CN116223701B - Optimization method for detecting chromatographic peak type by using cabot Wei Yexiang - Google Patents
Optimization method for detecting chromatographic peak type by using cabot Wei Yexiang Download PDFInfo
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- CN116223701B CN116223701B CN202211636863.9A CN202211636863A CN116223701B CN 116223701 B CN116223701 B CN 116223701B CN 202211636863 A CN202211636863 A CN 202211636863A CN 116223701 B CN116223701 B CN 116223701B
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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- G—PHYSICS
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- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
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Abstract
The invention provides a method for optimizing detection chromatographic peak type of cabot Wei Yexiang, which comprises the following steps of: the method is characterized in that an aqueous solution of citric acid is used as a mobile phase A, a mixed solution of acetonitrile and methanol is used as a mobile phase B, the detection wavelength is 254nm, the column temperature is 40 ℃, the flow rate is 1.0mL/min, the sample injection amount is 10 mu L, and the mixed solution of EDTA-2Na and acetonitrile is used as a diluent. Therefore, the complex between the cabozagrel molecules and the metal ions can be effectively improved, and the peak tailing problem of cabozagrel in the high-performance liquid chromatography analysis method can be improved.
Description
Technical Field
The invention relates to the technical field of substance detection methods, in particular to a liquid phase detection method of cabozagrel, and specifically relates to a chromatographic peak type optimization method of cabozagrel Wei Yexiang detection.
Background
Cabozavir (GSK 1265744) is an analog of the integrase chain transfer inhibitor (instri) dolutegravir (dolutegradvir), which exhibits sub-nanomolar potency and antiviral activity against a broad range of HIV-1 strains. Once daily oral cabot Wei Biao exhibits acceptable safety and tolerability profiles, long half-life (40 h) and few drug-drug interactions. Rilpivirine (TMC 278) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved as a once daily oral drug for HIV-1 treatment. Briefly, cabozavir is a type 1 human immunodeficiency virus (HIV-1) integrase chain transfer inhibitor (INSTI) that has been demonstrated to be useful in combination with other antiretroviral drugs for the treatment of HIV-1 infections. Moreover, if the virus is not resistant to the inhibitor, it would be planned to co-administer cabazithromycin or the like to adults who, despite their current receipt of antiretroviral therapy and integrase chain transfer inhibitors, have no detectable levels of human immunodeficiency virus in their blood. Therefore, further research into cabozavir is necessary.
As shown in FIG. 1, cabot Wei Hua is known under the name (3S, 11 AR) -N- [ (2, 4-difluorophenyl) methyl ] -2,3,5,7,11,11A-hexahydro-6-hydroxy-3-methyl-5, 7-dioxooxazolo [3,2-A ] pyrido [1,2-D ] pyrazine-8-carboxamide. As can be seen from the chemical structural formula of cabozagrel, the carbonyl groups at the 5-position and the 7-position of the cabozagrel molecule and the oxygen atom in the hydroxyl group at the adjacent 6-position contain lone pair electrons, which are easy to form complexation with metal ions in a chromatographic column, so that repeated retention is avoided, further peak type abnormality is caused, and the detection of cabozagrel related substances and content is quite unfavorable.
In the prior art, vejendla A et al, vejendla A, talari S, moturu R, et al method development and validation for Cabotegravir and Rilpivirine by using HPLC and its degradants are characterized by LCMS and FTIR [ J ]. Future Journal of Pharmaceutical Sciences,2021,7 (1) liquid phase detection of cabozavir was performed using UPLC detection. Wherein, UPLC detection chromatographic conditions include: the chromatographic column model and specification are as follows: UPLC BEH phenyl1.7 μm,150mm×2.1mm, flow rate 0.36ml/min; (2) Mobile phase a was a 10mM ammonium formate solution (adjusted to ph=3.5 with formic acid); (3) The mobile phase B is acetonitrile, gradient elution is carried out, the sample injection amount is 3 mu L, the column temperature is 22 ℃, and the detection wavelength is 258nm.
However, this method of detection of cabot Wei Yexiang is not suitable for conventional HPLC detection and does not solve the problem of cabot Wei Feng type tailing.
In view of the above, we have invented a method for optimizing the detection chromatographic peak pattern of cabot Wei Yexiang.
Disclosure of Invention
The invention aims to provide a method for optimizing the detection chromatographic peak type of cabot Wei Yexiang, which takes citric acid solution as a mobile phase and EDTA as an additive in a diluent, can effectively improve the complexation between cabot molecules and metal ions, and can improve the peak type tailing problem of cabot in a high performance liquid chromatography analysis method.
