CN114778745B - Method for detecting Lobrazil intermediate and enantiomer impurities thereof by high performance liquid chromatography - Google Patents
Method for detecting Lobrazil intermediate and enantiomer impurities thereof by high performance liquid chromatography Download PDFInfo
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Abstract
The invention relates to a method for detecting an ambroxen intermediate and enantiomer impurities thereof by high performance liquid chromatography, wherein a chromatographic column of the method is xylonite IE 250 x 4.6mm, 5 mu m or xylonite IC 250 x 4.6mm, 5 mu m; the mobile phase and the proportion are n-hexane: ethanol: 85 (0-15) and 0-15 of isopropanol; the detection wavelength is 205-230 nm; the column temperature is 20-30 ℃; the flow rate of the mobile phase is 0.5-1.5 ml/min; the method for detecting the Lobrazil intermediate and the enantiomer impurity thereof by the high performance liquid chromatography provided by the invention can realize that the separation degree R of the Lobrazil intermediate main component and the enantiomer impurity thereof is more than or equal to 2.0, the content RSD of the enantiomer impurity measured by 6 parts of test solution is less than or equal to 2.0%, the repeatability is good, the durability of the method is good, and the method can be used for quality control of the Lobrazil intermediate.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for detecting an ambroxen intermediate and enantiomer impurities thereof by using a high performance liquid chromatography.
Background
Lombarey (Lemborexant) is a drug developed by Weizier R & D management Co., Ltd for the treatment of insomnia, the pharmacological mechanism of action of which is a dual orexin OX1R and OX2R receptor inhibitor, for the treatment of difficulty in falling asleep or maintaining sleep, and orexin receptor antagonists are considered by academia as having a function of suppressing arousal without disturbing external arousal stimuli, as compared with conventional hypnotics.
Methyl ((1R,2S) -2- (3-fluorophenyl) -2- ((tosyloxy) methyl) cyclopropyl) acetate is a preparative intermediate for ranbrazil, and has the following structural formula:
patent CN104114524B describes a method for analyzing impurities of the intermediate and its enantiomer, but the method has poor separation of main component and enantiomer, and the use of a coating type chromatographic column has poor tolerance, which cannot satisfy the reaction monitoring (part of the reaction liquid sample may damage the chromatographic column). At present, no other literature reports about the analysis method of the preparation intermediate of the ranbrazier and the enantiomer impurities thereof. The structural formula of the enantiomer impurity of the preparation intermediate of the Lobrazil is as follows:
disclosure of Invention
The invention provides a method for detecting an Lunebutide intermediate and enantiomer impurities thereof by using a high performance liquid chromatography.
The technical scheme adopted by the invention is as follows:
a method for detecting impurities of a structure shown in a formula (I) and an enantiomer thereof by high performance liquid chromatography, wherein the structure shown in the formula (I) is as follows:
the method is characterized in that:
1) chromatographic conditions are as follows: the chromatographic column is of Daluosite IE 250 x 4.6mm, 5 μm or Daluosite IC 250 x 4.6mm, 5 μm; the mobile phase and the proportion are n-hexane: ethanol: (ii) 85 (0-15) and 0-15% of isopropyl alcohol; the detection wavelength is 205-230 nm; the column temperature is 20-30 ℃; the flow rate of the mobile phase is 0.5-1.5 mL/min;
2) preparing a test solution: dissolving a sample by using isopropanol, and diluting by using normal hexane;
3) and (3) determination: precisely measuring the test solution, injecting into a liquid chromatograph, and recording the chromatogram.
The chromatographic column of the method is xylonite IE 250 x 4.6mm, 5 μm;
the chromatographic column of the method is xylonite IC 250 x 4.6mm, 5 μm;
according to the method, the ratio of normal hexane to ethanol of the mobile phase is 85: 15.
according to the method, the ratio of n-hexane to ethanol to isopropanol of a mobile phase is 85: 10: 5.
the ratio of the normal hexane to the ethanol to the isopropanol of the mobile phase in the method is 85: 5: 10.
the ratio of the normal hexane to the isopropanol of the mobile phase in the method is 85: 15.
the detection wavelength of the method is 205nm, 210nm, 220nm or 230 nm.
The column temperature of the method is 20 ℃, 25 ℃ or 30 ℃.
The flow rate of the mobile phase in the method is 0.5mL/min, 1.0mL/min or 1.5 mL/min.
The concentration of the test sample in the method is 0.5-2 mg/ml.
The concentration of the test sample in the method is 0.5mg/ml, 1mg/ml, 1.5mg/ml or 2 mg/ml.
