CN110865130B - Olopatadine hydrochloride and detection method of related substances thereof - Google Patents
Olopatadine hydrochloride and detection method of related substances thereof Download PDFInfo
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Abstract
The application relates to a detection method of olopatadine hydrochloride and related substances thereof, which comprises the step of detecting by adopting high performance liquid chromatography, wherein the liquid chromatography conditions are as follows: adopting an octyl silane bonded silica gel chromatographic column; the mobile phase A is an aqueous solution containing 0.01 to 1 percent of ion pair reagent, 0.3 to 1 percent of monoamine and 0.001 to 0.1mol/L buffer salt, and the mobile phase B is acetonitrile and/or methanol for gradient elution; the pH value of the buffer solution is 2.5-3.5, and the detection wavelength is 220-280 nm. The method for detecting olopatadine hydrochloride and related substances thereof can effectively separate olopatadine hydrochloride and impurities thereof, improve the accuracy of detection results and reduce clinical medication risks.
Description
Technical Field
The application belongs to the technical field of analysis and detection, and particularly relates to a detection method of olopatadine hydrochloride and related substances thereof.
Background
The molecular formula of the olopatadine hydrochloride is C 21 H 24 ClNO 3 Named (Z) -11- [3- (dimethylamino) propylene]-6, 11-dihydrodibenzo [ b, e]The oxazepine-2-acetate hydrochloride has an English name of Olopatadine Hydrochloride, a CAS number of 140462-76-6 and a structural formula shown as formula 1, is an antiallergic agent developed and marketed by Japanese Kogyo fermentation company, can be used for treating allergic rhinitis and urticaria, and can improve the symptoms of skin diseases accompanied with pruritus.
The detection methods of olopatadine hydrochloride related substances are described in United states pharmacopoeia USP41 and Japanese pharmacopoeia JP17, and the inventor finds out through experiments that the detection methods of olopatadine hydrochloride related substances described in USP41 and JP17 have fewer detected impurities due to reasons such as wavelength, gradient and flow, can not fully reflect the quality of products, and bring potential safety risks to clinical medication.
Disclosure of Invention
In order to solve the problems, the application provides a detection method of olopatadine hydrochloride and related substances thereof, which comprises the following specific scheme:
the method for detecting olopatadine hydrochloride and related substances thereof comprises the step of detecting a sample by adopting high performance liquid chromatography, wherein the liquid chromatography conditions are as follows:
chromatographic column: adopting an octyl silane bonded silica gel chromatographic column;
the detection wavelength is as follows: 220 nm-280 nm;
mobile phase: the mobile phase B is methanol and/or acetonitrile, the mobile phase A is a buffer solution containing 0.01% -1% (g/ml) of ion pair reagent and 0.3% -1% (ml/ml) of monoamine, the concentration of the buffer solution is 0.001-0.1 mol/L, the pH value of the mobile phase A is 2.5-3.5, a flow gradient elution method is adopted, and the gradient elution is carried out according to the following table:
according to the method for detecting olopatadine hydrochloride and related substances thereof, provided by the application, a proper mobile phase is adopted, a proper amount of cationic ion pair reagent is added into a buffer solution, the pH value and gradient elution program of the buffer solution are reasonably set, and after the conditions are comprehensively considered, the special method for detecting olopatadine hydrochloride and related substances thereof is obtained, so that the olopatadine hydrochloride and other impurities can be effectively and fully separated, and the detection result is superior to that of the prior art.
Preferably, the buffer salt is phosphate and/or acetate.
Preferably, the detection wavelength is: 230 nm-250 nm.
Preferably, the ion pair reagent is selected from one or more of sodium octane sulfonate, sodium hexane sulfonate, sodium heptane sulfonate and sodium pentane sulfonate.
More preferably, the ion pair reagent is sodium octyl sulfonate.
Preferably, the monoamine is triethylamine and/or diethylamine.
