
a detector: a single quadrupole mass spectrometer (preferably Agilent 6120MS detection); an ion source: electrospray (ESI); scanning mode: a positive ion; detection mode: selecting an ion mode (SIM); flow rate of drying gas: 12L/min; atomizing gas pressure: 45 psig; temperature of the drying gas: 350 ℃; capillary voltage: 3000V;
positive ion:
| compound (I) | Retention time (min) | SIM ion | Voltage of collision and fragmentation |
| JH-ZZD | 9.2 | 77 | 70 |
(4) And (3) respectively injecting 10 mu l of the solution obtained in the step (1) and the step (2) into a mass spectrometer, recording a chromatogram, and reading at least one piece of information of impurities from the chromatogram: the amount of impurities, the type of impurities, the degree of separation between peaks of the spectra of the impurities, and the peak area of each peak of the spectra.
In one embodiment, the column temperature is changed to 38 ℃, the flow rate is changed to 0.48ml/min, the initial ratio is 37: 63;
in one embodiment, the column temperature was changed to 42 ℃, the flow rate was changed to 0.52ml/min, the initial ratio was 33: 67;
in one embodiment, the ammonium acetate solution concentration is changed to 0.0045 mol/L;
in one embodiment, the ammonium acetate solution concentration is changed to 0.0055 mol/L.
Drawings
FIG. 1 shows the LC-MS spectrum of a blank solution in the specialization of suplatast tosilate in example 1.
FIG. 2 shows the LC-MS spectrum of the control solution in the specialization of suplatast tosilate in example 1.
FIG. 3 shows the LC-MS spectrum of the test solution in the specialization of suplatast tosilate in example 1.
FIG. 4 shows the LC-MS spectrum of the mixed solution in the specialization of suplatast tosilate in example 1.
FIG. 5 shows the LC-MS spectrum of the control solution in case of suplatast tosilate sensitivity 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 to the scope of the invention.
The reagents used in the following examples are readily available on the market.
Example 1
Instrument device sample:
a detection step:
taking 90% acetonitrile water solution as a blank solution; weighing an appropriate amount of impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to obtain solution containing JH-ZZD 0.5.5 μ g per ml as reference substance solution; weighing a proper amount of the suplatast tosilate sample, precisely weighing, adding the weighed sample into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.5mg of the suplatast tosilate per ml to serve as a test solution; weighing appropriate amount of the suplatast tosilate sample and 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 0.5mg of suplatast tosilate and 0.5 mu g of JH-ZZD 0.5 per ml as a mixed solution; precisely measuring 10 mu l of each solution, injecting into a mass spectrometer, and recording a chromatogram; the chromatogram is shown in FIGS. 1-4. 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 the impurity JH-ZZD; as can be seen from FIG. 2, the impurity JH-ZZD appears a peak at about 9.6min, and no interference exists nearby; as can be seen from FIG. 3, the sample solution showed no interference in the vicinity of the peak formed by impurity JH-ZZD, and as can be seen from FIG. 4, the mixed solution showed no interference in the vicinity of the peak.
TABLE 1
Example 2
Instrument device sample: the chromatographic conditions were the same as in example 1,
weighing a proper amount of impurity JH-ZZD reference substance, precisely weighing, adding into a volumetric flask, and mixing with 90% acetonitrile water solution to prepare a solution containing 0.0047 μ g of impurity JH-ZZD 0.0047 per ml as a quantitative limiting solution. Precisely measuring 10 mu l of the quantitative limiting solution, injecting the quantitative limiting solution 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 ℃, the flow rate was changed to 0.48ml/min, the initial ratio was 37:63, and other conditions were not changed. The result is basically the same as that of example 1, and the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution has no adjacent interference peak, and the content of the warning structure impurity in the test solution is basically consistent with that of example 1.
Example 4
Essentially the same procedure as in example 1, except that the column temperature was changed to 42 ℃, the flow rate was changed to 0.52ml/min, the initial ratio was 33:67, and the other conditions were not changed. The result is basically the same as that of example 1, and the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution has no adjacent interference peak, and the content of the warning structure impurity in the test solution is basically consistent with that of example 1.