The separation degree is used for evaluating the separation degree between a substance to be detected and a substance to be separated, is a key index for measuring the separation efficiency of a chromatographic system, and is represented by R, wherein R is equal to the ratio of the retention time difference of adjacent chromatographic peaks to the width-average value of the two chromatographic peaks. A larger R indicates a better separation of two adjacent components. Generally, when R < 1.0, the peaks overlap partially, the degree of separation can reach 98% when R is 1.0, and 99.7% when R is 1.5.
The method for detecting the ranbrazier intermediate and the enantiomer impurity thereof by using the high performance liquid chromatography provided by the invention can realize that the separation degree R of the ranbrazier intermediate and the enantiomer impurity thereof is more than or equal to 2.0, the content RSD of the enantiomer impurity measured by 6 parts of test solution is less than or equal to 2.0%, the repeatability is good, the durability of the method is good, and the method can be used for quality control of the ranbrazier intermediate.
The range of any numerical range includes the end points and any intermediate values. Such as 0.5-1.5 including 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, etc.
Drawings
FIG. 1 example 2 method specificity experiment-location of formula (I)
FIG. 2 example 2 method specificity experiments-enantiomeric impurity localization of formula (I)
FIG. 3 example 2 method specificity experiment-System applicability solution
Detailed Description
Example 1: screening of chromatographic conditions
The chromatographic conditions are determined by screening through chromatographic columns, mobile phases, wavelengths, flow rates, and the like.
Example 1-a
And (3) chromatographic column: xylonite AD-H250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 25 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, isopropanol 90: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: referring to the prior patent method (CN104114524B), the solvent is dissolved by isopropanol, and the main component is poorly separated from the enantiomer.
Example 1 b
A chromatographic column: xylonite OD-H250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 25 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, isopropanol 90: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: by replacing the OD-H column with that of example 1-a, there was no improvement in the separation of the main component from the enantiomer.
Examples 1 to c
A chromatographic column: xylonite AS-H250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 25 ℃; sample injection amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, ethanol 70: 30, isocratic elution for 0min and 60 min;
and (4) conclusion: the ASH column was used instead of example 1-a, the main component and the enantiomer were not separated,
the peak pattern is also poor.
Examples 1 d
A chromatographic column: xylonite IC 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample injection amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, ethanol 70: 30, eluting according to isocratic of 0min and 60 min;
and (4) conclusion: the IC column was replaced on the basis of example 1-c, and the main component was substantially separated from the enantiomer with a degree of separation of 1.8.
Examples 1 to e
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample injection amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, ethanol is 70: 30, isocratic elution for 0min and 60 min;
and (4) conclusion: the IE column was used instead of example 1-d, and the degree of separation of the main component from the enantiomer was 1.88.
Example 1-f
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, ethanol, isopropanol 70: 20: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: on the basis of the example 1-e, isopropanol is added into ethanol, the separation of the main component and the enantiomer is improved, the separation degree is 2.58, and the adjacent position behind the main peak is suspected to be wrapped by impurities.
Example 1-g
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.5 mL/min;
the mobile phase is n-hexane, ethanol 85: 15, isocratic elution is carried out for 0min and 60 min;
and (4) conclusion: the ethanol ratio was reduced on the basis of example 1-e, with a main component having an enantiomeric separation of 2.37, without interference before and after, but with a late peak.
Examples 1-h
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.8 mL/min;
the mobile phase is n-hexane, ethanol 85: 15, isocratic elution for 0min and 60 min;
and (4) conclusion: the flow rate was increased on the basis of example 1-g, the main component and the enantiomer appeared to be well peaked, and the degree of separation was 2.21.
Example 1-I
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 210 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 0.8 mL/min;
n-hexane, ethanol, isopropanol 85: 5: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: on the basis of example 1-h, isopropanol was added to ethanol to improve the separation of the main component from the enantiomer with a degree of separation of 2.88.
Example 1-j
A chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 1.0 mL/min;
n-hexane, ethanol, isopropanol 85: 5: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: the flow rate was increased on the basis of example 1-i, the main component and the enantiomer appeared to be suitable, with no interference before and after, and the degree of separation was 2.74.
Example 1-k
A chromatographic column: xylonite ID 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 1.0 mL/min;
n-hexane, ethanol, isopropanol 85: 5: 10, isocratic elution for 0min and 60 min;
and (4) conclusion: the ID column was replaced on the basis of example 1-j, and the main component and the enantiomer were not separated.
Example 2: method specificity
Step 1, preparation of a mobile phase:
precisely measuring 850ml of n-hexane, 50ml of ethanol and 100ml of isopropanol, uniformly mixing, and carrying out ultrasonic treatment for later use.
