CN107917972A - A kind of method of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate - Google Patents
A kind of method of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate Download PDFInfo
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Abstract
The invention belongs to Pharmaceutical Analysis technical field, is related to a kind of method of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate.It is 35 ~ 40 DEG C that the method for separating and detecting of the present invention, which is used with octadecylsilane chemically bonded silica packed column, chromatographic column column temperature, and Composition distribution, phosphate buffer solution is eluted with acetonitrile and methanol mixed solution.Simple, quickly and accurately separation detection Austria shellfish cholic acid and its synthetic intermediate are realized, the separation detection containing Austria's shellfish cholic acid raw material and preparation is solved the problems, such as, ensures that shellfish cholic acid difficult to understand and composition or the quality controllability of preparation containing shellfish cholic acid difficult to understand.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical field, is related in a kind of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthesis
The method of mesosome.
Background technology
Shellfish cholic acid category farnesoid X receptor activator difficult to understand, by activating farnesoid X receptor, suppresses cytochromes 7A1 indirectly
(CYP7A1) gene expression.Since CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, shellfish cholic acid difficult to understand can suppress cholic acid
Synthesis, for treating primary biliary cirrhosis and non-alcohol fatty liver.Shellfish cholic acid difficult to understand is by U.S. Intercept
Pharmaceuticals, Inc. are researched and developed successfully, in May, 2014, and U.S. FDA authorizes the shellfish courage difficult to understand of Intercept drugmakers
Sour quick examination ＆ approval passage identification.Shellfish cholic acid difficult to understand is that first research and development are used for the medicine for treating cholestatic liver disease over 20 years, at the same time
And medicine of FDA ratifies over 20 years the 2nd for treating primary biliary cirrhosis；Shellfish cholic acid molecules formula difficult to understand is
C26H44O4, chemical entitled 6 α-ethyl-3 α, 7 α-dihydroxy-5 β-cholan-24-oic acid, structural formula are：
Pass through multiple steps in the synthesis technique of shellfish cholic acid difficult to understand, it is pure that the intermediate materials of these steps can influence shellfish cholic acid raw material difficult to understand
Degree, these intermediate impurities are remained in the feed, so as to influence the quality and security of medicine.Therefore, control shellfish cholic acid difficult to understand miscellaneous
The content of matter, the quality to improving shellfish cholic acid raw material and preparation difficult to understand, ensures that the drug safety of many patients is of great significance.
Intermediate 1
Intermediate 2
Intermediate 3
Intermediate 4
Intermediate 1, intermediate 2, intermediate 3,4 impurity of intermediate can be produced in shellfish cholic acid building-up process difficult to understand（Structure such as above formula）.
Patent CN201710001220 protects the detection method in relation to material in a kind of shellfish cholic acid difficult to understand and its preparation, using efficient liquid phase
Chromatography, uses C18 columns；Diode array detector, column temperature：20 DEG C~30 DEG C；It is molten with mixture of acetonitrile-phosphate buffer-methanol
Liquid carries out isocratic elution for mobile phase.But the data branch that its impurity and product be able to can be effectively separated in this method
Hold.Austria's shellfish cholic acid there is no unified quality standard at present, in order to preferably control the quality of shellfish cholic acid bulk pharmaceutical chemicals difficult to understand, establish a set of
It is very necessary to efficiently separate detection method.
The content of the invention
For the above situation, the present invention is intended to provide a kind of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate
Method.Analysis shellfish cholic acid difficult to understand and the intermediate impurities of building-up process can simply, quickly and accurately be separated by this method,
Preparation process and finished product quality control available for shellfish cholic acid difficult to understand.
Specifically, the present invention adopts the following technical scheme that：
A kind of method of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate, it is characterised in that：Sample Austria shellfish cholic acid
Concentration be 1 ~ 5mg/ml;Mobile phase is phosphate buffer solution and the mixed solution of acetonitrile and methanol, the phosphate-buffered
Solution is 0.005mol/L ~ 0.02mol/L phosphate aqueous solutions, and the phosphate is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphoric acid
Sodium dihydrogen, disodium hydrogen phosphate, the flowing are that the volume ratio of phosphate buffer solution, acetonitrile and methanol is that phosphate-buffered is molten
Liquid：Acetonitrile：Methanol=（20~30）：（50~60）：（10~20）(v:v:v)；Chromatographic column is to be made with octadecylsilane chemically bonded silica
For the chromatographic column of filler, chromatographic column column temperature is 35 ~ 40 DEG C；Detector is Composition distribution, and the temperature of detector is 35 ~ 40
℃。
Above-mentioned method for separating and detecting can be implemented as follows：
1）Take the sample comprising shellfish cholic acid difficult to understand and intermediate appropriate, with flowing phased soln, be configured to the sample that concentration is 1 ~ 5mg/ml
Product solution；
2）Mobile phase is prepared, mobile phase is that the volume ratio of phosphate buffer solution, acetonitrile and methanol is phosphate buffer solution：Second
Nitrile：Methanol=（20~30）：（50~60）：（10~20）(v:v:v)；
3）Setting flow rate of mobile phase is 0.8 ~ 1.0ml/min, and using C18 columns, chromatographic column column temperature is 35 ~ 40 DEG C, Composition distribution,
Detector temperature is 35 ~ 40 DEG C；
4）Take step 1）50 ~ 100 μ l of sample solution of middle preparation, inject high performance liquid chromatograph, record chromatogram, return by area
One, which changes method, calculates, and theoretical cam curve presses shellfish cholic acid difficult to understand and calculates >=2000, main peak purity >=95%, it is maximum it is single it is miscellaneous≤2.0%, shellfish courage difficult to understand
It is sour to answer >=1.5 with each intermediate separating degree, complete separation detection process.
