CN110632221A - Method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation - Google Patents
Method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation Download PDFInfo
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- CN110632221A CN110632221A CN201910915903.5A CN201910915903A CN110632221A CN 110632221 A CN110632221 A CN 110632221A CN 201910915903 A CN201910915903 A CN 201910915903A CN 110632221 A CN110632221 A CN 110632221A
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- acetone
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- acetic acid
- formic acid
- ipratropium bromide
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 270
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 261
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 178
- 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 89
- 235000019253 formic acid Nutrition 0.000 title claims abstract description 89
- 238000000034 method Methods 0.000 title claims abstract description 60
- 229960001361 ipratropium bromide Drugs 0.000 title claims abstract description 41
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 title claims abstract description 41
- 239000000243 solution Substances 0.000 claims abstract description 86
- 238000001514 detection method Methods 0.000 claims abstract description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000010828 elution Methods 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000337 buffer salt Substances 0.000 claims abstract description 4
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000000945 filler Substances 0.000 claims abstract description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical class CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000004007 reversed phase HPLC Methods 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012085 test solution Substances 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 17
- 230000014759 maintenance of location Effects 0.000 claims description 13
- 239000012088 reference solution Substances 0.000 claims description 10
- 239000012266 salt solution Substances 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000013558 reference substance Substances 0.000 claims description 7
- 239000007836 KH2PO4 Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000007975 buffered saline Substances 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010812 external standard method Methods 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- 239000010452 phosphate Substances 0.000 claims 2
- 239000002994 raw material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 20
- 238000000926 separation method Methods 0.000 description 16
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- 239000000284 extract Substances 0.000 description 14
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 10
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- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000523 sample Substances 0.000 description 8
- 238000011895 specific detection Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
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- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 3
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- 238000005259 measurement Methods 0.000 description 3
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- 238000011084 recovery Methods 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
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- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
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- 150000007524 organic acids Chemical class 0.000 description 2
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- 238000012795 verification Methods 0.000 description 2
- 206010014561 Emphysema Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
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- 229940044601 receptor agonist Drugs 0.000 description 1
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- 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
- G01N30/86—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
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- 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
- G01N30/89—Inverse chromatography
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- 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
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Abstract
The invention discloses a method for detecting formic acid, acetic acid and acetone in an inhaled ipratropium bromide solution, which solves the problem that no method in the prior art can simultaneously detect formic acid, acetic acid and acetone in the inhaled ipratropium bromide solution. The detection method adopts reversed-phase high performance liquid chromatography for detection, uses diisopropyl substituted octadecylsilane chemically bonded silica as a filling agent, uses a buffer salt solution with the pH value of 2.0-3.3 as a mobile phase A, uses an organic solvent as a mobile phase B, and comprises the following steps of A: and B is 90-100: and (3) after the formic acid and the acetic acid are eluted out of peaks by 0-10, adding the components in the ratio of A: b is 75-100: 0-25 peak elution of acetone; the organic solvent is selected from one or more of acetonitrile, isopropanol, ethanol, tetrahydrofuran and methanol. The method can quickly and accurately measure the formic acid, the acetic acid and the acetone in the ipratropium bromide solution for inhalation, effectively ensure the product quality of the ipratropium bromide solution for inhalation and ensure the medication safety.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation.
Background
The inhaled ipratropium bromide solution is used as bronchodilator for the maintenance therapy of bronchospasm caused by chronic obstructive pulmonary diseases, including chronic bronchitis and emphysema. It is often used clinically in combination with inhaled beta receptor agonists for the treatment of chronic obstructive pulmonary diseases including chronic bronchitis and acute bronchospasm caused by asthma.
Formic acid, acetic acid and acetone are extracts of the solution of ipratropium bromide for inhalation, and the contents of formic acid, acetic acid and acetone need to be controlled in order to ensure the safety of medication. Formic acid and acetic acid are strong organic acids, and methods for measuring the organic acids in the prior art include gas chromatography, liquid chromatography, ion chromatography and the like. The gas chromatography usually needs to carry out derivatization treatment on a sample, so that the operation is complicated and the accuracy is low; the ion chromatography mostly adopts dilute strong acid, such as dilute hydrochloric acid and dilute sulfuric acid, as an eluent, has a certain corrosion effect on equipment, and interferes with the determination when the content of coexisting inorganic anions is high. Acetone is a common residual solvent in medicines, and most of the prior art methods for measuring acetone are gas chromatography. In addition, no method for simultaneously measuring formic acid, acetic acid and acetone exists in the prior art.