Further, the liquid chromatography conditions also include a mobile phase flow rate of 0.5ml/min to 2.0ml/min, preferably 1.5ml/min.
Further, the conditions of the liquid chromatography further comprise a column temperature of 20-50 ℃, preferably 40 ℃.
Further, the detection method further comprises the following steps:
sample solution preparation: adding olopatadine hydrochloride bulk drug or preparation into a diluent, fully dissolving by stirring, ultrasonic treatment, heating and the like, then adding the diluent to a constant volume to a concentration of 0.2mg/mL, and filtering to obtain a sample solution; wherein the diluent is a mixed solution of mobile phase A and mobile phase B with the volume ratio of (60-95) to (40-5).
Further preferably, the olopatadine hydrochloride customization agent comprises: sustained release, controlled release or common type eye drops, injection, tablet, capsule, granule, oral liquid, injection, pellicle, powder, pill, suppository or aerosol.
Further, the related substances are 10 substances as shown in table 1.
TABLE 1 specific Structure and code number of olopatadine hydrochloride related substances
The detection method of olopatadine hydrochloride and related substances thereof provided by the application can realize effective separation of olopatadine hydrochloride and 10 known impurities, and has high sensitivity. Compared with the prior art, the method has better detection effect on the number and the impurity amount of impurities, effectively improves the accuracy of the detection result of the olopatadine hydrochloride, reduces the clinical medication risk, and has great significance on the quality control of the olopatadine hydrochloride active substance.
Drawings
FIG. 1 example 1 liquid chromatogram of sample solution;
FIG. 2 example 2 liquid chromatogram of sample solution;
FIG. 3 example 3 liquid chromatogram of sample solution;
FIG. 4 liquid chromatogram of example 4 mixed control;
FIG. 5 liquid chromatogram of example 5 mixed control;
FIG. 6 liquid chromatogram of example 6 mixed control.
Detailed Description
The present application is further described below with reference to the drawings and examples, which are only for explaining the present application and are not intended to limit the scope of the present application.
In the context of the present application, the term "mobile phase" refers to a substance that carries the component to be measured forward during chromatography.
In the context of the present application, the term "reverse chromatography column" refers to a chromatography column with mobile phase polarity greater than stationary phase polarity. The present application may use a reverse phase chromatography column conventional in the art.
In the examples of the present application, one or more substances in table 1 are selected as relevant substances of olopatadine hydrochloride for detection control, including starting materials, process impurities, degradation impurities, intermediates, and the like.
In the application, the test sample and the impurity reference substance can be obtained by purchasing commercial products or by self-making.
Example 1
Sample solution for sample: weighing 50mg of an olopatadine hydrochloride sample to be detected, placing the sample into a 100ml measuring flask, adding a diluent, performing ultrasonic dissolution, then fixing the volume to a scale, shaking uniformly, and filtering to obtain the olopatadine hydrochloride; wherein the diluent is: a volume ratio of 0.05mol/L phosphate buffer solution (pH 3.5) to acetonitrile was 3:2.
The sample solution is taken and injected into a liquid chromatograph, a chromatogram is recorded, the measurement is completed, the obtained chromatogram is shown in fig. 1, and the analysis of impurity results is shown in table 2.
The detection method comprises the following steps: the method for detecting olopatadine hydrochloride and related substances specified in JP17 comprises the following specific detection conditions:
detection instrument: the Shimadzu LC-20AT high performance liquid chromatograph;
wavelength: 299nm;
chromatographic column: c8 250X 4.6mm,5 μm;
sample injection amount: 30 μl;
column temperature: 40 ℃;
mobile phase: 2.3g of sodium dodecyl sulfate is dissolved in 1000ml of a mixed solution of 0.05mol/L phosphate buffer solution (pH 3.5) and acetonitrile with the volume ratio of 11:9;
flow rate: the flow rate is regulated to make the main peak appear at about 11 min;
acquisition time: the main peak retention time was 2 times.