In order to achieve the above purpose, the present invention proposes the following technical scheme:
the optimization method for detecting chromatographic peak type of cabot Wei Yexiang comprises a liquid chromatograph, wherein the chromatographic conditions are as follows:
octadecylsilane chemically bonded silica column with a specification of 150mm×4.6mm,2.7 μm;
gradient elution is adopted;
the mobile phase A is 40-60mmol/L citric acid solution, and the pH of the mobile phase A is regulated to 3.3-3.7 by ammonia water;
the mobile phase B is a mixed solution of acetonitrile and methanol;
a suitable amount of diluent;
the detection wavelength is 254nm;
column temperature is 40 ℃;
the flow rate was 1.0mL/min, and the sample injection amount was 10. Mu.L.
In addition to the above, and as a preferred embodiment of the above, the liquid chromatograph is a Agilent infinity II1260DAD high performance liquid chromatograph.
Based on the scheme and as a preferable scheme of the scheme, the volume ratio of acetonitrile and methanol of the mobile phase B is 1-4:1, and acetonitrile and methanol are uniformly mixed according to a fixed volume ratio to be used as the mobile phase B.
On the basis of the scheme and as a preferable scheme of the scheme, the diluent is EDTA-2Na and acetonitrile mixed solution.
On the basis of the scheme and as a preferable scheme of the scheme, the diluent is prepared by taking EDTA-2Na and acetonitrile as solutes and ultrapure water as a solution.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
the invention discloses a method for optimizing the detection chromatographic peak type of cabot Wei Yexiang, which takes citric acid as a mobile phase A, acetonitrile and methanol mixed solution as a mobile phase B, the detection wavelength is 254nm, the column temperature is 40 ℃, the flow rate is 1.0mL/min, the sample injection amount is 10mL, EDTA-2Na and acetonitrile mixed solution diluent, so that the complexation between cabot molecules and metal ions can be effectively improved, and the peak type tailing problem of cabot in the high performance liquid chromatography analysis method can be improved.
It should be understood that all combinations of the foregoing concepts, as well as additional concepts described in more detail below, may be considered a part of the subject disclosure, provided that such concepts are not mutually inconsistent.
The foregoing and other aspects, embodiments, and features of the teachings of the present invention will be more fully understood from the following description. Other additional aspects of the invention, such as features and/or advantages of the exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of the embodiments according to the teachings of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a structural formula of cabot Wei Huaxue;
FIG. 2 is a chromatogram of the cabot Wei Yexiang of the present invention;
FIG. 3 is a chromatogram of a comparative example, cabobot Wei Yexiang;
FIG. 4 is a chromatogram of a comparative example dicarboxbert Wei Yexiang;
FIG. 5 is a chromatogram of a comparative example tricobaot Wei Yexiang;
FIG. 6 is a chromatogram of comparative example four cabobot Wei Yexiang;
FIG. 7 is a chromatogram of comparative example pentacabobot Wei Yexiang;
fig. 8 is a graph of the linear relationship between different concentrations of cabozagrel and peak areas.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The terms "first," "second," and the like in the description and in the claims, are not used for any order, quantity, or importance, but are used for distinguishing between different elements. Also, unless the context clearly indicates otherwise, singular forms "a," "an," or "the" and similar terms do not denote a limitation of quantity, but rather denote the presence of at least one. The terms "comprises," "comprising," or the like are intended to cover a feature, integer, step, operation, element, and/or component recited as being present in the element or article that "comprises" or "comprising" does not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. "up", "down", "left", "right" and the like are used only to indicate a relative positional relationship, and when the absolute position of the object to be described is changed, the relative positional relationship may be changed accordingly.
As shown in fig. 1, according to the structural formula of cabot Wei Huaxue:
the carbonyl groups at the 5 th and 7 th positions of the cabot-West molecule and the oxygen atom in the hydroxyl group at the adjacent 6 th position contain lone pair electrons, so that complexation with metal ions in a chromatographic column is extremely easy to form, no repeated retention is generated, and peak type abnormality is caused.
