CN117451884A - Method for determining formic acid and/or acetic acid content in fatty alcohol polyoxyethylene ether - Google Patents
Method for determining formic acid and/or acetic acid content in fatty alcohol polyoxyethylene ether Download PDFInfo
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- CN117451884A CN117451884A CN202311388973.2A CN202311388973A CN117451884A CN 117451884 A CN117451884 A CN 117451884A CN 202311388973 A CN202311388973 A CN 202311388973A CN 117451884 A CN117451884 A CN 117451884A
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- Prior art keywords
- fatty alcohol
- polyoxyethylene ether
- acetic acid
- formic acid
- preparation
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 99
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 66
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 235000019253 formic acid Nutrition 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 26
- 229940051841 polyoxyethylene ether Drugs 0.000 title claims abstract description 24
- 229920000056 polyoxyethylene ether Polymers 0.000 title claims abstract description 24
- 150000002191 fatty alcohols Chemical class 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000741 silica gel Substances 0.000 claims abstract description 11
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 11
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 9
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 21
- 238000001514 detection method Methods 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229920001363 Polidocanol Polymers 0.000 claims description 6
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 6
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 6
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 6
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 claims description 6
- 229960002226 polidocanol Drugs 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 description 8
- 238000007865 diluting Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 5
- ZMZINYUKVRMNTG-UHFFFAOYSA-N acetic acid;formic acid Chemical compound OC=O.CC(O)=O ZMZINYUKVRMNTG-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229940025913 polidocanol injection Drugs 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 239000012535 impurity Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000239290 Araneae Species 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010046996 Varicose vein Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000027185 varicose disease Diseases 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
- G01N30/38—Flow patterns
- G01N30/46—Flow patterns using more than one column
- G01N30/461—Flow patterns using more than one column with serial coupling of separation columns
-
- 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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
-
- 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
- G01N2030/042—Standards
- G01N2030/047—Standards external
Landscapes
- 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)
- Engineering & Computer Science (AREA)
- Library & Information Science (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention provides a method for measuring the content of formic acid and acetic acid in fatty alcohol polyoxyethylene ether and a preparation thereof, which adopts an inverse high performance liquid chromatography, adopts an amino-bonded silica gel column to be connected in series with an octadecyl silane-bonded silica gel packed column or an octyl silane-bonded silica gel packed column or an equivalent column, and uses phosphate buffer solution and acetonitrile to form a mobile phase system, thus being capable of accurately measuring the formic acid and/or acetic acid in the fatty alcohol polyoxyethylene ether and the preparation thereof. The method has high sensitivity and good durability, and can control the product quality well.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a method for measuring the content of formic acid and/or acetic acid in fatty alcohol polyoxyethylene ether.
Background
Fatty alcohol and ethylene oxide are added to form polyoxyethylene ether, and formic acid and acetic acid are impurities generated by the polyoxyethylene ether. It is reported in literature that both impurities can stimulate the nose and eyes, have certain corrosiveness, can cause conjunctivitis, ocular edema, difficult-to-treat rhinitis, bronchitis and the like, and can sensitize. Quality control is clearly required in the method for determining the residual solvent in annex 0861 of the fourth part of the pharmacopoeia in 2020, but a gas phase detection method is adopted in the pharmacopoeia, so that the operation is complex. The method of formic acid and acetic acid detection kit (produced by R-Biopharm, germany) is adopted in the imported registration standard (JX 20150310), so that the method has the advantages of long acquisition time, high price and certain use limitation.
The fatty alcohol polyoxyethylene ether series products take polidocanol as an example, have wide application in medicines, and the polidocanol injection is suitable for hardening treatment of central veins, reticulate veins and varicose veins of spider web-like veins.
Based on the above circumstances, the present invention provides a high performance liquid chromatography method for determining the content of formic acid and/or acetic acid in fatty alcohol-polyoxyethylene ether and its preparation.
Disclosure of Invention
In order to overcome the limitations of the existing detection methods, the invention aims to provide a simple and accurate method for detecting the content of formic acid and/or acetic acid in fatty alcohol-polyoxyethylene ether series products such as polidocanol and preparations thereof, thereby ensuring the safety of medication.
The above object of the present invention is achieved by the following technical solutions:
a method for determining formic acid and/or acetic acid in fatty alcohol-polyoxyethylene ether and a preparation thereof, the method comprising:
providing a fatty alcohol polyoxyethylene ether solution to be tested;
performing high performance liquid chromatography analysis on the fatty alcohol-polyoxyethylene ether solution to obtain a chromatogram of the fatty alcohol-polyoxyethylene ether to be detected;
the conditions for the high performance liquid chromatography include:
mobile phase: phosphate buffer solution-acetonitrile solution, wherein the phosphate in the mobile phase is 0.015-0.025 mol/L potassium dihydrogen phosphate buffer solution (ammonia water is added into each 1L for 4-6 ml, the pH value is adjusted to 5.6 by phosphoric acid), and the volume ratio of the phosphate buffer solution to the acetonitrile is (45-60): 48.
in the above method, the detector used for the high performance liquid chromatography is an ultraviolet detector or a diode array detector.