Yin Aobei cholic acid and its intermediate UV absorption intensity are low, and existing impurity may be can't detect using UV detector.
The present invention uses Composition distribution, defects inspecting high sensitivity, being capable of effectively Analyze ＆ separate Austria shellfish cholic acid and its synthetic mesophase
Body；Selective flow phased soln sample, it is ensured that the stability of solution.By optimize flow rate of mobile phase, chromatographic column column temperature and into
The parameters such as sample volume, improve the symmetry of chromatographic peak.The present invention solves the problems, such as the separation detection containing shellfish cholic acid raw material difficult to understand,
Ensure that shellfish cholic acid difficult to understand and composition or the quality controllability of preparation containing shellfish cholic acid difficult to understand.
Brief description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of shellfish cholic acid and its intermediate reference substance difficult to understand under the conditions of embodiment 1.
Fig. 2 is the HPLC collection of illustrative plates of shellfish cholic acid and its intermediate reference substance difficult to understand under the conditions of embodiment 2.
Fig. 3 is the HPLC collection of illustrative plates of the shellfish cholic acid difficult to understand independently synthesized under the conditions of embodiment 2.
Fig. 4 is the HPLC collection of illustrative plates of shellfish cholic acid and its intermediate reference substance difficult to understand under the conditions of embodiment 3.
Fig. 5 is the HPLC collection of illustrative plates of the shellfish cholic acid difficult to understand independently synthesized under the conditions of embodiment 3.
Embodiment
The technical solution in the present invention is made below in conjunction with specific embodiments further elucidated above.Unless otherwise saying
Bright, reagent, material and instrument used in the following example can be obtained by routine business means.
Embodiment 1：
Instrument and condition：
High performance liquid chromatograph：High performance liquid chromatograph（Agilent 1260）；
Chromatographic column：Thermo Syncronis C18 columns（250mm × 4.6mm, 5 μm）；
Mobile phase：0.01mol/L potassium dihydrogen phosphates：Acetonitrile：Methanol=30：55：15(v:v:v)；
Flow velocity：1.0ml/min；
Column temperature：35℃；
Detector temperature：35℃；
Sampling volume：100μl.
Implementation steps：
Weigh shellfish cholic acid 300mg difficult to understand, 1mg is put in 100ml measuring bottles each intermediate respectively, with flowing phased soln, dilute constant volume, as
Test solution.Above-mentioned 100 μ l of solution injections liquid chromatograph is measured, chromatogram is recorded, as a result such as Fig. 1.By area normalization
Method calculates, and theoretical cam curve presses shellfish cholic acid difficult to understand and calculates >=2000, main peak purity >=95%, it is maximum it is single it is miscellaneous≤2.0%, shellfish cholic acid difficult to understand with
Each intermediate separating degree answers >=1.5.
As shown in Figure 1, the retention time of intermediate 1 is 8.727min, and the retention time of intermediate 3 is 11.551min, in
The retention time of mesosome 4 is 14.067, and the retention time of intermediate 2 is 20.290min, and the retention time of shellfish cholic acid difficult to understand is
24.027min, adjacent peak separating degree are followed successively by 7.98,6.15,11.64,5.21.
Embodiment 2：
Instrument and condition：
High performance liquid chromatograph：High performance liquid chromatograph（Agilent 1260）；
Chromatographic column：Thermo Syncronis C18 columns（250mm × 4.6mm, 5 μm）；
Mobile phase：0.005mol/L potassium dihydrogen phosphates：Acetonitrile：Methanol=30：55：15(v:v:v)；
Flow velocity：1.0ml/min；
Column temperature：35℃；
Detector temperature：35℃；
Sampling volume：100μl.