Therefore, it is an urgent need to provide a detection method capable of simultaneously detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation, with simple operation and accurate result.
Disclosure of Invention
The technical problem solved by the invention is as follows: the method for detecting the formic acid, the acetic acid and the acetone in the ipratropium bromide solution for inhalation is simple and convenient to operate, accurate in result and capable of solving the problem that no method capable of simultaneously measuring the formic acid, the acetic acid and the acetone in the ipratropium bromide solution for inhalation exists in the prior art.
The technical scheme adopted by the invention is as follows:
the invention relates to a method for detecting formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation, which adopts reversed-phase high performance liquid chromatography for detection, and the chromatographic conditions are as follows: the method comprises the following steps of (1) taking diisopropyl substituted octadecylsilane chemically bonded silica as a filler, taking a buffer salt solution with the pH of 2.0-3.3 as a mobile phase A, taking an organic solvent as a mobile phase B, and performing mixing according to the volume ratio of A: and B is 90-100: after the peak is eluted by formic acid and acetic acid by 0-10, the volume ratio of A: b is 75-100: 0-25 peak elution of acetone; the organic solvent is one or the combination of more than two of acetonitrile, isopropanol, ethanol, tetrahydrofuran and methanol.
As some examples of the invention, gradient elution was performed as specified in the following table,
as some examples of the invention, gradient elution was performed as specified in the following table,
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95～100 | 0～5 |
| 8～11 | 85～95 | 5～15 |
| 11～13 | 95～100 | 0～5 |
| 13～20 | 95～100 | 0～5 |
。
As an example of the present invention, gradient elution was performed as specified in the following table,
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 10 | 90 | 10 |
| 12 | 100 | 0 |
| 15 | 100 | 0 |
。
According to some embodiments of the invention, the organic solvent is selected from acetonitrile or methanol; preferably, it is selected from acetonitrile.
According to the embodiment of the invention, the buffer salt solution is phosphate buffer salt solution, and the concentration of the phosphate buffer salt solution is 0.01-0.2 mol/L;
the pH value of the buffered salt solution is 2.7;
preferably, the buffered saline solution is KH2PO4Solutions or NaH2PO4A solution;
preferably, the concentration of the buffered salt solution is 0.05 mol/L.
According to an embodiment of the invention, the buffered saline solution is adjusted to the pH with phosphoric acid.
The detection method adopts an ultraviolet detector, the detection wavelength of formic acid and acetic acid is 215nm, and the detection wavelength of acetone is 265 nm.
As an embodiment of the invention, the detection method adopts an ultraviolet detector, when the length of a chromatographic column is 250mm and the retention time is 0-6 min, the detection wavelength is 215 nm; when the retention time is 6-15 min, the detection wavelength is 265 nm.
In some embodiments of the invention, the column temperature of the chromatographic column is 25-35 ℃ and the flow rate of the mobile phase is 0.8-1.2 ml/min.
As an example of the present invention, the column temperature of the chromatography column was 30 ℃;
as an example of the present invention, the flow rate of the mobile phase was 1.0 ml/min.
The detection method comprises the following steps:
and 3, respectively injecting 10 mu l of each of the test solution and the reference solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and calculating the contents of formic acid, acetic acid and acetone in the test solution by peak areas according to an external standard method.
As an embodiment of the present invention, in the step 2, each 1ml of the control solution contains about 10.0. mu.g of formic acid, 35.0. mu.g of acetic acid, and 60.0. mu.g of acetone.
Compared with the prior art, the invention has the following beneficial effects:
the method is simple, is easy to operate, can quickly and accurately measure the formic acid, the acetic acid and the acetone in the ipratropium bromide solution for inhalation, can effectively ensure the product quality of the ipratropium bromide solution for inhalation, and ensures the medication safety.
