CN114295750A - Method for detecting related substances in ursodeoxycholic acid synthesis - Google Patents
Method for detecting related substances in ursodeoxycholic acid synthesis Download PDFInfo
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Abstract
The invention provides a method for detecting related substances in ursodeoxycholic acid synthesis, which adopts high performance liquid chromatography to detect and analyze 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurity 1. The method can accurately detect the known impurity 1, and the main peak of the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid can be effectively separated from the peak of the known impurity 1, so that the method is a brand-new detection and analysis method which is beneficial to the quality control of the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid. The method has the advantages of high sensitivity, wide linear range, good specificity and repeatability and simple and convenient operation.
Description
Technical Field
The invention relates to the technical field of drug detection and analysis, in particular to a method for detecting related substances in ursodeoxycholic acid synthesis.
Background
3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid is a raw material or intermediate frequently used in chemical synthesis, is also an intermediate in the synthesis process of ursodeoxycholic acid, and has a molecular formula of C32H56O4Si with molecular weight of 532.88 and structural formula
In the preparation of the above intermediates, the following impurities are produced in addition to the target compound:
impurity 1: (Z) -3 alpha-tert-butyldimethylsilyloxy-6-ethylene-7-carbonyl-5 beta-cholestane-24-oic acid
The analysis and detection of the intermediate and the impurities play an important role in controlling the synthesis reaction of the ursodeoxycholic acid and improving the yield, and simultaneously directly influence the quality of the final ursodeoxycholic acid product. However, no relevant literature reports an analysis and detection method for the intermediate and the impurities, and the intermediate and the impurities have similar structures, so that it is necessary to establish an analysis and detection method which is simple to operate, stable and effective to analyze and detect the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and the impurities.
Disclosure of Invention
The invention aims to provide a method for detecting related substances in ursodeoxycholic acid synthesis, which can effectively separate various impurities and has the advantages of high detection sensitivity, wide linear range, and good specificity and repeatability.
The invention provides the following technical scheme:
a method for detecting related substances in ursodeoxycholic acid synthesis is characterized in that liquid chromatography is adopted to detect and analyze 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and/or impurities; adopting a chromatographic column with octyl silane bonded silica gel as a filler, taking a phosphoric acid solution as a mobile phase A and a lower alkyl alcohol solution as a mobile phase B, and carrying out isocratic elution.
Preferably, the lower alkyl alcohol solution is a mixed solution of methanol and isopropanol.
In some embodiments, a method for detecting a substance of interest in ursodeoxycholic acid synthesis, comprising the steps of:
(1) injecting the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid sample solution into a chromatograph;
(2) carrying out high performance liquid chromatography detection on the test solution: adopting a chromatographic column with octyl silane bonded silica gel as a filler, wherein the column temperature is 20-40 ℃, a phosphoric acid solution is taken as a mobile phase A, a methanol-isopropanol mixed solution is taken as a mobile phase B, the detection wavelength is 237-241 nm, and the flow rate is 0.5-1.5 ml/min, and performing isocratic elution;
(3) recording a chromatogram, and calculating the content of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurities by adopting a peak area normalization method.
Wherein the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid has the following structure:
the impurity is impurity 1, and the structure is as follows:
in some embodiments, the volume fraction of mobile phase B at isocratic elution is maintained between 80% and 85% with a run time of 30 min.
In some preferred embodiments, the volume fraction of mobile phase B at isocratic elution is maintained at 83%; the running time was 30 min.
In some embodiments, the mobile phase a phosphoric acid solution has a concentration of 0.1%; the volume ratio of methanol to isopropanol in the mobile phase B is 7: 3-9: 1.
In some preferred embodiments, the mobile phase a phosphoric acid solution has a concentration of 0.1%; the volume ratio of methanol to isopropanol in the mobile phase B was 8: 2.
In some embodiments, the detector for liquid chromatography is a diode array detector, the column temperature is 20 ℃ to 40 ℃, and the detection wavelength is 237nm to 241 nm. Preferably, the column temperature is 25 ℃ to 35 ℃ and the detection wavelength is 237nm to 241 nm.
In some preferred embodiments, the column temperature is 30 ℃ and the detection wavelength is 239 nm.