In the above method, the detection wavelength used for the HPLC analysis is 205 to 220nm.
In the above method, the chromatographic column used in the high performance liquid chromatography is an amino-bonded silica gel column connected in series with an octadecylsilane-bonded silica gel packed column or an octyl silane-bonded silica gel column.
In the method, the buffer salt in the mobile phase is 0.015-0.025 mol/L potassium dihydrogen phosphate buffer solution (4-6 ml of ammonia water is added into each 1L), and the pH value is 5.2-6.2.
The invention is suitable for measuring the content of formic acid and/or acetic acid in the fatty alcohol-polyoxyethylene ether same series products and preparations thereof, and preferably, the fatty alcohol-polyoxyethylene ether to be measured is polidocanol. The preparation can be injection, patch and compound preparation. The analysis method provided by the invention has the advantages of high sensitivity, good repeatability, simplicity, convenience and rapidness. Can effectively control the quality of the product and ensure the medication safety.
Drawings
FIG. 1: EXAMPLE 1 control solution chromatogram
Fig. 2: EXAMPLE 1 Polypolidocanol raw material sample solution chromatography
Fig. 3: EXAMPLE 1 test solution chromatograms of polidocanol injection
In the figure, peak 1 represents formic acid and peak 2 represents acetic acid
Detailed Description
The examples are provided for further illustration of the summary and are not intended to be limiting.
Example 1: determination of formic acid and acetic acid content in raw materials and preparation
Chromatographic column: the amino-bonded silica gel column and the octadecyl silane-bonded silica gel packed column are connected in series
Mobile phase: 0.02mol/L Potassium dihydrogen phosphate buffer (Potassium dihydrogen phosphate 2.72g, dissolved in water, added with concentrated ammonia water 5ml, diluted with water to 10000ml, pH adjusted to 5.6 with phosphoric acid) -acetonitrile (52:48)
Detection wavelength: 205nm flow rate: sample injection amount of 0.8 ml/min: 100 μl of
Preparing a reference substance solution: weighing 100mg of formic acid and acetic acid respectively, placing into 50ml measuring flask, diluting to scale with mobile phase, shaking to obtain mother liquor of formic acid and acetic acid reference substance, precisely weighing 1ml of mother liquor respectively, placing into the same 50ml measuring flask, diluting to scale with mobile phase, and shaking to uniform; then precisely measuring 1ml from the solution, placing the solution into a 10ml measuring flask, diluting the solution to a scale by using a mobile phase, and shaking the solution uniformly to obtain a mixed solution containing 4 mug/ml of each of formic acid and acetic acid.
Raw material test solution: precisely weighing about 0.5g of polidocanol raw material, placing into a 10ml measuring flask, adding mobile phase to dissolve and dilute to scale, and shaking uniformly.
Preparation of test sample solution: taking polidocanol injection and directly injecting.
The peak-out sequence is formic acid and acetic acid in turn.
Assay: precisely measuring 100 μl of each of the reference solution, the raw material sample solution and the preparation solution, respectively injecting into a liquid chromatograph, recording the chromatogram, wherein the chromatogram of the sample solution has chromatographic peaks with the retention time consistent with that of formic acid and acetic acid, and calculating according to external standard method with peak area.
Results: the separation degree between formic acid and acetic acid in the reference substance solution is more than 1.5, and meets the requirements. The content of formic acid in the raw material is 0.02%, and acetic acid is not detected; the polidocanol injection contains 0.04% formic acid and 0.03% acetic acid.
Example 2 sensitivity and precision
According to the definition and verification method of the four general rules 9101 (the verification guiding principle of the drug quality standard analysis method), the detection limit, the quantitative limit and the precision of formic acid and acetic acid are detected by adopting a reference method, and the result shows that the quantitative limit of the formic acid is 40ng and the quantitative limit of the acetic acid is 37ng; the detection limit of formic acid is 20ng, the detection limit of acetic acid is 15ng, and the method has high sensitivity; in the precision test, the relative standard deviation of the areas of formic acid and acetic acid peaks is 3.5 percent and 2.7 percent respectively, and the method has good precision.