TABLE 2 analysis of results of detection of olopatadine hydrochloride crude drug by JP17 detection method
Example 2
Sample solution for sample: weighing 20mg of olopatadine hydrochloride samples to be detected in the same batch of the embodiment 1, placing the sample into a 100ml measuring flask, adding a diluent, performing ultrasonic dissolution, then fixing the volume to a scale, shaking uniformly, and filtering to obtain the olopatadine hydrochloride sample to be detected, wherein the diluent is a mobile phase.
The sample solution is taken and injected into a liquid chromatograph, a chromatogram is recorded, the measurement is completed, the obtained chromatogram is shown in fig. 2, and the analysis of impurity results is shown in table 3.
The detection method comprises the following steps: the method for detecting olopatadine hydrochloride and related substances specified in USP41 comprises the following specific detection conditions:
detection instrument: agilent 1260 high performance liquid chromatograph;
wavelength: 299nm;
chromatographic column: c8 150X 4.6mm,5 μm;
flow rate: 1.0ml/min;
sample injection amount: 30 μl;
column temperature: 40 ℃;
buffer solution: 13.6g of potassium dihydrogen phosphate is dissolved in 1L of water, 1mL of triethylamine is added, and after mixing, the pH is adjusted to 3.0 by phosphoric acid;
mobile phase: a mixed solution of acetonitrile and buffer solution in a volume ratio of 28:72;
acquisition time: collected to 2.5 times the main peak retention time.
TABLE 3 analysis of results of detection of olopatadine hydrochloride crude drug by USP41 detection method
Example 3
Sample solution for sample: weighing 20mg of olopatadine hydrochloride to be detected samples in the same batch as in example 1, placing the sample into a 100ml measuring flask, adding a diluent, performing ultrasonic dissolution, then fixing the volume to a scale, shaking uniformly, and filtering to obtain the olopatadine hydrochloride to be detected sample, wherein the diluent is a mixed solution of a mobile phase A and a mobile phase B in a volume ratio of 75:25.
The sample solution was taken and injected into a liquid chromatograph, the chromatogram was recorded, the measurement was completed, the chromatogram obtained was shown in fig. 3, and the impurity result analysis was shown in table 4.
The specific detection conditions are as follows:
detection instrument: agilent 1260 high performance liquid chromatograph;
wavelength: 240nm;
chromatographic column: c8 150X 4.6mm,5 μm;
flow rate: 1.0ml/min;
sample injection amount: 30 μl;
column temperature: 40 ℃;
mobile phase a: an aqueous solution containing 0.01mol/L phosphate, 0.1% sodium octane sulfonate and 0.4% triethylamine, and adjusting the pH to 3 with phosphoric acid;
mobile phase B: acetonitrile;
gradient elution conditions:
TABLE 4 analysis of results of detection of olopatadine hydrochloride crude drug by USP41 detection method
As can be seen from comparative examples 1, 2 and 3, the maximum unknown impurity and impurity C content detected by the three methods are not different, but are different in the number of impurities and the total impurity content, the detection methods of USP41 and JP17 respectively detect two and three impurities, the total impurity content is 0.13% and 0.1%, but the number of detected impurities is 6 by the detection method provided by the application, the total impurity content is 0.23%, the accuracy and sensitivity of the olopatadine hydrochloride detection are greatly improved, the data are more reliable, the drug quality control is facilitated, and the clinical medication risk is reduced.
Example 4
Preparation of a mixed control: respectively taking appropriate amounts of AL-2, AL-3, AL-4, AL-5-A, AL-5-B, triazophos and olopatadine hydrochloride reference substances, putting the reference substances into a measuring flask, adding a diluent, fully dissolving the reference substances, and then fixing the volume until the contents of impurities and the olopatadine hydrochloride reference substances are 50 mug/ml, thereby obtaining a first stock solution; respectively taking a proper amount of impurity A, impurity B and impurity C, placing into a measuring flask, adding a diluent for full dissolution, and then fixing the volume until the impurity content is 25 mug/ml to obtain a second stock solution; mixing the first stock solution and the second stock solution in equal volume to obtain a mixed control sample solution; wherein the diluent is: the volume ratio of acetonitrile to buffer solution is 75:25, wherein the buffer solution is an aqueous solution containing 0.01mol/L potassium dihydrogen phosphate, 0.1 percent sodium octane sulfonate and 0.4 percent triethylamine, and the pH value is adjusted to 3.0 by phosphoric acid.