Example 5
Substantially the same procedure as in example 1, except that the ammonium acetate salt concentration was changed to 0.0045mol/L and 0.0055mol/L, and other conditions were not changed. The result is basically the same as that of example 1, and the blank solvent does not interfere with the detection of the impurity JH-ZZD, the impurity JH-ZZD in the system solution has no adjacent interference peak, and the content of the warning structure impurity in the test solution is basically consistent with that of example 1.
Claims (10)
1. The detection method of impurity JH-ZZD in suplatast tosilate, wherein the impurity JH-ZZD is as follows:
the method is characterized in that: the detection method adopts a liquid chromatography-mass spectrometry chromatography, and comprises the following steps:
(1) preparing a mobile phase:
mobile phase A: 0.003-0.010 mol/L ammonium salt buffer solution
Mobile phase B: acetonitrile;
(2) preparing a test solution: weighing a suplatast tosilate sample, and mixing the suplatast tosilate sample with 60-90 vol% acetonitrile aqueous solution to prepare a test solution containing 0.1-1 mg of suplatast tosilate per ml for later use;
(3) preparation of impurity JH-ZZD control solution: weighing an impurity JH-ZZD reference substance, adding the reference substance into a volumetric flask, and mixing with 60-90 vol% acetonitrile water solution to prepare a reference substance solution containing 0.1-1 mu g of impurity JH-ZZD 0.1 per ml for later use;
(4) preparing a mixed solution: weighing a suplatast tosilate sample and an impurity JH-ZZD reference substance, adding the suplatast tosilate sample and the impurity JH-ZZD reference substance into a volumetric flask, and mixing with 60-90 vol% acetonitrile water solution to prepare a mixed solution containing 0.1-1 mg of suplatast tosilate and 0.1-1 mu g of impurity JH-ZZD 0.1 per ml for later use;
(5) respectively sucking the equal amounts of the test solution, the reference solution and the mixed solution, injecting the solutions into a liquid chromatograph-mass spectrometer for determination, wherein the chromatographic conditions comprise:
liquid chromatography conditions:
a chromatographic column: silica gel column
Flow rate: 0.4-0.6 ml/min;
column temperature: 30-50 ℃;
detection wavelength: 195 nm-220 nm
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 mass spectrum is cut in 6.5-13 min, waste liquid is cut in 0-6.5 min and 13-20 min; the valve switching time can be properly adjusted according to the actual peak output time;
Conditions of Mass Spectrometry
A detector: a single quadrupole mass spectrometer;
an ion source: electrospray (ESI);
scanning mode: a positive ion;
detection mode: selecting an ion mode (SIM);
flow rate of drying gas: 9-12L/min;
atomizing gas pressure: 40-50 psig;
temperature of the drying gas: 330-360 ℃;
capillary voltage: 3000V;
positive ion:
2. The detection method according to claim 1, characterized in that: in the step (5), the chromatographic column is: 75 mm-150 mm long, 2 mm-10 mm inner diameter, 2 μm-10 μm filler particle size.
3. The detection method according to claim 1, characterized in that: in the step (5), the detection wavelength is 210 nm.
4. The detection method according to claim 1, characterized in that: in the step (5), the column temperature is 40 ℃.
5. The detection method according to claim 1, characterized in that: in the step (5), the flow rate is 0.5 ml/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, and the concentration is 0.005 mol/L.
7. The detection method according to any one of claims 1 to 5, characterized in that: the concentration of the test solution in the step (2) is 0.01 mg/ml-10 mg/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 solution is 0.01 to 1 mu g/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 mu g/ml, and the concentration of the suplatast tosilate is 0.1-1 mg/ml.
10. The detection method according to any one of claims 1 to 5, characterized in that: wherein the sample solution, the reference solution and the mixed solution are respectively 10-50 mul; injecting into a liquid chromatograph.
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