Implementation steps：Weigh shellfish cholic acid 300mg difficult to understand, 1mg is put in 100ml measuring bottles each intermediate respectively, with flowing phased soln,
Constant volume is diluted, as test solution.Above-mentioned 100 μ l of solution injections liquid chromatograph is measured, chromatogram is recorded, as a result such as Fig. 2.
Weigh the shellfish cholic acid 300mg difficult to understand independently synthesized to be placed in 100ml measuring bottles, with flowing phased soln, dilute constant volume, it is molten as test sample
Liquid.Above-mentioned 100 μ l of solution injections liquid chromatograph is measured, chromatogram is recorded, as a result such as Fig. 3.Calculate, manage by area normalization method
Press shellfish cholic acid difficult to understand by the number of plates and calculate >=2000, main peak purity >=95%, it is maximum it is single it is miscellaneous≤2.0%, shellfish cholic acid difficult to understand and each intermediate
Separating degree answers >=1.5.
As shown in Figure 2, the retention time of intermediate 1 is 8.715min, and the retention time of intermediate 3 is 11.545min, in
The retention time of mesosome 4 is 14.048, and the retention time of intermediate 2 is 20.280min, and the retention time of shellfish cholic acid difficult to understand is
23.549min, adjacent peak separating degree are followed successively by 7.48,5.96,11.76,3.29.
From the figure 3, it may be seen that the material that retention time is 8.724min is intermediate 1, retention time is that 10.943min is unknown
Impurity 1, the material that retention time is 11.554min are intermediates 3, and retention time is that the material of 12.619min is unknown impuritie
2, the material that retention time is 20.353min is intermediate 2, and retention time is that the material of 24.199min is shellfish cholic acid difficult to understand, adjacent
Peak separating degree is followed successively by 6.39,1.66,2.76,15.39,5.67.
Embodiment 3：
Instrument and condition：
High performance liquid chromatograph：High performance liquid chromatograph（Agilent 1260）；
Chromatographic column：Thermo Syncronis C18 columns（250mm × 4.6mm, 5 μm）；
Mobile phase：0.005mol/L sodium dihydrogen phosphates：Acetonitrile：Methanol=25：57：18(v:v:v)；
Flow velocity：1.0ml/min；
Column temperature：40℃；
Detector temperature：40℃；
Sampling volume：80μl.
Implementation steps：Weigh shellfish cholic acid 300mg difficult to understand, 1mg is put in 100ml measuring bottles each intermediate respectively, with flowing phased soln,
Constant volume is diluted, as test solution.Above-mentioned 80 μ l of solution injections liquid chromatograph is measured, chromatogram is recorded, as a result such as Fig. 4.
Weigh the shellfish cholic acid 300mg difficult to understand independently synthesized to be placed in 100ml measuring bottles, with flowing phased soln, dilute constant volume, it is molten as test sample
Liquid.Above-mentioned 80 μ l of solution injections liquid chromatograph is measured, chromatogram is recorded, as a result such as Fig. 5.Calculate, manage by area normalization method
Press shellfish cholic acid difficult to understand by the number of plates and calculate >=2000, main peak purity >=95%, it is maximum it is single it is miscellaneous≤2.0%, shellfish cholic acid difficult to understand and each intermediate
Separating degree answers >=1.5.
As shown in Figure 4, the retention time of intermediate 1 is 7.860min, and the retention time of intermediate 3 is 9.540min, in
The retention time of mesosome 4 is 10.993, and the retention time of intermediate 2 is 14.974min, and the retention time of shellfish cholic acid difficult to understand is
17.129min, adjacent peak separating degree are followed successively by 4.25,3.29,7.16,3.15.
As shown in Figure 5, retention time is that the material of 7.742min is intermediate 1, and retention time is the material of 9.365min
It is intermediate 3, the material that retention time is 10.695min is intermediate 4, and retention time is that the material of 13.299min is unknown
Impurity 1, the material that retention time is 14.608min are intermediates 2, and retention time is that the material of 16.671min is shellfish cholic acid difficult to understand,
Adjacent peak separating degree is followed successively by 4.36,2.62,4.46,2.25,3.11.
Claims (5)
1. a kind of method of efficient liquid phase chromatographic analysis Austria shellfish cholic acid and its synthetic intermediate, it is characterised in that：Sample Austria shellfish courage
The concentration of acid is 1 ~ 5mg/ml;Mobile phase is phosphate buffer solution and the mixed solution of acetonitrile and methanol；Chromatographic column is with ten
Chromatographic column of the eight alkyl silane bonded silica gels as filler, chromatographic column column temperature are 35 ~ 40 DEG C；Detector is Composition distribution.
2. the method for analysis Austria's shellfish cholic acid according to claim 1 and its synthetic intermediate, it is characterised in that：The phosphoric acid
Salt buffer solution is 0.005mol/L ~ 0.02mol/L phosphate aqueous solutions；The phosphate is potassium dihydrogen phosphate, phosphoric acid hydrogen two
Potassium, sodium dihydrogen phosphate, disodium hydrogen phosphate.
