CN110824027A - Detection method for separating tenofovir alafenamide and enantiomer thereof - Google Patents
Detection method for separating tenofovir alafenamide and enantiomer thereof Download PDFInfo
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- CN110824027A CN110824027A CN201810915820.1A CN201810915820A CN110824027A CN 110824027 A CN110824027 A CN 110824027A CN 201810915820 A CN201810915820 A CN 201810915820A CN 110824027 A CN110824027 A CN 110824027A
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Abstract
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a detection method for separating tenofovir alafenamide and enantiomers thereof. The method comprises the following steps: performing high performance liquid chromatography, using polysaccharide derivative chiral chromatographic column, using n-hexane-isopropanol as mobile phase, adding alkaline reagent to adjust peak shape, and performing isocratic elution under certain conditions. The invention can effectively separate tenofovir alafenamide and enantiomer thereof, and can more accurately detect the content of the enantiomer. The method adopts a normal phase method, isocratic elution is adopted, the operation is simple and easy, the peak shape is good, and the separation degree is qualified; the methodological verification shows that the method has strong specificity, high sensitivity, good accuracy and good durability.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a high performance liquid chromatography for detecting tenofovir alafenamide enantiomer.
Background
Tenofovir alafenamide: the chemical name is (((S) - ((((((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphoryl) amino) - (S) -isopropyl propionate, the molecular formula is C21H29O5N6P, molecular weight 476.47, its chemical formula is:
enantiomers: the chemical name is ((R) - (((S) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) methyl) (phenoxy) phosphorusAcyl) amino) - (R) -isopropyl propionate of formula C21H29O5N6P, molecular weight 476.47, its chemical formula is:
hepatitis B is an epidemic infectious disease with high morbidity, strong infectivity and serious harm to human health, and China is a high incidence area. According to the seroepidemiological survey of Hepatitis B Virus (HBV) infected people in 2002, the prevalence of HBsAg is 9.09%, i.e., about 1.2 million people carry HBV, and among them, about 3000 or more million patients with chronic hepatitis B. More than 30 million people die of hepatitis B related complications every year in China, wherein the 5-year fatality rates of chronic hepatitis B, compensatory cirrhosis and decompensated cirrhosis are 0% -2%, 14% -20% and 70% -86% respectively.
Tenofovir alafenamide was developed by gillidde science (Gilead Sciences). The medicine is a novel experimental prodrug of tenofovir (tenofovir), and is mainly used for treating AIDS (HIV) infection and hepatitis B virus infection. The product is approved to be marketed in the European Union at 09.01.2017, 11.10.2016 in the United states, and 19.12.2016 in the European Union under the name of Vemlidy. Clinically, the medicine has smaller administration dosage and higher safety.
It is reported in the literature that enantiomers of tenofovir alafenamide are less effective than tenofovir alafenamide, and thus, the contents of enantiomers in tenofovir alafenamide need to be strictly controlled in consideration of safety and effectiveness of administration.
At present, the tenofovir alafenamide raw material and related preparations have no legal standards such as pharmacopoeia and the like. Therefore, there is a need to develop a method for detecting enantiomers in tenofovir alafenamide, which method must be capable of effectively separating tenofovir alafenamide and its enantiomers. In view of this, the present invention provides a method, which can meet the requirement, and the method can effectively separate tenofovir alafenamide and its enantiomer, ensure the effectiveness of detection, and accurately and strictly control the quality of tenofovir alafenamide.
Disclosure of Invention
The invention provides an HPLC method for detecting enantiomers in tenofovir alafenamide, which can effectively separate the tenofovir alafenamide and the enantiomers thereof, ensure the effectiveness of detection, accurately and strictly control the quality of the tenofovir alafenamide, and has strong specificity, high sensitivity, good accuracy and durability.
The invention provides a high performance liquid chromatography analysis method for effectively separating tenofovir alafenamide and enantiomers thereof. The method comprises the following steps: performing high performance liquid chromatography, using polysaccharide derivative chiral chromatographic column, using n-hexane-isopropanol as mobile phase, adding alkaline reagent to adjust peak shape, and performing isocratic elution under certain conditions. The method comprises the following steps:
detecting on a high performance liquid chromatograph
Chromatographic column packing agent: polysaccharide derivatives
Column temperature: 25-35 deg.C
Flow rate: 0.8 mL/min-1.2 mL/min
Detection wavelength: 258nm-262nm
Mobile phase: adding alkaline reagent to regulate peak shape, wherein phase A is n-hexane and phase B is alcohol
Diluting liquid: anhydrous ethanol
Preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer reference substance and a tenofovir alafenamide reference substance, dissolving and diluting with absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of the tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution.