Taking a mixed control sample solution, injecting the mixed control sample solution into a liquid chromatograph, detecting according to the detection method provided in the embodiment 1, recording a chromatogram, and completing the determination; the obtained chromatogram is shown in FIG. 4, and the compounds detected from short to long retention time in FIG. 4 are AL-3, impurity C, AL-2, AL-5-A, phosphorus trioxide, impurity A, impurity B and olopatadine hydrochloride reference substances respectively.
Example 5
Preparation of a mixed control: same as in example 4;
30 μl of the mixed control sample was taken, injected into a liquid chromatograph, detected by the detection method of example 2, and the chromatogram was recorded to complete the measurement; the obtained chromatogram is shown in FIG. 5, and the compounds detected from short to long retention time in FIG. 5 are impurity C, impurity A, olopatadine hydrochloride control, impurity B and AL-2, respectively.
Example 6
Preparation of a mixed control: same as in example 4.
Taking a mixed control sample, injecting the mixed control sample into a liquid chromatograph, detecting according to the detection method of the embodiment 3, recording a chromatogram, and completing the determination; the obtained chromatogram is shown in FIG. 6, and the compounds detected from short to long retention time in FIG. 6 are AL-5-A, impurity C, AL-3, impurity A, olopatadine hydrochloride reference, impurity B, AL-2, phosphorus tribenzoxide, AL-5-B, AL-5 and AL-4, respectively.
As can be seen from comparison of the results of examples 4, 5 and 6, the detection methods provided in examples 4 and 5 can not completely detect all the impurities in the mixed control sample, but the detection method provided in the application can effectively detect all the known impurities, so that not only is the separation effect of the impurities and the active substances good, but also the impurities are effectively separated.
Example 7
Preparation of mixed control solutions: taking appropriate amounts of AL-2, AL-3, AL-4, AL-5-A, AL-5-B, triazophos and olopatadine hydrochloride reference substances respectively, placing the reference substances into a measuring flask, adding a diluent, fully dissolving the reference substances, and then fixing the volume until the contents of impurities and the olopatadine hydrochloride reference substances are 50 mug/ml, thereby obtaining a first stock solution; respectively taking a proper amount of impurity A, impurity B and impurity C, placing into a measuring flask, adding a diluent for full dissolution, and then fixing the volume until the impurity content is 25 mug/ml to obtain a second stock solution; mixing the first stock solution and the second stock solution in equal volume to obtain a mixed control sample solution, wherein the diluent is as follows: a mixed solution of mobile phase A and mobile phase B in a volume ratio of 80:20.
The mixed control sample solution was taken and injected into a liquid chromatograph, and the detection was performed under the following chromatographic conditions, and the chromatogram was recorded, and the measurement was completed, with the results shown in table 5.
Chromatographic conditions: an octyl silane bonded silica gel chromatographic column; mobile phase a: an aqueous solution containing 0.1mol/L phosphate, 0.2% sodium heptanesulfonate and 0.4% triethylamine, and adjusting the pH to 3 with phosphoric acid; mobile phase B: acetonitrile; flow rate: 1.0ml/min; the detection wavelength is 240nm; the sample injection amount is 30 μl; column temperature: 35 ℃; gradient elution conditions:
table 5: EXAMPLE 7 detection results of the mixed control sample solution
Test results: under the condition of liquid chromatography, all impurities and main peaks can be completely separated, and the separation degree among all the impurities is good, so that the method is more suitable.