The invention creatively adopts a method to simultaneously detect formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation, and the result shows that the separation degree of each chromatographic peak is good, the baseline separation is realized, and the ipratropium bromide and each auxiliary material are free from interference. The verification result of the method of the invention shows that all verification items meet the requirements. The method of the invention is adopted to determine the content of formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation, and the result is accurate.
The mobile phase of the invention has simple composition and only adopts KH2PO4 buffered saline solution and organic solvent; the sample does not need to be pretreated, and the ipratropium bromide solution for inhalation can be directly used for sample injection, so that the operation is simple, convenient and quick.
Drawings
FIG. 1 is a typical overlay of HPLC of the test solution, the reference solution and the reference preparation in example 1 of the present invention.
FIG. 2 is a high performance liquid chromatogram of a control solution in example 6 of the present invention.
FIG. 3 is a typical overlay of HPLC of the test solution, the reference solution and the diluent in example 7 of the present invention.
FIG. 4 is a high performance liquid chromatogram of a control solution in example 8 of the present invention.
Detailed Description
The present invention will be further described with reference to the following description and examples, which include but are not limited to the following examples.
The HPLC, the electronic balance and the pH meter used in the examples of the present invention are commercially available.
The reagents used in the examples of the present invention are all commercially available.
Example 1
The embodiment discloses a method for measuring formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation by adopting a high performance liquid chromatography, which specifically comprises the following steps:
instrument and chromatographic conditions:
shimadzu LC-2010AHT liquid chromatograph; the chromatographic column is as follows: agilent ZORBAX SB-Aq 4.6X 250mm, 5 μm; the temperature of the chromatographic column is 30 ℃; KH at 0.05mol/L2PO4Taking buffer solution (pH is adjusted to 2.7 by phosphoric acid) as mobile phase A, taking acetonitrile as mobile phase B, and performing gradient elution at flow rate of 1.0 ml/min; detection wavelength: detecting by adopting variable wavelength, wherein the detection time is 215nm when the detection time is 0-6 min, and the detection time is 265nm when the detection time is 6-15 min; the gradient elution procedure was as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 10 | 90 | 10 |
| 12 | 100 | 0 |
| 15 | 100 | 0 |
。
The specific detection steps are as follows:
step 3, preparation of a reference substance solution: precisely transferring appropriate amount of formic acid, acetic acid and acetone, placing into a same measuring flask, adding water for dilution, and making into control solution containing 10.0 μ g formic acid, 35.0 μ g acetic acid and 60.0 μ g acetone per 1 ml;
and 4, respectively injecting 10 mu l of each of the test solution, the reference preparation solution and the reference solution into a liquid chromatograph, measuring according to the chromatographic conditions, and recording a chromatogram, wherein the result is shown in the attached figure 1. It should be noted that: in the attached figure 1, the detection wavelength is 215nm when the retention time is 0-6 min, and the detection wavelength is 265nm when the retention time is 6-15 min; since it is a spectrum of variable wavelengths, only the first detection wavelength is labeled in fig. 1: 215 nm.
Test results show that the separation degree among formic acid, acetic acid and acetone in the reference solution is good, the baseline separation is achieved, and the symmetry of peaks is good; and the corresponding positions of the peaks of formic acid, acetic acid and acetone in the test solution have no other peaks, which indicates that the main drug and other substances in the test solution do not interfere the determination of each extract; in the reference preparation solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that the main drug and other substances in the reference preparation solution do not interfere the determination of each extract, and indicates that the method has good specificity.
Example 2
This example discloses the accuracy test of the detection method of the present invention.
The accuracy test was performed using the method of example 1, if as shown in the following table:
| extract name | Recovery rate | RSD |
| Formic acid | 98.6％～104.7％ | 2.1％ |
| Acetic acid | 99.8％～101.8％ | 0.7％ |
| Acetone (II) | 98.7％～101.4.0％ | 0.9％ |
The table shows that the recovery rates of formic acid, acetic acid and acetone are all between 95.0% and 105.0%, and the RSD of each recovery rate is less than 5%, which indicates that the method has good accuracy.
The accuracy evaluation method in this embodiment is the prior art.
Example 3
This example discloses the detection limit and quantitation limit tests of the detection method of the invention.