Preparing a sample solution: taking a proper amount of the product, precisely weighing, placing into a measuring flask, dissolving with absolute ethyl alcohol and diluting to prepare a solution of about 1 mg/ml.
Preparing a control solution: a suitable amount of the sample solution was diluted with absolute ethanol to prepare a solution containing about 2. mu.g/ml.
The chromatographic column uses polysaccharide derivative as filler, preferably CHIRALPAK AD-H (4.6 mm × 250mm, 5 μm) column.
The alcohol of the mobile phase B is one or more of ethanol, isopropanol, n-butanol and the like, and preferably isopropanol.
The volume ratio of the mobile phase A to the mobile phase B is 45:55-55:45, preferably 50: 50.
The alkaline reagent is diethylamine.
The volume of the alkaline reagent accounts for 0.0-0.5% of the mobile phase.
The column temperature is 25 ℃ to 35 ℃, preferably 30 ℃.
The flow rate is 0.8 mL/min to 1.2 mL/min, preferably 1.0 mL/min.
The wavelength is 258nm to 262nm, preferably 260 nm.
The system has the advantages that the separation between peaks in the applicable solution can reach the baseline, and the separation degree is more than or equal to 1.5.
The calculation method of the enantiomer is a self-control method.
The detection method provided by the invention can effectively separate tenofovir alafenamide from enantiomer thereof, ensures the detection effectiveness, can accurately and strictly control the quality of the tenofovir alafenamide, and has the advantages of strong specificity, high sensitivity, and good accuracy and durability.
Detailed Description
To illustrate the present invention in detail, the following examples are further illustrated, and the following examples are only for illustrating the present invention and do not limit the scope of the present invention. Any simple modification, equivalent change and modification made to the following embodiments in accordance with the technical spirit of the present invention are within the scope of the present invention as claimed.
Example 1
Specificity test
The method of the invention is adopted.
A chromatographic column: CHIRALPAK AD-H (4.6 mm X250 mm, 5 μm)
Mobile phase: n-Hexane-Isopropanol-diethylamine (50: 50: 0.2)
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Detection wavelength: 260nm
Sample introduction volume: 10 μ l
The experimental steps are as follows:
blank solvent: anhydrous ethanol
Preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer reference substance and a tenofovir alafenamide reference substance, dissolving and diluting with absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of the tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution.
Preparing a sample solution: taking a proper amount of the product, precisely weighing, placing into a measuring flask, dissolving with absolute ethyl alcohol and diluting to prepare a solution of about 1 mg/ml.
Preparing a control solution: a suitable amount of the sample solution was diluted with absolute ethanol to prepare a solution containing about 2. mu.g/ml.
And (4) taking the solutions, respectively injecting the solutions into a high performance liquid chromatograph, and recording a chromatogram.
The results for the blank solvent are shown in FIG. 1.
The results of the system suitability solution are shown in figure 2.
The results of the sample solutions are shown in FIG. 3.
The results for the control solution are shown in FIG. 4.
As a result: the blank solvent does not interfere the detection of tenofovir alafenamide and enantiomers thereof, and the method has good specificity. In the attached figure 2, the enantiomers, TNa-D2 and tenofovir alafenamide are sequentially arranged from left to right, the separation degrees are respectively 2.80 and 2.78, and are both more than 1.5, and the baseline separation can be achieved.
Example 2
The method of the invention is adopted.
A chromatographic column: CHIRALPAK AD-H (4.6 mm X250 mm, 5 μm)
Mobile phase: n-Hexane-Isopropanol-diethylamine (45: 55: 0.2)
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Detection wavelength: 260nm
Sample introduction volume: 10 μ l
The experimental steps are as follows:
diluting liquid: anhydrous ethanol
Preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer reference substance and a tenofovir alafenamide reference substance, dissolving and diluting with absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of the tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution.
And (4) taking each solution, respectively injecting the solution into a high performance liquid chromatograph, and recording a chromatogram by adopting the chromatographic conditions.
The results of the system suitability solution are shown in figure 5.
