CN112903866A - Method for determining triethylamine content in propane fumarate tenofovir - Google Patents
Method for determining triethylamine content in propane fumarate tenofovir Download PDFInfo
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- CN112903866A CN112903866A CN202110142388.9A CN202110142388A CN112903866A CN 112903866 A CN112903866 A CN 112903866A CN 202110142388 A CN202110142388 A CN 202110142388A CN 112903866 A CN112903866 A CN 112903866A
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- triethylamine
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 238000000034 method Methods 0.000 title claims abstract description 28
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 17
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 15
- YYHPFNLBMMEMQU-TYYBGVCCSA-N (e)-but-2-enedioic acid;propane Chemical compound CCC.OC(=O)\C=C\C(O)=O YYHPFNLBMMEMQU-TYYBGVCCSA-N 0.000 title claims abstract description 10
- 238000001514 detection method Methods 0.000 claims abstract description 9
- 238000002013 hydrophilic interaction chromatography Methods 0.000 claims abstract description 8
- 239000013558 reference substance Substances 0.000 claims abstract description 7
- 238000012360 testing method Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 4
- 230000005264 electron capture Effects 0.000 claims abstract description 4
- 239000012488 sample solution Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims abstract 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000010829 isocratic elution Methods 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims 3
- 239000013068 control sample Substances 0.000 claims 1
- 239000012071 phase Substances 0.000 abstract description 9
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000001179 sorption measurement Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- 238000005259 measurement Methods 0.000 description 5
- 239000000523 sample Substances 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 235000011087 fumaric acid Nutrition 0.000 description 3
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 3
- 229960004134 propofol Drugs 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- -1 { [ (2R) -1- (6-amino-9H-purin-9-yl) prop-2-yl ] -oxy } methyl Chemical group 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/70—Electron capture detectors
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Sampling And Sample Adjustment (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for determining triethylamine content in propane fumarate tenofovir, which comprises the following steps: A) preparing a triethylamine reference substance solution and a test sample solution; B) detecting on a high performance liquid chromatograph by adopting an electron capture detector; the chromatographic conditions for detection are as follows: eluting with HILIC column and acid water solution as mobile phase. The discovery adopts a liquid phase determination method, thoroughly solves the problems related to adsorption, and has the advantages of high accuracy of determination results, good reproducibility and easy operation.
Description
Technical Field
The invention relates to the technical field of analysis and detection, and particularly relates to a method for determining triethylamine content in propane fumarate tenofovir.
Background
Propofovir fumarate, chemically known as prop-2-yl N- [ (S) - ({ [ (2R) -1- (6-amino-9H-purin-9-yl) prop-2-yl ] -oxy } methyl) (phenoxy) phosphoryl ] -l-alaninate, (2E) -but-2-enedioic acid (2:1), having the chemical structure:
propofovir fumarate was developed by Giliddes science (Gilead Sciences). The medicine is mainly used for treating AIDS (HIV) infection and hepatitis B virus infection. Approved for marketing in the European Union in 2017 at 09/01/10/2016, approved for marketing in the United states in 2016, approved for marketing in the European Union at 19/12/2016
Clinically, the medicine has smaller administration dosage and higher safety.
Triethylamine is a solvent adopted in the synthesis process of the propane fumarate tenofovir, and the content of the triethylamine needs to be accurately controlled.
Triethylamine is used as a residual solvent, and is usually measured by a gas phase method, for example, patent No. cn202010286832.x adopts a gas chromatography (headspace sampling) method for detecting triethylamine in propofol fumarate tenofovir, and during the actual measurement process, triethylamine is adsorbed in a gas phase system, which causes inaccurate measurement, and the phenomenon is a ubiquitous phenomenon. The result is poor reproducibility, easy contamination of the gas phase system, and frequent cleaning of the gas phase system.
Disclosure of Invention
In view of the above, the technical problem to be solved by the invention is to provide a method for determining triethylamine content in tenofovir disoproxil fumarate, which has the advantages of high accuracy and good reproducibility.
In order to achieve the purpose, the invention provides a method for measuring the triethylamine content in the fumaric acid Propofol tenofovir, which comprises the following steps:
A) preparing a triethylamine reference substance solution and a test sample solution;
B) an electron capture detector (hereinafter referred to as: a CAD detector);
the chromatographic conditions for detection are as follows: eluting with HILIC column and acid water solution as mobile phase.
The invention provides a method for detecting the triethylamine content in propane fumarate tenofovir, which can effectively separate and quantitatively determine triethylamine in the propane fumarate tenofovir, and methodological verification is carried out on the aspects of specificity, linearity and range, solution stability, accuracy, precision, quantitative limit, detection limit and the like, so that the verification requirements can be met, and the actual detection effect is good.
According to the invention, 1 mu g of triethylamine is preferably contained in each 1mL of triethylamine reference substance solution, namely the content of triethylamine in the triethylamine reference substance is 1 mu g/mL.
In a preferred embodiment of the present invention, each 1ml of the test solution contains 0.2mg of the sample of Propofovir fumarate.
Preferably, the acidic compound in the aqueous acid solution is one or more selected from formic acid, acetic acid and trifluoroacetic acid. More preferably trifluoroacetic acid (TFA).