The detection limit test was carried out using the method of example 1, if as shown in the following table:
test result table of detection limit
| Extract name | Detection limit (ng) | S/N |
| Formic acid | 5.61 | ＞3 |
| Acetic acid | 21.03 | ＞3 |
| Acetone (II) | 36.27 | ＞3 |
。
The quantitative limit test was carried out using the method of example 1, if as shown in the following table:
quantitative limit test result table
| Extract name | Quantitative limit (ng) | S/N | Peak area RSD |
| Formic acid | 18.7 | ＞10 | ＜5.0％ |
| Acetic acid | 70.1 | ＞10 | ＜5.0％ |
| Acetone (II) | 120.9 | ＞10 | ＜5.0％ |
。
The result shows that when the signal-to-noise ratio S/N is more than 3, the detection limits of formic acid, acetic acid and acetone in the detection method are 5.61ng, 21.03ng and 36.27ng respectively. When the S/N signal-to-noise ratios are all larger than 10, the detection limits of formic acid, acetic acid and acetone in the detection method are respectively 18.7ng, 70.1ng and 120.9 ng. By adopting the detection method, the quantitative limits of formic acid, acetic acid and acetone are ng grade, which shows that the method has high sensitivity and can effectively and quantitatively detect trace formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation, thereby ensuring the safety of the medicine.
In the embodiment, the detection limit test method and the quantitative limit test method are both the prior art.
Example 4
This example discloses a linearity & range test of the detection method of the present invention.
The linearity & range test was performed using the method of example 1. The results show that formic acid, acetic acid and acetone are subjected to linear regression with the sample concentration as abscissa and the peak area as ordinate in the LOQ-200% concentration range, the linear correlation coefficients r are respectively 0.9998, 0.9999 and 0.9996, and the Y-axis intercepts are respectively: 1.7%, 0.6%, 1.0%.
The method has good linear relation in the LOQ-200% concentration range, and is suitable for quantitative detection of trace formic acid, acetic acid and acetone.
The linear & range test method in this example is prior art.
Example 5
This example is a comparative example and high performance liquid chromatography was used to measure formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation.
Instrument and chromatographic conditions:
shimadzu LC-2010AHT liquid chromatograph; the chromatographic column is as follows: cosmosil 5C8-MS 4.6X 250mm, 5 μm; the temperature of the chromatographic column is 40 ℃; KH is 0.05mol/L of methanol2PO4The buffer solution (pH adjusted to 2.7 with phosphoric acid) (3: 97) is used as mobile phase, and isocratic elution is carried out for 15min, and the flow rate is 1.0 ml/min; the detection wavelength is 215 nm. The specific detection procedure was the same as in example 1.
As a result, acetone was not detected, the retention times of formic acid and acetic acid were 7min and 10min, respectively, and the base line was uneven.
Example 6
This example is a comparative example.
Instrument and chromatographic conditions:
shimadzu LC-2010AHT liquid chromatograph; the chromatographic column is as follows: cosmosil 5C8-MS 4.6X 250mm, 5 μm; the temperature of the chromatographic column is 30 ℃; KH is 0.05mol/L of methanol2PO4The buffer solution (pH adjusted to 2.7 with phosphoric acid) (3: 97) is used as mobile phase, and isocratic elution is carried out for 20min, and the flow rate is 1.0 ml/min; detection wavelength: 215nm for 0-12 min and 265nm for 12-20 min.
In the embodiment, the scanning is performed within the wavelength range of 400-200 nm, and the maximum absorption wavelength of acetone is 265nm, so that two detection wavelengths are adopted, namely variable wavelength detection is adopted, formic acid and acetic acid are detected at the wavelength of 215nm, and acetone is detected at the wavelength of 265 nm.
Under the chromatographic condition, the separation degree of formic acid, acetic acid and acetone in the reference substance solution is detected. The method comprises the following specific steps:
the control solution in example 1 was used as a control solution, 10. mu.l of the control solution was taken and injected into a liquid chromatograph, measurement was performed under the above-mentioned chromatographic conditions, and a chromatogram was recorded, and the results are shown in FIG. 2. It should be noted that: in the attached figure 2, the detection wavelength is 215nm when the retention time is 0-12 min, and the detection wavelength is 265nm when the retention time is 12-20 min; since it is a spectrum of variable wavelengths, only the first detection wavelength is labeled in fig. 2: 215 nm.