In some embodiments, the flow rate of the mobile phase is 0.5ml/min to 1.5ml/min and the sample size is 10. mu.l. Preferably, the flow rate is between 0.6ml/min and 1.0 ml/min. More preferably, the flow rate of the mobile phase is 0.8 ml/min.
In some embodiments, the detection method further comprises a test solution formulation: taking a 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid test sample, dissolving and diluting the test sample by using a diluent to obtain a test sample solution, wherein the diluent is methanol. In some other embodiments, the diluent may be any other suitable solvent. In some preferred embodiments, the 3 α -tert-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid is present in an amount of 10mg to 30mg per 1ml of the test solution.
In some embodiments, the detection method further comprises system suitability solution formulation: taking a 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid reference substance and an impurity 1 reference substance, dissolving and diluting the reference substances by using a diluent to prepare a system applicability solution. In some preferred embodiments, 3 α -tert-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid is present in an amount of 10mg to 30mg and impurity 1 is present in an amount of 10 μ g to 30 μ g per 1ml of system suitability solution.
In some embodiments, impurity 1 content is no greater than 0.3%.
In some embodiments, the column is an Ascentis Express C8 column, 4.6mm by 150mm in specification, 2.7 μm in packing size, and 10 μ l in sample size.
Has the advantages that:
the chromatographic column with the octyl silane bonded silica gel as the filler has strong retention capacity on sample components and good peak shape. The method has strong specificity: the blank solution has no interference to the detection; the separation degree between the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and adjacent impure bees is far more than 1.5. In a repeatability test, the retention time and the purity of a main peak have no obvious change; RSD values are all lower than 3%, and repeatability is good. The method has a good linear relationship: the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid has a concentration range of 0.435 mu g/ml to 3.837 mu g/ml, a regression equation of y 6.1994x +0.1537, a correlation coefficient r of 0.9999 (not less than 0.990) and an intercept deviation of 0.82% (less than 2%). The detection limit (signal to noise ratio 3:1) of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurities is as low as 0.109 mu g/ml; the limit of quantitation for 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and impurities (signal to noise ratio 10:1) is as low as 0.435. mu.g/ml. When the proportion of a mobile phase, the column temperature, the detection wavelength and the flow rate in a chromatographic condition are slightly changed, the separation degree of impurities and a main peak is far more than 1.5, and the change is not too large, so that the method has good durability. In the actual sample detection test, the separation degree of the main peak and the impurity peak meets the requirement, the method is simple and convenient to operate and short in analysis time, and the detection of the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid sample and the impurities can be realized.
Drawings
FIG. 1 is a high performance liquid chromatogram of an air-white solution in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of a solution with system applicability in example 1 of the present invention, which sequentially comprises the following steps in order of appearance time: 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid, impurity 1;
FIG. 3 is a high performance liquid chromatogram of a test solution in example 5 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be described in detail below. Unless otherwise indicated, reagents, materials and equipment used in the following examples are all available by conventional commercial means.
Example 1 specificity test
The instrument comprises the following steps: thermo Ulitimate 3000 high performance liquid chromatograph, Diode Array Detector (DAD)
A chromatographic column: ascentis expressC84.6 x 150mm, 2.7 μm
Column temperature: 30 deg.C
Mobile phase A: 0.1% H3PO4Aqueous solution
Mobile phase B: methanol: isopropyl alcohol 8:2
Volume ratio of mobile phase: phase A-phase B (17:83)
Detection wavelength: 239nm
Flow rate: 0.8ml/min
Sample introduction amount: 10 μ l
Operating time: 30min
Diluent (blank solution): methanol.
Preparation of impurity positioning solution: respectively taking a proper amount of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and an impurity 1 reference substance, precisely weighing, respectively adding methanol to dissolve and dilute, and preparing into solutions with the contents of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurity 1 of about 10mg and 30 mu g in each 1ml, wherein the solutions are respectively used as a 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid positioning solution and an impurity 1 positioning solution.
System applicability solution formulation: taking 3 alpha-tert-butyl dimethylAppropriate amounts of siloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid reference substance and impurity 1 reference substance are precisely weighed, dissolved and diluted by adding methanol to prepare a solution with the content of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid of about 10mg and the impurity 1 of about 30 mu g in each 1ml, and the solution is used as a system applicability solution.
The methanol used in the preparation process is a diluent, and the methanol can be replaced by any other suitable solvent according to the situation.