In the present invention, the content of the acidic compound is preferably 0.05% to 30%. More preferably 0.1%.
Preferably, the flow rate of the mobile phase is 0.5-1.5 mL/min. More preferably 1.0 mL/min.
According to the invention, the temperature of the HILIC column is preferably 20-45 ℃. More preferably 40 deg.c.
Preferably, the elution mode is gradient elution or isocratic elution. More preferably isocratic elution.
Compared with the prior art, the invention provides a method for determining the triethylamine content in the fumaric acid Propofol tenofovir, which comprises the following steps: A) preparing a triethylamine reference substance solution and a test sample solution; B) an electron capture detector (hereinafter referred to as: a CAD detector); the chromatographic conditions for detection are as follows: eluting with HILIC column and acid water solution as mobile phase. The discovery adopts a liquid phase determination method, thoroughly solves the problems related to adsorption, and has the advantages of high accuracy of determination results, good reproducibility and easy operation.
Detailed Description
In order to further illustrate the present invention, the following examples are given to describe the method for determining triethylamine content in tenofovir disoproxil fumarate provided by the present invention in detail.
Example 1
The method comprises the following operation steps: HPLC-CAD detector, column temperature 40 deg.C, flow rate 1.0ml/min, mobile phase 0.1% TFA, and chromatography column HILIC column. Taking a proper amount of triethylamine, using methanol as a blank solvent to prepare triethylamine with the concentration of 1ug/ml, using the triethylamine as a triethylamine reference solution, and preparing 6 parts by the same method. Taking the propane fumarate tenofovir, adding methanol to prepare a sample containing 0.2mg of propane fumarate tenofovir per 1ml of the test solution, taking the sample as the test solution, and preparing 6 parts by the same method. The injection volume was 20 ul.
1. Sampling 1 part of triethylamine reference substance solution for 6 times, measuring the precision of the instrument, and the result is shown in the following table 1:
TABLE 1 Triethylamine control 6 test results
2. Taking 1 part of the reference solution and 6 parts of the test solution, and measuring the repeatability, wherein the results are shown in the following table 2:
TABLE 2 repeatability measurements
Example 2
The same procedure as in example 1 was followed to determine 6 parts of the sample, and the results were compared with 6 parts of the results obtained in example 1, and the results were calculated for an intermediate precision of 12 parts, as shown in Table 3:
TABLE 3 results of precision measurement
The tests show that the detection method provided by the invention has higher accuracy and good reproducibility.
Example 3
Taking a proper amount of the propane phenol fumarate tenofovir and triethylamine, adding methanol to prepare a mixed solution containing 0.2mg of the propane phenol fumarate tenofovir per 1ml and 1ug of triethylamine, and preparing 6 parts of the mixed solution as an accuracy solution by the same method. The control solution and the above accuracy solution of example 1 were sampled and the recovery rate was determined. The results are shown in table 4 below:
TABLE 4 results of recovery measurement
The tests show that the detection method provided by the invention has higher recovery rate.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A method for determining the content of triethylamine in propane fumarate tenofovir comprises the following steps:
A) preparing a triethylamine reference substance solution and a test sample solution;
B) detecting on a high performance liquid chromatograph by adopting an electron capture detector;
the chromatographic conditions for detection are as follows: eluting with HILIC column and acid water solution as mobile phase.
2. The method according to claim 1, wherein the acidic compound in the aqueous acid solution is one or more selected from formic acid, acetic acid, and trifluoroacetic acid.
3. The method according to claim 2, wherein the content of the acidic compound is 0.05% to 30%.
4. The method according to claim 3, wherein the content of the acidic compound is 0.1%.
5. The method according to claim 1, wherein the flow rate of the mobile phase is 0.5 to 1.5 mL/min.
6. The assay according to claim 5, wherein the flow rate of the mobile phase is 1.0 mL/min.
7. The method according to claim 1, wherein the HILIC column has a column temperature of 20 to 45 ℃.
8. The assay of claim 1, wherein the HILIC column has a column temperature of 40 ℃.
9. The method according to claim 1, wherein the elution is carried out by gradient elution or isocratic elution.
10. The assay method according to claim 1, wherein the triethylamine control sample contains triethylamine in an amount of 1 μ g/mL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110142388.9A CN112903866A (en) | 2021-02-02 | 2021-02-02 | Method for determining triethylamine content in propane fumarate tenofovir |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110142388.9A CN112903866A (en) | 2021-02-02 | 2021-02-02 | Method for determining triethylamine content in propane fumarate tenofovir |
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| CN112903866A true CN112903866A (en) | 2021-06-04 |
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|---|---|---|---|---|
| CN103018387A (en) * | 2012-12-17 | 2013-04-03 | 四川科伦药物研究有限公司 | Method for detecting residual quantity of triethylamine in beta-lactam antibiotic |
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| CN111323519A (en) * | 2020-04-13 | 2020-06-23 | 江苏海悦康医药科技有限公司 | Method for detecting triethylamine in propane fumarate tenofovir disoproxil through gas chromatography |
-
2021
- 2021-02-02 CN CN202110142388.9A patent/CN112903866A/en active Pending
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