The results show that: in this example, formic acid, acetic acid and acetone were detected, and the separation degree between peaks was good, but a peak inversion occurred at the peak of formic acid.
Example 7
This example is a comparative example. In this example, the flow rate of the mobile phase is adjusted based on example 6, and gradient elution is adopted, specifically as follows:
shimadzu LC-2010AHT liquid chromatograph; the chromatographic column is as follows: cosmosil 5C8-MS 4.6X 250mm, 5 μm; the temperature of the chromatographic column is 30 ℃; detection wavelength: 215nm for 0-10 min and 265nm for 10-20 min. KH at 0.05mol/L2PO4Performing gradient elution with buffer solution (pH is adjusted to 2.7 with phosphoric acid) as mobile phase A and methanol as mobile phase B at flow rate of 0.8 ml/min; the gradient elution procedure was as follows:
| time (min) | Mobile phase A% | Mobile phase B% (methanol) |
| 0 | 100 | 0 |
| 14 | 93 | 7 |
| 20 | 100 | 0 |
The specific detection procedure was the same as in example 1.
Taking the test solution in example 1 as a test solution;
taking the reference substance solution in the example 1 as a reference substance solution;
diluent agent: a blank formulation of the inhalation ipratropium bromide solution without API was prepared as in the preparation of the test article solution of example 1 to give a diluent.
The sample solution, diluent, and control solution each 10 μ l are injected into liquid chromatograph, measured according to the chromatographic conditions, and chromatogram recorded, and the result is shown in figure 3. It should be noted that: in the attached figure 3, the detection wavelength is 215nm when the retention time is 0-10 min, and the detection wavelength is 265nm when the retention time is 10-20 min; since it is a spectrum of variable wavelengths, only the first detection wavelength is labeled in fig. 3: 215 nm.
The results show that: formic acid, acetic acid and acetone can be detected, the separation degree between peaks is good, but an impurity peak in the test solution interferes with the measurement of formic acid.
Example 8
This example is a comparative example.
The instrument and chromatographic conditions were as follows:
shimadzu LC-2010AHT liquid chromatograph; the chromatographic column is as follows: agilent ZORBAX SB-Aq 4.6X 250mm, 5 μm; the temperature of the chromatographic column is 30 ℃; KH at 0.05mol/L2PO4Taking buffer solution (pH is adjusted to 2.7 by phosphoric acid) as mobile phase A, taking methanol as mobile phase B to carry out gradient elution, and the flow rate is 1.0 ml/min; detection wavelength: 215nm for 0-6 min and 265nm for 6-15 min; the gradient elution procedure was as follows:
| time (min) | Mobile phase A% | Mobile phase B% (methanol) |
| 0 | 100 | 0 |
| 6 | 100 | 0 |
| 12 | 94 | 6 |
| 13 | 100 | 0 |
| 15 | 100 | 0 |
Under the chromatographic condition, the separation degree of formic acid, acetic acid and acetone in the reference substance solution is detected. The method comprises the following specific steps:
the control solution in example 1 was used as a control solution, 10. mu.l of the control solution was taken and injected into a liquid chromatograph, measurement was performed under the above-mentioned chromatographic conditions, and a chromatogram was recorded, and the results are shown in FIG. 4. It should be noted that: in FIG. 4, the detection wavelength is 215nm when the retention time is 0-6 min, and the detection wavelength is 265nm when the retention time is 6-15 min; since it is a spectrum of variable wavelengths, only the first detection wavelength is labeled in fig. 4: 215 nm.
The results show that the acetone peak profile is poor and the theoretical plate number is less than 2000.
Example 9
The embodiment discloses a method for measuring formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation by adopting a high performance liquid chromatography, which specifically comprises the following steps:
the liquid chromatograph and the chromatographic column are the same as those in example 1.