In the use of a chromatograph, chromatographic conditions generally include mobile phase, chromatographic column, detection wavelength, flow rate and sample injection amount. The mobile phase is related to water and reagent solutions used to prepare the mobile phase, the water generally requires ultrapure water or other water having a resistivity of no more than 18.2 megaohms, and the reagent solutions require chromatography levels because of the prevention of interference of impurities in the water and reagent solutions with the chromatographic results. The chromatographic columns have different requirements due to different varieties, each chromatographic column has the cleaning requirement, and the unreasonable operation can cause the decline of the chromatographic column effect and the shortened service life of the chromatographic column. The detection wavelength of the chromatograph may also have different requirements according to different varieties, and it should be noted that the observation of the change of the energy of the deuterium lamp of the detector, such as large baseline fluctuation, abrupt decrease of the response value of the active ingredient, etc., may be caused by the insufficient energy of the deuterium lamp, and the deuterium lamp generally suggests 800 hours for use, but the actual use time is longer and can be replaced according to the actual situation. The flow rate also varies depending on the type, and is generally 1.0ml/min.
Under the condition of meeting the operating conditions of a general chromatograph, the invention adopts citric acid as inorganic salt in the mobile phase A, and the citric acid can be used as a metal chelating agent to be combined with free metal ions on a chromatographic column sieve plate and a wall, so that the cabot-tevir is not involved in a complexation step as much as possible, and is reserved only on a chromatographic column stationary phase, thereby improving tailing, and then the mixture of EDTA-2Na aqueous solution and acetonitrile is used as the mobile phase, thereby further ensuring that the metal ions are not complexed with cabot-tevir molecules.
Specifically, the invention discloses a method for optimizing the detection chromatographic peak type of cabot Wei Yexiang, which comprises the following steps of:
octadecylsilane chemically bonded silica column with a specification of 150mm×4.6mm,2.7 μm;
gradient elution is adopted;
the mobile phase A is 40-60mmol/L citric acid solution, and the pH of the mobile phase A is regulated to 3.3-3.7 by ammonia water;
the mobile phase B is a mixed solution of acetonitrile and methanol;
a suitable amount of diluent;
the detection wavelength is 254nm;
column temperature is 40 ℃;
the flow rate was 1.0mL/min, and the sample injection amount was 10. Mu.L.
In the examples and comparative examples of the present invention, sample solution preparation and detection were performed as follows, unless otherwise specified:
test solution: 20mg of cabozagrel is weighed, placed in a 100mL volumetric flask, dissolved by a diluent, fixed in volume to a scale and shaken well.
Example 1
Using a Agilent infinity II1260DAD high performance liquid chromatograph, chromatographic conditions: using octadecylsilane chemically bonded silica gel chromatographic column with specification of 150mm×4.6mm,2.7 μm, gradient eluting with 50mmol/L citric acid solution as mobile phase A, and regulating pH of mobile phase A to 3.5 with ammonia water; the mobile phase B is acetonitrile and methanol which are uniformly mixed according to the volume ratio of 2:1, the detection wavelength is 254nm, the column temperature is 40 ℃, the flow rate is 1.0mL/min, and the sample injection amount is 10 mu L. Gradient elution conditions were as follows:
in this example, the diluent was prepared by weighing 3.362g of EDTA-2Na, pouring it into 1L of ultrapure water, then adding 1L of acetonitrile thereto, and uniformly mixing.
The test solutions were then tested according to chromatographic conditions and the results are shown in figure 2.
Comparative example 1
Unlike example 1 above, mobile phase a had citric acid solution as the inorganic salt solution portion, and no EDTA-2Na was added to the diluent. Wherein mobile phase a was a 10mM citric acid solution as the inorganic salt solution fraction and was adjusted to ph=3.5 with aqueous ammonia. The test results are shown in FIG. 3.
Comparative example 2
Unlike example 1 described above, mobile phase a had formic acid solution as the inorganic salt solution portion, specifically 0.1% formic acid solution as the inorganic salt solution portion in the mobile phase. The test results are shown in FIG. 4.
Comparative example 3
Unlike example 1 described above, mobile phase a had ammonium formate solution as the inorganic salt solution portion, specifically 10mM ammonium formate as the inorganic salt solution portion in mobile phase a. The test results are shown in FIG. 5.
Comparative example 4
Unlike example 1 described above, mobile phase A had ammonium formate solution as the inorganic salt solution portion, specifically 10mM ammonium formate solution as the inorganic salt solution portion of mobile phase A. Further, the test conditions are different from those of example 1, specifically, the detection is performed by using ultra-high-performance liquid chromatography, and the chromatographic conditions are as follows: the chromatographic column is UPLC BEH Phenyl1.7 μm,150mm×2.1mm; mobile phase a was 10mM ammonium formate solution (ph=3.5 adjusted with formic acid), mobile phase B was acetonitrile, gradient eluted, detection wavelength 258nm, column temperature 22 ℃, flow rate 0.36mL/min, and sample injection amount 3 μl. The test results are shown in FIG. 6.