As a result: in FIG. 5, the enantiomers, TNa-D2 and tenofovir alafenamide are shown in sequence from left to right, the resolution is 2.52 and 2.74 respectively, and both are greater than 1.5, which enables baseline separation to be achieved.
Example 3
The method of the invention is adopted.
A chromatographic column: CHIRALPAK AD-H (4.6 mm X250 mm, 5 μm)
Mobile phase: n-Hexane-Isopropanol-diethylamine (50: 50: 0.2)
Flow rate: 1.0ml/min
Column temperature: 35 deg.C
Detection wavelength: 260nm
Sample introduction volume: 10 μ l
The experimental steps are as follows:
diluting liquid: anhydrous ethanol
Preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer reference substance and a tenofovir alafenamide reference substance, dissolving and diluting with absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of the tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution.
And (4) taking each solution, respectively injecting the solution into a high performance liquid chromatograph, and recording a chromatogram by adopting the chromatographic conditions.
The results of the system suitability solution are shown in figure 6.
As a result: in figure 6, the enantiomers, TNa-D2 and tenofovir alafenamide are shown in sequence from left to right, the resolution is 2.80 and 2.88 respectively, and both are greater than 1.5, which can achieve baseline separation.
Example 4
Detection limit and quantification limit tests.
The chromatographic procedure used in example 1 was followed.
The experimental steps are as follows:
blank solvent: anhydrous ethanol
Detection limit and quantification limit solutions: taking appropriate amount of tenofovir alafenamide reference substance and enantiomer reference substance, respectively adding anhydrous ethanol to obtain a series of solutions with concentration, and determining by the method. The quantitation limit and detection limit of the species were determined as signal-to-noise ratio and the results are given in the following table:
example 5
Linear relationship and range
The chromatographic procedure used in example 1 was followed.
The experimental steps are as follows:
blank solvent: anhydrous ethanol
Linear solution: taking appropriate amount of tenofovir alafenamide reference substance and enantiomer reference substance, respectively adding anhydrous ethanol to obtain a series of solutions with concentration, and determining by the method.
As a result: the enantiomer of tenofovir alafenamide has good linear relation in the concentration range of 0.1717 mu g/ml to 2.8611 mu g/ml, and the enantiomer of tenofovir alafenamide has good linear relation in the concentration range of 0.1636 mu g/ml to 2.7269 mu g/ml, and the specific results are shown in the following table:
example 6
Recovery test
The chromatographic procedure used in example 1 was followed.
The experimental steps are as follows:
precisely weighing a proper amount of tenofovir alafenamide, placing into a measuring flask, precisely adding a proper amount of tenofovir alafenamide enantiomer stock solution, dissolving with absolute ethanol, diluting to scale, preparing into solutions with relative concentrations of LOQ, 40%, 100% and 120%, and shaking uniformly to obtain a test solution. Each concentration was made in parallel with 3 parts. And precisely weighing a proper amount of tenofovir alafenamide, dissolving the tenofovir alafenamide in ethanol, diluting the mixture to a scale, and shaking the mixture uniformly to obtain a blank sample solution. In addition, a proper amount of tenofovir alafenamide enantiomer stock solution is precisely measured, and absolute ethyl alcohol is quantitatively diluted to prepare a solution with a proper concentration to be used as a reference solution. Precisely measuring 10 μ l of each solution, injecting into a liquid chromatograph, and recording chromatogram and peak area. And calculating the recovery rate.
As a result: the recovery rate of the tenofovir alafenamide enantiomer at each concentration meets the pharmacopoeia regulations, the method has good accuracy, and the specific data are shown in the following table:
EXAMPLE 7 durability test
The chromatographic procedure used in example 1 was followed.
The experimental steps are as follows:
preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer and a tenofovir alafenamide reference substance, dissolving and diluting with absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution.
Preparing a test solution: precisely weighing a proper amount of tenofovir alafenamide, placing into a measuring flask, precisely adding a proper amount of tenofovir alafenamide enantiomer stock solution, dissolving with absolute ethanol, diluting to scale, and shaking uniformly to obtain a test solution.
Preparing a control solution: taking a proper amount of the test solution, and diluting the test solution by using absolute ethyl alcohol to prepare a solution containing about 2 mu g/ml.
Precisely measuring 10 μ l of each solution, injecting into a liquid chromatograph, and recording chromatogram and peak area.