EXAMPLE 3 Linear relationship
Storage solution of formic acid-acetic acid mixed reference substance: taking about 100mg of formic acid and acetic acid reference substances, precisely weighing, respectively placing into 50ml measuring flasks, dissolving with mobile phase, diluting to scale, shaking, precisely weighing 1ml of the dissolved solution respectively, placing into the same 25ml measuring flask, diluting with mobile phase to scale, and shaking to obtain the formic acid-acetic acid mixed reference substance stock solution.
A linear relationship solution; and respectively precisely measuring 0.05, 0.1, 0.2, 0.5, 1, 1.5, 2.0, 3.0 and 5.0ml from the storage liquid of the formic acid acetic acid reference substance, placing the storage liquid into a 10ml measuring flask, diluting to a scale by using a mobile phase, and shaking uniformly to obtain the solution for the linear relation test 1-6.
And (3) measuring: 100 μl of the linear relation test solution was measured precisely, and the solution was injected into a liquid chromatograph to record the chromatogram. The results show that the concentration of formic acid in the range of 0.41-40.6 mug/ml and acetic acid in the range of 0.45-45.0 mug/ml have good linear relation with peak area, R is not less than 0.999, and Y-axis intercept is within 25% of the 100% response value.
Example 4 recovery
Taking a proper amount of polidocanol, adding a mobile phase to dissolve, adding a storage solution of a formic acid-acetic acid mixed reference substance according to 50%, 100% and 150% of the limit, and operating three times in parallel for each concentration to calculate the recovery rate and RSD.
The results show that: the recovery rate is 98.9%, the RSD is 2.6%, and the recovery rate is good.
Example 5 durability test
On the basis of the chromatographic conditions, the mobile phase is inspected respectively in different proportions, flow rates, chromatographic columns of different batches and different instruments, and the durability of the chromatographic conditions of formic acid and acetic acid inspection is inspected.
The results show that the ratio, the flow rate, the chromatographic column and the instrument of the mobile phase are changed when the formic acid and the acetic acid are measured, the measurement result is not changed obviously, and the durability is good.
The invention can conveniently and accurately detect the content of formic acid and/or acetic acid in fatty alcohol polyoxyethylene ether series products.
The embodiments described above are some, but not all, embodiments of the invention. The detailed description of the embodiments of the invention is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Claims (5)
1. A method for measuring the content of formic acid and/or acetic acid in fatty alcohol polyoxyethylene ether and a preparation thereof comprises the following steps:
providing a fatty alcohol polyoxyethylene ether solution to be tested;
performing high performance liquid chromatography analysis on the fatty alcohol-polyoxyethylene ether solution to obtain a chromatogram of the fatty alcohol-polyoxyethylene ether to be detected;
the conditions for the high performance liquid chromatography include:
mobile phase: phosphate buffer solution-acetonitrile solution, wherein the phosphate in the mobile phase is 0.015-0.025 mol/L potassium dihydrogen phosphate buffer solution (ammonia water is added into each 1L for 4-6 ml, the pH value is adjusted to 5.6 by phosphoric acid), and the volume ratio of the phosphate buffer solution to the acetonitrile is (45-60): 48.
2. the method of claim 1, wherein the detection wavelength is 205-220 nm.
3. The method according to claim 1, wherein the chromatographic column is an amino-bonded silica gel column in series with an octadecylsilane-bonded silica gel packed column or an octyl silane-bonded silica gel column.
4. The method according to claim 1, wherein the pH of the potassium dihydrogen phosphate buffer (4-6 ml of aqueous ammonia is added to 1L) is 5.2-6.2 in an amount of 0.015-0.025 mol/L.
5. The method for determining the content of formic acid and/or acetic acid in the fatty alcohol-polyoxyethylene ether raw material and the preparation thereof according to claim 1, wherein the method comprises the following steps: the method is suitable for the mixture of one or more of fatty alcohol-polyoxyethylene ether and other analogues in pharmaceutically acceptable forms, which need to be subjected to formic acid and/or acetic acid content detection, and the preparation thereof, wherein the fatty alcohol-polyoxyethylene ether to be detected is polidocanol, and the preparation is injection, patch and compound preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311388973.2A CN117451884A (en) | 2023-10-25 | 2023-10-25 | Method for determining formic acid and/or acetic acid content in fatty alcohol polyoxyethylene ether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311388973.2A CN117451884A (en) | 2023-10-25 | 2023-10-25 | Method for determining formic acid and/or acetic acid content in fatty alcohol polyoxyethylene ether |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117451884A true CN117451884A (en) | 2024-01-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311388973.2A Pending CN117451884A (en) | 2023-10-25 | 2023-10-25 | Method for determining formic acid and/or acetic acid content in fatty alcohol polyoxyethylene ether |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117451884A (en) |
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2023
- 2023-10-25 CN CN202311388973.2A patent/CN117451884A/en active Pending
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