3. the method for analysis Austria's shellfish cholic acid according to claim 1 and its synthetic intermediate, it is characterised in that：The flowing
The volume ratio for being mutually phosphate buffer solution, acetonitrile and methanol is phosphate buffer solution：Acetonitrile：Methanol=（20~30）：（50~
60）：（10~20）(v:v:v).
4. the method for analysis Austria's shellfish cholic acid according to claim 1 and its synthetic intermediate, it is characterised in that：The detection
The temperature of device is 35 ~ 40 DEG C.
5. the method for analysis Austria's shellfish cholic acid according to claim 1 and its synthetic intermediate, it is characterised in that：
Comprise the following steps：
（1）Take the sample comprising shellfish cholic acid difficult to understand appropriate, with flowing phased soln, be configured to the sample solution that concentration is 1 ~ 5mg/ml；
（2）Mobile phase is prepared, mobile phase is that the volume ratio of phosphate buffer solution, acetonitrile and methanol is phosphate buffer solution：
Acetonitrile：Methanol=（20~30）：（50~60）：（10~20）(v:v:v)；
（3）Setting flow rate of mobile phase is 0.8 ~ 1.0ml/min, and using C18 columns, chromatographic column column temperature is 35 ~ 40 DEG C, differential detection
Device, detector temperature are 35 ~ 40 DEG C；
（4）Take step（1）50 ~ 100 μ l of sample solution of middle preparation, inject high performance liquid chromatograph, chromatogram are recorded, by area
Normalization method calculates, and theoretical cam curve presses shellfish cholic acid calculating >=2000 difficult to understand, main peak purity >=95%, maximum single miscellaneous≤2.0%, Ao Bei
Cholic acid answers >=1.5 with each intermediate separating degree.
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Cited By (5)
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| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN109187779A (en) * | 2018-08-29 | 2019-01-11 | 四川百特芳华医药科技有限公司 | A kind of analysis method of steroidal compounds |
| CN109655571A (en) * | 2019-01-08 | 2019-04-19 | 丽珠集团新北江制药股份有限公司 | A kind of HPLC analytical method of Austria's shellfish cholic acid |
| CN110208398A (en) * | 2019-05-17 | 2019-09-06 | 湖南华腾制药有限公司 | The analyzing detecting method of glycocholic acid polyethyleneglycol derivative |
| CN114236027A (en) * | 2021-12-22 | 2022-03-25 | 中山百灵生物技术股份有限公司 | Method for detecting (E) -6-ethylidene-3 alpha-hydroxy-7-keto-5 beta-cholestane-24-acid |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108680696A (en) * | 2018-05-15 | 2018-10-19 | 南京正大天晴制药有限公司 | A kind of detection method of Austria's shellfish cholic acid starting material |
| CN108680696B (en) * | 2018-05-15 | 2020-06-30 | 南京正大天晴制药有限公司 | Detection method of obeticholic acid starting material |
| CN109187779A (en) * | 2018-08-29 | 2019-01-11 | 四川百特芳华医药科技有限公司 | A kind of analysis method of steroidal compounds |
| CN109655571A (en) * | 2019-01-08 | 2019-04-19 | 丽珠集团新北江制药股份有限公司 | A kind of HPLC analytical method of Austria's shellfish cholic acid |
| CN109655571B (en) * | 2019-01-08 | 2021-07-13 | 丽珠集团新北江制药股份有限公司 | High performance liquid chromatography analysis method of obeticholic acid |
| CN110208398A (en) * | 2019-05-17 | 2019-09-06 | 湖南华腾制药有限公司 | The analyzing detecting method of glycocholic acid polyethyleneglycol derivative |
| CN110208398B (en) * | 2019-05-17 | 2022-01-04 | 湖南华腾制药有限公司 | Analytical detection method of glycocholic acid polyethylene glycol derivative |
| CN114236027A (en) * | 2021-12-22 | 2022-03-25 | 中山百灵生物技术股份有限公司 | Method for detecting (E) -6-ethylidene-3 alpha-hydroxy-7-keto-5 beta-cholestane-24-acid |
| CN114236027B (en) * | 2021-12-22 | 2024-01-12 | 中山百灵生物技术股份有限公司 | Detection method of (E) -6-ethylene-3 alpha-hydroxy-7-keto-5 beta-cholestane-24-acid |
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Denomination of invention: A method for analyzing obecholic acid and its synthetic intermediates by high performance liquid chromatography Effective date of registration: 20211124 Granted publication date: 20200811 Pledgee: China Construction Bank Corporation Nanjing Zhongyangmen sub branch Pledgor: SKYRUN PHARMA Co.,Ltd. Registration number: Y2021980013111 |
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