As a result: under the condition of slight change of chromatographic conditions, the content of enantiomers is basically not different, the resolution of a system applicability solution under each condition is more than 1.5, baseline separation can be achieved, and the method has good durability. The specific results are shown in the following table:
description of the drawings:
the results for the blank solvent are shown in FIG. 1;
the results of the system suitability solution are shown in FIG. 2;
the results of the sample solutions are shown in FIG. 3;
the results for the control solution are shown in FIG. 4;
the results of the system suitability solution are shown in FIG. 5;
the results of the system suitability solution are shown in figure 6.
Claims (8)
1. A detection method for separating tenofovir alafenamide and enantiomers thereof is characterized by comprising the following steps: 1) detecting on a high performance liquid chromatograph, wherein a chromatographic column filler is a polysaccharide derivative, and the column temperature is 25-35 ℃; the flow rate is 0.8 mL/min-1.2 mL/min; the detection wavelength is 258nm-262 nm; the mobile phase A is n-hexane, the phase B is alcohol, and an alkaline reagent is added to adjust the peak shape; the diluent is absolute ethyl alcohol;
2) preparing a system applicability solution: respectively taking appropriate amount of an impurity TNa-D2 reference substance, an enantiomer reference substance and a tenofovir alafenamide reference substance, dissolving and diluting the appropriate amount of the impurity TNa-D2 reference substance, the enantiomer reference substance and the tenofovir alafenamide reference substance by using absolute ethyl alcohol to prepare a mixed solution containing 10 mu g of the impurity TNa-D2 and the enantiomer TNa-D4 and 1mg of the tenofovir alafenamide in each 1ml, and taking the mixed solution as a system applicability solution;
3) preparing a sample solution: taking a proper amount of the product, precisely weighing, placing into a measuring flask, dissolving with absolute ethyl alcohol, and diluting to prepare a solution of about 1 mg/ml;
4) preparing a control solution: a suitable amount of the sample solution was diluted with absolute ethanol to prepare a solution containing about 2. mu.g/ml.
2. The method of claim 1, wherein the chromatography column is CHIRALPAK AD-H (4.6 mm x 250mm, 5 μ ι η).
3. The method according to claim 1, wherein the alcohol of the mobile phase B is one or more of ethanol, isopropanol, n-butanol, etc., preferably isopropanol.
4. The process according to claim 1, characterized in that the volume ratio of mobile phase a to B is 45:55 to 55:45, preferably 50: 50.
5. The method of claim 1, wherein the alkaline agent is diethylamine; the alkaline agent accounts for 0.0-0.5% of the mobile phase.
6. The method according to claim 1, characterized in that the column temperature is 25 ℃ to 35 ℃, preferably 30 ℃; the flow rate is 0.8 mL/min to 1.2 mL/min, preferably 1.0 mL/min; the wavelength is 258nm to 262nm, preferably 260 nm.
7. The method of claim 1, wherein a baseline separation is achieved between peaks in the system suitability solution, with a degree of separation of greater than or equal to 1.5.
8. The method of claim 1, wherein the calculation of the enantiomers is a self-control method.
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| CN114252538A (en) * | 2021-12-31 | 2022-03-29 | 北京鑫开元医药科技有限公司 | Tenofovir alafenamide fumarate and separation and determination method of isomer thereof |
| CN115015445A (en) * | 2022-03-29 | 2022-09-06 | 浙江美诺华药物化学有限公司 | Detection and analysis method of L-alanine isopropyl ester hydrochloride and isomer thereof |
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2018
- 2018-08-13 CN CN201810915820.1A patent/CN110824027A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111189947A (en) * | 2020-03-30 | 2020-05-22 | 济南新科医药科技有限公司 | Analysis method for separating and detecting propane fumarate tenofovir disoproxil isomer |
| CN111189947B (en) * | 2020-03-30 | 2022-06-17 | 济南新科医药科技有限公司 | Analysis method for separating and detecting propane fumarate tenofovir disoproxil isomer |
| CN114252538A (en) * | 2021-12-31 | 2022-03-29 | 北京鑫开元医药科技有限公司 | Tenofovir alafenamide fumarate and separation and determination method of isomer thereof |
| CN115015445A (en) * | 2022-03-29 | 2022-09-06 | 浙江美诺华药物化学有限公司 | Detection and analysis method of L-alanine isopropyl ester hydrochloride and isomer thereof |
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