[ step 2 ] solution preparation:
dissolving the sample of the ranbrazil intermediate and the enantiomer of the ranbrazil intermediate in normal hexane respectively by isopropanol to dilute the sample and prepare a test solution with the concentration of 1.0mg/mL, a self-control solution with the concentration of 0.01mg/mL and a system applicability solution containing the ranbrazil intermediate with the concentration of 1.0mg/mL and the enantiomer of 0.01 mg/mL.
The chromatographic conditions were as follows:
a chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 30 ℃; sample introduction amount: 10 mu L of the solution; flow rate: 1.0 mL/min;
n-hexane, ethanol, isopropanol 85: 5: 10, isocratic elution for 0min and 60 min;
as a result: retention time of the structure of formula (I): 22.31 min; enantiomeric impurity retention times of formula (I): 24.30 min;
the method can realize the complete separation of the impurities of the formula (I) and the enantiomer thereof, and has good specificity.
Example 3: repeatability test
Taking 6 parts of test solution, carrying out continuous sample injection, and recording a chromatogram map, wherein the result is as follows:
(1) retention time of the erbitux enantiomer: 24.370 min; peak area: 2.2237, respectively; content of enantiomer: 0.48 percent;
(2) retention time of the erbitux enantiomer: 24.377 min; peak area: 2.2497, respectively; content of enantiomer: 0.46 percent;
(3) retention time of the erbitux enantiomer: 24.370 min; peak area: 2.2676, respectively; content of enantiomer: 0.48 percent;
(4) retention time of the erbitux enantiomer: 24.380 min; peak area: 2.2056, respectively; content of enantiomer: 0.46 percent;
(5) retention time of the erbitux enantiomer: 24.387 min; peak area: 2.2368, respectively; content of enantiomer: 0.47%;
(6) retention time of the erbitux enantiomer: 24.373 min; peak area: 2.2754, respectively; content of enantiomer: 0.48 percent;
the results of the repeatability experiments show that: 6 parts of test solution is continuously injected, the retention time RSD of the main component and the enantiomer is less than 2.0 percent, the content RSD of the enantiomer is less than 2.0 percent, and the repeatability of the experimental method is good.
Example 4: durability test
By adjusting the flow rate, mobile phase ratio, column temperature, wavelength, etc. of the chromatographic conditions, the degree of tolerance of the measurement results not affected is determined.
Example 4-a durability test at different flow rates
The chromatographic conditions were as follows:
a chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 25 ℃; sample introduction amount: 10 mu L of the solution; the flow rate is 0.5-1.5 mL/min;
n-hexane, ethanol, isopropanol 85: 10: 5, isocratic elution is carried out for 0min and 60 min;
the results are as follows:
(1) the flow rate is 0.5mL/min, and the resolution is 3.20;
(2) the flow rate was 1.0mL/min and the degree of separation was 2.72;
(3) the flow rate is 1.5mL/min, and the resolution is 2.41;
durability test results for different flow rates show: the testing method changes at the flow rate of 0.5-1.5 mL/min, has little influence on the testing result, and shows that the method has good durability.
Example 4-b durability test with different mobile phase ratios
The chromatographic conditions were as follows:
a chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 25 ℃; sample introduction amount: 10 mu L of the solution; the flow rate is 1 mL/min;
n-hexane, ethanol, isopropanol (0-15) and (0-15), and eluting at an isocratic rate of 0min and 60 min;
the results are as follows:
(1) n-hexane, ethanol 85: 15, degree of separation of 2.09;
(2) n-hexane, ethanol, isopropanol 85: 10: 5, degree of separation of 2.72;
(3) n-hexane, ethanol, isopropanol 85: 5: 10, degree of separation 3.78;
(4) n-hexane isopropanol 85: 15, degree of separation of 4.78;
the results of the tests for different initial proportions of mobile phase of durability show that: the proportion of the mobile phase in the test method is changed from 85 (0-15) to 0-15, the influence on the test result is small, and the method is good in durability.
Example 4-c durability test at different column temperatures
The chromatographic conditions were as follows:
a chromatographic column: xylonite IE 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 20-30 ℃; sample introduction amount: 10 mu L of the solution; the flow rate is 1 mL/min;
n-hexane, ethanol, isopropanol 85: 10: 5, isocratic elution is carried out for 0min and 60 min;
the results are as follows:
(1) the column temperature was 20 ℃ and the degree of separation was 2.90;
(2) the column temperature was 25 ℃ and the degree of separation was 2.72;
(3) the column temperature was 30 ℃ and the degree of separation was 2.55;
the test results of different column temperatures of durability show that: the testing method changes at the column temperature of 20-30 ℃, has little influence on the testing result, and shows that the method has good durability.