And (3) sample determination: respectively measuring 10 mul of blank solution, 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid positioning solution, impurity 1 positioning solution and system applicability solution, respectively injecting into a liquid chromatograph, and recording chromatogram. The blank solution chromatogram is shown in FIG. 1, and the system suitability solution chromatogram is shown in FIG. 2. The retention times and degrees of separation of the compounds are shown in Table 2.
TABLE 23 results of specificity tests for alpha-t-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and impurities
And (4) conclusion: the blank solution has no interference to the detection; the separation degree between the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and the impurity 1 peak is more than 1.5, which meets the requirement, so the method has strong specificity.
Example 2: repeatability test
Preparation of test solution: taking a proper amount of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid to be tested, precisely weighing, dissolving with methanol, diluting, and preparing a solution containing about 10mg of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid in each 1ml as a test solution.
6 parts of a solution of 3 α -t-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid having a concentration of 10mg/ml was prepared in parallel as a test solution according to the procedure for preparing the test solution. The reproducibility of the quantitative measurement of the sample was examined under the chromatographic conditions of example 1, and the results are shown in Table 3.
TABLE 33 repeatability test results for alpha-t-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and impurities
| Sample (I) | Time of main peak | Purity of main peak | Content of |
| 1 | 13.653 | 99.83％ | 0.09％ |
| 2 | 13.645 | 99.82％ | 0.09％ |
| 3 | 13.662 | 99.84％ | 0.08％ |
| 4 | 13.612 | 99.83％ | 0.09％ |
| 5 | 13.628 | 99.81％ | 0.09％ |
| 6 | 13.973 | 99.82％ | 0.09％ |
| Mean value of | 13.370 | 99.83％ | 0.09％ |
| RSD | 1.29％ | 0.01％ | 4.62％ |
As can be seen from the data in Table 3, the retention time and purity of the main peak are not significantly changed, and the RSD% value is far lower than 5%, which meets the requirement, so the repeatability is good.
Example 3: linear test
An appropriate amount of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid reference substance was weighed precisely, dissolved in methanol and diluted to obtain solutions having relative concentrations of 0.05%, 0.06%, 0.15%, 0.24%, 0.3% and 0.45% of the concentrations (10mg/ml) of the test solutions of example 2, i.e., 0.435. mu.g/ml, 0.512. mu.g/ml, 1.279. mu.g/ml, 2.047. mu.g/ml, 2.558. mu.g/ml and 3.837. mu.g/ml, respectively, of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid. The prepared solutions were injected into a liquid chromatograph under the chromatographic conditions of example 1, and the respective chromatograms were recorded. The concentration is used as the abscissa and the peak area is used as the ordinate, and a curve is drawn. The results are shown in Table 4.
TABLE 43 results of a Linear test for alpha-t-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid
As is clear from the data in Table 4, the 3. alpha. -t-butyldimethylsilyloxy-6. beta. -ethyl-7-carbonyl-5. beta. -cholestane-24-oic acid had a good linearity because the correlation coefficient r was not less than 0.990 and the intercept deviation was less than 2% in the concentration range of 0.435. mu.g/ml to 3.837. mu.g/ml.
Example 4: limit of detection and limit of quantification test
Taking a proper amount of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid reference substance and each impurity reference substance, precisely weighing, dissolving with methanol and gradually diluting. Samples are respectively injected according to the chromatographic conditions of example 1, and the sample concentration at the signal-to-noise ratio of 3:1 is the detection limit concentration. The results are as follows: the detection limit of the impurity 1 is 0.154 mu g/ml, and the detection limit of the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid is 0.149 mu g/ml.
Taking a proper amount of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid reference substance and each impurity reference substance, precisely weighing, dissolving with methanol and gradually diluting. Samples were injected according to the chromatographic conditions of example 1, and the sample concentration at a signal-to-noise ratio of 10:1 was the quantitative limit concentration. The results are as follows: the limit of quantitation of impurity 1 is 0.412. mu.g/ml, and the limit of quantitation of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid is 0.435. mu.g/ml.
Under the detection limit of as low as 0.149 mu g/ml and the quantitative limit of as low as 0.435 mu g/ml, the 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurities can be well detected, and the reaction control and the yield improvement of the subsequent ursodeoxycholic acid synthesis are facilitated.