Comparative example 5
Unlike example 1 described above, mobile phase a had trifluoroacetic acid solution as the inorganic salt solution portion, specifically trifluoroacetic acid as the inorganic salt solution portion of mobile phase a, and triethylamine was added to adjust the pH to 3.5. The test results are shown in FIG. 7.
Further, the cabozavir is weighed to prepare linear solutions with various concentrations, and the linear solutions are prepared respectively: the 0.5mg/mL, 0.25mg/mL, 50. Mu.g/mL, 5. Mu.g/mL, 0.25. Mu.g/mL, 0.1. Mu.g/mL of cabozagrel solution was sampled and examined under the chromatographic conditions of example 1, and the peak areas of the corresponding chromatograms were calculated to obtain the relationship between the peak areas and the linear concentrations, as shown in FIG. 8.
According to the analysis results shown in fig. 2 to 8, citric acid is used as an inorganic salt in the mobile phase A, and the inorganic salt can be used as a metal chelating agent to be combined with free metal ions on a chromatographic column sieve plate and a wall, so that the cabot-tevir is kept on a chromatographic column stationary phase as far as possible without participating in a complexation step, the tailing is improved, and a mixture of EDTA-2Na aqueous solution and acetonitrile is used as the mobile phase, so that the metal ions are further ensured not to be complexed with cabot-tevir molecules. Practice proves that the complexing between the cabazitaxel molecules and metal ions can be effectively improved by taking citric acid solution as a mobile phase and EDTA-2Na as a diluent additive, and the peak tailing problem of cabazitaxel in a high performance liquid chromatography analysis method is improved.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, all technical solutions which can be obtained by logic analysis, reasoning or limited experiments based on the prior art by the person skilled in the art according to the inventive concept shall be within the scope of protection defined by the claims.
Claims (3)
1. The optimization method for detecting the chromatographic peak type by the cabot Wei Yexiang comprises a liquid chromatograph and is characterized by comprising the following steps of:
octadecylsilane chemically bonded silica column with a specification of 150mm×4.6mm,2.7 μm;
gradient elution is adopted;
gradient elution conditions were as follows:
The mobile phase A is 40-60mmol/L citric acid solution, and the pH of the mobile phase A is regulated to 3.3-3.7 by ammonia water;
the mobile phase B is a mixed solution of acetonitrile and methanol;
a suitable amount of diluent;
the detection wavelength is 254nm;
column temperature is 40 ℃;
the flow rate is 1.0mL/min, and the sample injection amount is 10 mu L;
the volume ratio of acetonitrile to methanol of the mobile phase B is 1-4:1, and acetonitrile and methanol are uniformly mixed according to a fixed volume ratio to be used as the mobile phase B;
the diluent is mixed solution of EDTA-2Na and acetonitrile.
2. The optimization method of detection chromatographic peak type of cabot Wei Yexiang according to claim 1, wherein the liquid chromatograph is an AgilentinfinityII1260DAD high performance liquid chromatograph.
3. The optimization method for detecting chromatographic peaks of cabot Wei Yexiang according to claim 2, wherein the diluent is prepared by using EDTA-2Na and acetonitrile as solutes and ultrapure water as solvents.
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| CN114994205A (en) * | 2022-05-30 | 2022-09-02 | 上海奥科达生物医药科技有限公司 | Method for detecting related impurities in deferasirox granules |
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| CN114994205A (en) * | 2022-05-30 | 2022-09-02 | 上海奥科达生物医药科技有限公司 | Method for detecting related impurities in deferasirox granules |
Non-Patent Citations (4)
| Title |
|---|
| A Validated Stability Indicating RP-HPLC Method Development for Simultaneous estimation of Cabotegravir and Rilpivirine in Pharmaceutical Dosage form;Anugu Prasanna等;World Journal of Pharmaceutical Sciences;第10卷(第10期);22-29 * |
| Anugu Prasanna等.A Validated Stability Indicating RP-HPLC Method Development for Simultaneous estimation of Cabotegravir and Rilpivirine in Pharmaceutical Dosage form.World Journal of Pharmaceutical Sciences.2022,第10卷(第10期),22-29. * |
| Method Development And Validation For The Simultaneous Estimation Of Cabotegravir And Rilpivirine In Bulk And Pharmaceutical Dosage Form And Stability Studies By Uplc;Mohammed Azeemuddin等;UGC CARE Listed ( Group -I) Journal;2385-2391 * |
| 彭银仙主编.工业分析.哈尔滨工程大学出版社,2014,42. * |
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