The temperature of the chromatographic column is 25 ℃; with 0.01mol/L NaH2PO4Taking buffer solution (pH is adjusted to 2.0 by phosphoric acid) as mobile phase A, taking methanol as mobile phase B to carry out gradient elution, and the flow rate is 0.8 ml/min; detecting formic acid and acetic acid at 215nm and acetone at 265nm by adopting variable wavelength detection; the gradient elution procedure was as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 99 | 1 |
| 10 | 89 | 11 |
| 12 | 99 | 1 |
| 15 | 99 | 1 |
The specific detection procedure was the same as in example 1. The control solution of this example contained 8.2. mu.g of formic acid, 29.7. mu.g of acetic acid, and 69.8. mu.g of acetone per 1 ml.
Test results show that the separation degree among formic acid, acetic acid and acetone in the reference solution is good, the baseline separation is achieved, and the symmetry of peaks is good; in the test solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that the sample does not interfere the determination of each extract; in the reference preparation solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that other substances in the reference preparation solution do not interfere with the determination of each extract, and indicates that the method has good specificity.
Example 10
The embodiment discloses a method for measuring formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation by adopting a high performance liquid chromatography, which specifically comprises the following steps:
the liquid chromatograph and the chromatographic column are the same as those in example 1.
The temperature of the chromatographic column is 35 ℃; with 0.2mol/L NaH2PO4Performing gradient elution with buffer solution (pH is adjusted to 3.3 with phosphoric acid) as mobile phase A and acetonitrile-methanol (volume ratio is 1: 1) as mobile phase B at flow rate of 1.2 ml/min; detecting formic acid and acetic acid at 215nm and acetone at 265nm by adopting variable wavelength detection; the gradient elution procedure was as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 97 | 3 |
| 10 | 87 | 13 |
| 12 | 97 | 3 |
| 15 | 97 | 3 |
The specific detection procedure was the same as in example 1. Wherein, each 1ml of the control solution of this example contains 12.2. mu.g of formic acid, 35.8. mu.g of acetic acid, and 50.2. mu.g of acetone.
Test results show that the separation degree among formic acid, acetic acid and acetone in the reference solution is good, the baseline separation is achieved, and the symmetry of peaks is good; in the test solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that the sample does not interfere the determination of each extract; in the reference preparation solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that other substances in the reference preparation solution do not interfere with the determination of each extract, and indicates that the method has good specificity.
Example 11
The embodiment discloses a method for measuring formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation by adopting a high performance liquid chromatography, which specifically comprises the following steps:
the liquid chromatograph and the chromatographic column are the same as those in example 1.
The temperature of the chromatographic column is 32 ℃; at 0.1mol/L KH2PO4Performing gradient elution with buffer solution (pH is adjusted to 3.0 with phosphoric acid) as mobile phase A and acetonitrile-methanol (volume ratio is 2: 1) as mobile phase B at flow rate of 1.1 ml/min; detecting formic acid and acetic acid at 215nm and acetone at 265nm by adopting variable wavelength detection; the gradient elution procedure was as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 10 | 85 | 15 |
| 12 | 95 | 5 |
| 15 | 95 | 5 |
The specific detection procedure was the same as in example 1. The control solution of this example contained 9.7. mu.g of formic acid, 39.6. mu.g of acetic acid, and 61.3. mu.g of acetone per 1 ml.
Test results show that the separation degree among formic acid, acetic acid and acetone in the reference solution is good, the baseline separation is achieved, and the symmetry of peaks is good; in the test solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that the sample does not interfere the determination of each extract; in the reference preparation solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that other substances in the reference preparation solution do not interfere with the determination of each extract, and indicates that the method has good specificity.
Example 12
The embodiment discloses a method for measuring formic acid, acetic acid and acetone in an ipratropium bromide solution for inhalation by adopting a high performance liquid chromatography, which specifically comprises the following steps:
the liquid chromatograph and the chromatographic column are the same as those in example 1.
The temperature of the chromatographic column is 27 ℃; KH at 0.15mol/L2PO4Performing gradient elution with buffer solution (pH is adjusted to 2.4 with phosphoric acid) as mobile phase A and acetonitrile-methanol (volume ratio is 1: 2) as mobile phase B at flow rate of 0.9 ml/min; detecting formic acid and acetic acid at 215nm and acetone at 265nm by adopting variable wavelength detection; the gradient elution procedure was as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 10 | 95 | 5 |
| 12 | 97 | 3 |
| 15 | 97 | 3 |
The specific detection procedure was the same as in example 1. The control solution of this example contained 8.2. mu.g of formic acid, 29.7. mu.g of acetic acid, and 69.8. mu.g of acetone per 1 ml.