Example 8
Preparation of mixed control solutions: same as in example 7.
The mixed control sample solution was taken and injected into a liquid chromatograph, the measurement was performed under the following chromatographic conditions, the chromatogram was recorded, and the measurement was completed, and the detection results are shown in table 6.
Chromatographic conditions: the difference from example 7 is the gradient elution conditions as follows:
table 6: example 8 detection results of mixed control solutions
Test results: under the condition of liquid chromatography, the retention time of each peak is short, the separation degree between peaks is small, the impurities A and AL-3, the impurities B and active substances and the impurities AL-5-B and phosphorus tribenzoxide cannot be effectively separated, and the condition is unfavorable.
Example 9
Preparation of mixed control solutions: same as in example 7.
The mixed control sample solution was taken and injected into a liquid chromatograph, and the measurement was performed under the following chromatographic conditions, and the chromatogram was recorded, and the measurement was completed, and the detection results are shown in table 7.
Chromatographic conditions: the difference from example 7 is the gradient elution conditions as follows:
table 7: example 9 detection results of mixed control solutions
Test results: under the condition of liquid chromatography, the separation degree between the active substance and the impurity B and between the AL-5-B and the AL-5 is less than 1.2, and the active substance and the impurity B cannot be effectively separated, so that the condition is unfavorable.
Example 10
Preparation of mixed control solutions: same as in example 7.
The mixed control sample solution was taken and injected into a liquid chromatograph, the measurement was performed under the following chromatographic conditions, the chromatogram was recorded, and the measurement was completed, and the detection results are shown in table 8.
Chromatographic conditions: the difference from example 7 is that the triethylamine content in mobile phase A is 0.1%.
Table 8: example 10 results of detection of mixed control solutions
Test results: under the condition of liquid chromatography, the tailing of the impurity A, B, C and the active substance is serious, the active substance and the impurity B cannot be effectively separated, and the condition is unfavorable.
Example 11
Preparation of mixed control solutions: same as in example 7.
The mixed control sample solution was taken and injected into a liquid chromatograph, and the measurement was performed under the following chromatographic conditions, and the chromatogram was recorded, and the measurement was completed, and the detection results are shown in table 9.
Chromatographic conditions: the difference from example 7 is that the triethylamine content in mobile phase A is 0.2%.
Table 9: EXAMPLE 11 mixing of results of detection of control solutions
Test results: under the liquid chromatography condition, the peak types of the impurity A and the impurity B meet the standard, but the tailing of the active substance and the impurity C is serious, the active substance and the impurity B cannot be effectively separated, and the condition is unfavorable.
Example 12
Preparation of mixed control solutions: same as in example 7.
The mixed control sample solution was taken and injected into a liquid chromatograph, the measurement was performed under the following chromatographic conditions, the chromatogram was recorded, and the measurement was completed, and the detection results are shown in table 10.
Chromatographic conditions: the difference from example 7 is that the triethylamine content in mobile phase A is 1.5%.
Table 10: example 12 detection results of mixed control solutions
Test results: under the condition of liquid chromatography, active substances and AL-2 have serious tailing, active substances and impurity B cannot be effectively separated, and the condition is unfavorable.
Example 13
Preparation of mixed control solutions: the difference from example 7 is that the diluents are: a mixed solution of mobile phase A and mobile phase B in a volume ratio of 60:40.
Chromatographic conditions: an octyl silane bonded silica gel chromatographic column; mobile phase a: an aqueous solution containing 0.1mol/L phosphate, 1% sodium hexanesulfonate and 0.3% triethylamine, and adjusting the pH to 3.5 with phosphoric acid; mobile phase B: acetonitrile; flow rate: 0.5ml/min; the detection wavelength is 230nm; sample injection amount is 20 μl; column temperature: 20 ℃; gradient elution conditions:
test results: under the condition of liquid chromatography, all impurities and main peaks can be completely separated, and the separation degree among all the impurities is good, so that the method is more suitable.