Example 5: durability test
The system suitability solution was prepared following the procedure for system suitability solution preparation in example 1. On the basis of the chromatographic conditions of example 1, the initial volume fraction of the organic phase in the mobile phase, the column temperature, the detection wavelength and the flow rate were each subjected to a small change, and the above-described system-applicable solution was subjected to chromatographic analysis. Other unchanged chromatographic conditions and procedures were determined for the separation of 3 α -t-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid and impurities in the system-compatible solution, respectively, with reference to example 1, in order to examine the durability of the detection method. The chromatographic conditions and the results of the detection are shown in Table 5.
TABLE 53 durability test results for alpha-t-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and impurities
As can be seen from the data in Table 5, the above minor changes were made to the chromatographic conditions, such as an organic phase volume fraction of 80% to 85%; the column temperature is 20-40 ℃; the volume fraction of the isopropanol is 30-10 percent; the flow rate is 0.6ml/min to 1.0ml/min, even 0.5ml/min to 1.5 ml/min; when the detection wavelength is 237 nm-241 nm, the separation degree of the main peak and the impurity peak is far more than 1.5, which meets the requirement, so the method has good durability.
Example 6: actual sample detection
A sample solution having a 3 α -t-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid concentration of 20mg/ml was prepared according to the procedure for the preparation of the sample solution in example 2. A sample solution (5. mu.l) was precisely measured and injected into a liquid chromatograph, and the sample solution was subjected to chromatographic analysis under the chromatographic conditions of example 1. 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid and impurities were calculated by peak area normalization. The results are shown in Table 6 and the spectra are shown in FIG. 3.
TABLE 63 results of detection of alpha-t-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-oic acid samples
And (4) conclusion: the actual sample detection result shows that the separation degree of the main peak and the impurity peak is far more than 1.5, which meets the requirement; the method can detect known impurities and realize the detection of 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid samples and impurities.
It is obvious to the person skilled in the art that the invention is not restricted to the details of the above-described exemplary embodiments; and that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (10)
1. A method for detecting related substances in ursodeoxycholic acid synthesis is characterized in that 3 alpha-tert-butyldimethylsilyloxy-6 beta-ethyl-7-carbonyl-5 beta-cholestane-24-acid and impurities are detected and analyzed by adopting a liquid chromatography, and isocratic elution is carried out by adopting a chromatographic column with octyl silane bonded silica gel as a filler and a phosphoric acid solution as a mobile phase A and a lower alkyl alcohol solution as a mobile phase B.
2. The method of detecting according to claim 1, wherein the 3 α -tert-butyldimethylsilyloxy-6 β -ethyl-7-carbonyl-5 β -cholestane-24-oic acid has a structure of:
the impurities are impurities 1:
3. the detection method according to claim 1, wherein the volume fraction of mobile phase B in isocratic elution is maintained at 80% to 85% and the run is carried out for 30 minutes.
4. The detection method according to claim 1, wherein the lower alkyl alcohol solution is a mixed solution of methanol and isopropanol.
5. The detection method according to claim 2, wherein the concentration of the mobile phase A phosphoric acid solution is 0.1-0.5%; the volume ratio of methanol to isopropanol in the mobile phase B is 7: 3-9: 1.
6. The detection method according to claim 2, wherein the concentration of the mobile phase A phosphoric acid solution is 0.1%; the volume ratio of methanol to isopropanol in the mobile phase B is 8: 2.
7. The detection method according to claim 1, wherein the detector for liquid chromatography is a diode array detector, the detection wavelength is 237nm to 241nm, and the column temperature of the chromatography is 20 ℃ to 40 ℃.
8. The detection method according to claim 6, wherein the detection wavelength is 239nm and the column temperature of the chromatographic column is 30 ℃.
9. The detection method according to claim 1, wherein the flow rate of the mobile phase is 0.5ml/min to 1.5 ml/min.
10. The detection method according to claim 1, wherein the volume fraction of the mobile phase B in isocratic elution is maintained at 83%, and the mobile phase is run for 30 minutes at a flow rate of 0.8 ml/min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105294801A (en) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | Method for synthesizing, separating and determining obeticholic acid (OCA) isomer |
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
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| CN105294801A (en) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | Method for synthesizing, separating and determining obeticholic acid (OCA) isomer |
| CN107674107A (en) * | 2017-09-30 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of process for purification of shellfish cholic acid difficult to understand |
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