Example 4-d durability test for different detection wavelengths
The chromatographic conditions were as follows:
and (3) chromatographic column: xylonite IE 250 × 4.6mm, 5 μm;
detection wavelength: 205-230 nm; column temperature: 25 ℃; sample injection amount: 10 mu L of the solution; the flow rate is 1 mL/min;
n-hexane, ethanol, isopropanol 85: 10: 5, isocratic elution is carried out for 0min and 60 min;
the results are as follows:
(1) the detection wavelength is 205nm, and the resolution is 2.46;
(2) the detection wavelength is 210nm, and the separation degree is 2.74;
(3) the detection wavelength is 220nm, and the separation degree is 2.72;
(4) the detection wavelength is 230nm, and the separation degree is 2.72;
the test results of different detection wavelengths of durability show that: the test method changes between detection wavelengths 205-230 nm, has little influence on the measurement result, and shows that the method has good durability.
Example 4-e durability test for different chromatography columns
The chromatographic conditions were as follows:
and (3) chromatographic column: cellosolve IE 250 x 4.6mm, 5 μm or cellosolve IC 250 x 4.6mm, 5 μm;
detection wavelength: 220 nm; column temperature: 25 ℃; sample introduction amount: 10 mu L of the solution; the flow rate is 1.0 mL/min;
n-hexane, ethanol, isopropanol 85: 10: 5, isocratic elution is carried out for 0min and 60 min;
the results are as follows:
(1) the chromatographic column was of greater xylonite IE 250 x 4.6mm, 5 μm, with a resolution of 2.72;
(2) the chromatographic column is of xylonite IC 250 x 4.6mm, 5 μm, and the separation degree is 2.43;
durability test results for different types of columns show: the chromatographic column of the test method is an IE column or an IC column, and the influence on the test result is little, which shows that the method has good durability.
Claims (9)
1. A method for detecting impurities of a structure shown in a formula (I) and an enantiomer thereof by high performance liquid chromatography, wherein the structure shown in the formula (I) is as follows:
the method is characterized in that:
1) chromatographic conditions are as follows: the chromatographic column is of Daluosite IE 250 x 4.6mm, 5 μm or Daluosite IC 250 x 4.6mm, 5 μm; the mobile phase and the proportion are n-hexane: ethanol: (ii) 85 (0-15) and 0-15% of isopropyl alcohol; the detection wavelength is 205-230 nm; the column temperature is 20-30 ℃; the flow rate of the mobile phase is 0.5-1.5 mL/min;
2) preparing a test solution: dissolving a sample by using isopropanol, and diluting by using normal hexane;
3) and (3) determination: precisely measuring the test solution, injecting into a liquid chromatograph, and recording the chromatogram.
2. The method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the ratio of the mobile phase n-hexane to the ethanol is 85: 15.
3. the method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the ratio of the n-hexane to the ethanol to the isopropanol of the mobile phase is 85: 10: 5.
4. the method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the ratio of the mobile phase n-hexane to the ethyl alcohol to the isopropyl alcohol is 85: 5: 10.
5. the method for detecting the impurities of the structure of formula (I) and the enantiomers thereof by high performance liquid chromatography according to claim 1, wherein: the ratio of the mobile phase n-hexane to the isopropanol is 85: 15.
6. the method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the detection wavelength is 205nm, 210nm, 220nm or 230 nm.
7. The method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the column temperature is 20 ℃, 25 ℃ or 30 ℃.
8. The method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the flow rate is 0.5mL/min, 1.0mL/min, or 1.5 mL/min.
9. The method for detecting the impurities of the structure (I) and the enantiomer thereof according to claim 1, wherein: the concentration of the test sample is 0.5-2 mg/ml.
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| CN104114524A (en) * | 2012-02-17 | 2014-10-22 | 卫材R&D管理有限公司 | Methods and compounds useful in the synthesis of orexin-2 receptor antagonists |
| CN111220727A (en) * | 2020-01-17 | 2020-06-02 | 北京鑫开元医药科技有限公司海南分公司 | Method for detecting enantiomer in ivabradine hydrochloride intermediate and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114524A (en) * | 2012-02-17 | 2014-10-22 | 卫材R&D管理有限公司 | Methods and compounds useful in the synthesis of orexin-2 receptor antagonists |
| CN111220727A (en) * | 2020-01-17 | 2020-06-02 | 北京鑫开元医药科技有限公司海南分公司 | Method for detecting enantiomer in ivabradine hydrochloride intermediate and application |
Non-Patent Citations (2)
| Title |
|---|
| Establishment of a simultaneous assay for lemborexant, a novel dualorexin receptor antagonist, and its three metabolites, and itsapplication to a clinical protein binding study;Yuji Mano等;《Journal of Pharmaceutical and Biomedical Analysis》;20201231;第187卷;全文 * |
| HPLC法测定盐酸伊伐布雷定及其片剂中有关物质;杨晓莉等;《中国药事》;20110520(第05期);全文 * |
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