Example 14
Preparation of a mixed control: the difference from example 7 is that the diluents are: a mixed solution of mobile phase A and mobile phase B in a volume ratio of 95:5.
Chromatographic conditions: an octyl silane bonded silica gel chromatographic column; mobile phase a: an aqueous solution containing 0.001mol/L acetate, 0.01% sodium pentanesulfonate and 0.6% diethylamine, and adjusting the pH to 2.5 with acetic acid; mobile phase B: acetonitrile and methanol in equal volume; flow rate: 2ml/min; the detection wavelength is 220nm; sample injection amount is 100 μl; column temperature: 50 ℃; gradient elution conditions:
test results: under the condition of liquid chromatography, all impurities and main peaks can be completely separated, and baseline separation can be achieved between all the impurities.
Example 15
Preparation of a mixed control: the difference from example 7 is that the diluents are: a mixed solution of mobile phase A and mobile phase B in a volume ratio of 75:25;
chromatographic conditions: an octyl silane bonded silica gel chromatographic column; mobile phase a: an aqueous solution containing 0.05mol/L phosphate and 0.4% of a mixture of sodium heptanesulfonate and sodium hexanesulfonate (mass ratio of 2:1) and 1% triethylamine, and adjusting the pH to 3 with phosphoric acid; mobile phase B: methanol; flow rate: 0.5ml/min; detection wavelength 280nm; the sample injection amount is 50 μl; column temperature: 40 ℃; gradient elution conditions:
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test results: under the condition of liquid chromatography, all impurities and main peaks can be completely separated, and baseline separation can be achieved between all the impurities.
Example 16
Preparation of a mixed control: the difference from example 7 is that the diluents are: a mixed solution of mobile phase A and mobile phase B in a volume ratio of 75:25;
chromatographic conditions: an octyl silane bonded silica gel chromatographic column; mobile phase a: an aqueous solution containing 0.05mol/L phosphate, 0.5% sodium heptanesulfonate and 0.5% triethylamine, and adjusting the pH to 3 with phosphoric acid; mobile phase B: acetonitrile; flow rate: 1ml/min; the detection wavelength is 230nm; the sample injection amount is 30 μl; column temperature: 35 ℃; gradient elution conditions:
test results: under the condition of liquid chromatography, all impurities and main peaks can be completely separated, and baseline separation can be achieved between all the impurities.
The above examples are only one of the preferred embodiments of the present application for detecting olopatadine hydrochloride related substances, but should not be construed as the detection method provided by the present application can only detect the above related substances, but all the technical problems solved by the present application are still consistent with the present application, and are included in the scope of protection of the present application even though the present application has no substantial modification or color change in the spirit and concept of the main body design.
Claims (1)
1. A method for separating and determining olopatadine hydrochloride related substances by using HPLC, comprising the following steps: adopting an octyl silane bonded silica gel chromatographic column; mobile phase a was an aqueous solution containing 0.1mol/L phosphate, 0.2% sodium heptanesulfonate and 0.4% triethylamine, and the pH was adjusted to 3 with phosphoric acid; mobile phase B is acetonitrile; the detection wavelength is 240nm; the flow rate is 1.0ml/min; the sample injection amount is 30 μl; the column temperature is 35 ℃; detecting related substances of olopatadine hydrochloride by an ultraviolet detector in a gradient elution mode;
the gradient elution procedure was:
The olopatadine hydrochloride related substances comprise AL-2, AL-3, AL-4, AL-5-A, AL-5-B, phosphorus tribenzoxide, impurity A, impurity B and impurity C, wherein the chemical structural formulas of the AL-2, the AL-3, the AL-4, the AL-5-A, AL-5-B, the phosphorus tribenzoxide, the impurity A, the impurity B and the impurity C are respectively as follows:
。
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| CN114646705A (en) * | 2022-03-22 | 2022-06-21 | 武汉绿合医药科技有限公司 | Method for detecting content of related substances in diquafosol sodium eye drops |
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