Test results show that the separation degree among formic acid, acetic acid and acetone in the reference solution is good, the baseline separation is achieved, and the symmetry of peaks is good; in the test solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that the sample does not interfere the determination of each extract; in the reference preparation solution, no other peak exists at the corresponding position of each peak of formic acid, acetic acid and acetone, which indicates that other substances in the reference preparation solution do not interfere with the determination of each extract, and indicates that the method has good specificity.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (10)
1. The method for detecting formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation is characterized in that the detection is carried out by adopting a reversed phase high performance liquid chromatography, and the chromatographic conditions are as follows: the method comprises the following steps of (1) taking diisopropyl substituted octadecylsilane chemically bonded silica as a filler, taking a buffer salt solution with the pH value of 2.0-3.3 as a mobile phase A, taking an organic solvent as a mobile phase B, and firstly, mixing the raw materials in a volume ratio of A: and B is 90-100: after the peak is eluted by formic acid and acetic acid by 0-10, the volume ratio of A: b is 75-100: 0-25 peak elution of acetone; the organic solvent is one or the combination of more than two of acetonitrile, isopropanol, ethanol, tetrahydrofuran and methanol.
2. The method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation according to claim 1, wherein the gradient elution is performed as specified in the following table,
。
3. The method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation according to claim 2, wherein the gradient elution is performed as specified in the following table,
。
4. The method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation according to claim 3, wherein the gradient elution is performed as specified in the following table,
。
5. The method for detecting formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation according to any one of claims 1 to 4, wherein the organic solvent is selected from acetonitrile or methanol; preferably, it is selected from acetonitrile.
6. The method for detecting formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation according to claim 5, wherein the buffered salt solution is phosphate buffered salt solution, and the concentration of the phosphate buffered salt solution is 0.01-0.2 mol/L;
the pH value of the buffered salt solution is 2.7;
preferably, the buffered saline solution is KH2PO4Solutions or NaH2PO4A solution;
preferably, the concentration of the buffered salt solution is 0.05 mol/L.
7. The method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation according to claim 1, wherein the detection wavelength of formic acid and acetic acid is 215nm and the detection wavelength of acetone is 265nm by using an ultraviolet detector.
8. The method for detecting formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation according to claim 1, wherein an ultraviolet detector is adopted, the detection wavelength is 215nm when the length of a chromatographic column is 250mm and the retention time is 0-6 min; when the retention time is 6-15 min, the detection wavelength is 265 nm.
9. The method for detecting formic acid, acetic acid and acetone in the ipratropium bromide solution for inhalation according to claim 1, wherein the column temperature of the chromatographic column is 25-35 ℃, and the flow rate of the mobile phase is 0.8-1.2 ml/min; preferably, the column temperature of the chromatographic column is 30 ℃; preferably, the mobile phase flow rate is 1.0 ml/min.
10. The method for detecting formic acid, acetic acid and acetone in ipratropium bromide solution for inhalation according to claim 1, comprising the steps of:
step 1, preparation of a test solution: taking an ipratropium bromide solution for inhalation as a test solution;
step 2, preparation of a reference substance solution: precisely transferring appropriate amount of formic acid, acetic acid and acetone respectively, placing into a same measuring flask, adding water for dilution, and making into control solution containing formic acid 8.0-12.0 μ g, acetic acid 30.0-40.0 μ g and acetone 50.0-70.0 μ g per 1 ml;
step 3, respectively injecting 10 mu l of each of the test solution and the reference solution into a liquid chromatograph, measuring according to the chromatographic conditions, recording a chromatogram, and calculating the contents of formic acid, acetic acid and acetone in the test solution by peak areas according to an external standard method;
preferably, in the step 2, each 1ml of the control solution contains 10.0 μ g of formic acid, 35.0 μ g of acetic acid and 60.0 μ g of acetone.
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